AJP - Regu Track the topics, authors and articles important to you
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 QUICK SEARCH:   [advanced]


     


Am J Physiol Regul Integr Comp Physiol 274: R577-R595, 1998;
0363-6119/98 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Meldrum, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Meldrum, D. R.
Vol. 274, Issue 3, R577-R595, March 1998

INVITED REVIEW
Tumor necrosis factor in the heart

Daniel R. Meldrum

Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262

    ABSTRACT
Top
Abstract
Introduction
References

The heart is a tumor necrosis factor (TNF)-producing organ. Both myocardial macrophages and cardiac myocytes themselves synthesize TNF. Accumulating evidence indicates that myocardial TNF is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Indeed, locally (vs. systemically) produced TNF contributes to postischemic myocardial dysfunction via direct depression of contractility and induction of myocyte apoptosis. Lipopolysaccharide or ischemia-reperfusion activates myocardial P38 mitogen-activated protein (MAP) kinase and nuclear factor kappa B, which lead to TNF production. TNF depresses myocardial function by nitric oxide (NO)-dependent and NO-independent (sphingosine dependent) mechanisms. TNF activation of TNF receptor 1 or Fas may induce cardiac myocyte apoptosis. MAP kinases and TNF transcription factors are feasible targets for anti-TNF (i.e., cardioprotective) strategies. Endogenous anti-inflammatory ligands, which trigger the gp130 signaling cascade, heat shock proteins, and TNF-binding proteins, also control TNF production and activity. Thus modulation of TNF in cardiovascular disease represents a realistic goal for clinical medicine.

mitogen-activated protein kinase; nuclear factor kappa B; lipopolysaccharide; heat shock proteins; ischemia and reperfusion; myocardium

    INTRODUCTION
Top
Abstract
Introduction
References

ACCUMULATING EVIDENCE indicates that cytokines are important mediators of cardiovascular disease (27, 104, 105, 154, 161, 216, 223, 224, 272-274, 303, 304). A working understanding of inflammatory cytokines and their relationship to myocardial disease is of growing importance to basic and clinical cardiovascular scientists, immunologists, and clinicians. In this regard, tumor necrosis factor (TNF) is a proinflammatory cytokine that has been implicated in the pathogenesis of cardiovascular diseases, including acute myocardial infarction, chronic heart failure, atherosclerosis, viral myocarditis, cardiac allograft rejection, and sepsis-associated cardiac dysfunction (27, 154, 161, 216, 223, 224, 272-274, 303, 304). Although initially described solely as a lipopolysaccharide (LPS)-induced macrophage product, evidence now indicates that cardiac myocytes themselves produce substantial amounts of TNF in response to ischemia (Fig. 1) as well as LPS (104, 137). Indeed, ischemia-provoked myocardial TNF production may prove more clinically significant than sepsis-induced myocardial TNF production by an order of magnitude.


View larger version (101K):
[in this window]
[in a new window]
 
Fig. 1.   Immunohistochemical images (confocal, magnification ×100) of 5-µm sections of human myocardium stained for human tumor necrosis factor (TNF)-alpha before (A) or after (B) cardiopulmonary bypass (cold ischemia-reperfusion injury). Before bypass (A), TNF (red) is located primarily in the interstitial cells (arrow); however, after bypass there is dense TNF accumulation within the cardiomyocytes (arrow, cross-striations), as well as in the interstitial cells. Nuclear counterstain appears blue.

Ischemia and LPS are two of several clinically relevant stimulants that induce TNF production in the heart. The intracellular signal pathways that provoke TNF production are being elucidated with increasing clarity (265). The discovery of the mitogen-activated protein kinases (MAPKs) and TNF transcription factors offer feasible targets for anti-TNF strategies. Furthermore, activation of endogenous anti-inflammatory strategies such as ligands for the gp130 subunit, induction of heat shock proteins (HSPs), and infusion of TNF-binding proteins now hold therapeutic promise.

Control of TNF's destructive role in cardiovascular disease represents a realistic goal for clinical medicine. The purposes of this review are to 1) examine evidence implicating the myocardium as an important source of TNF, 2) dissect the mechanisms of TNF-induced cardiac dysfunction, 3) outline the mechanisms of TNF-induced apoptosis, 4) delineate clinically accessible signaling steps that lead to TNF production, and 5) identify therapeutic strategies for preventing TNF-mediated cardiovascular disease.

    TNF

TNF is a proinflammatory cytokine. Proinflammatory cytokines act to increase their own production and the synthesis of small inflammatory mediators such as platelet-activating factor (PAF), eicosanoids, and oxidative radicals. Proinflammatory cytokines also recruit and stimulate cellular components of the immune system. TNF is an endogenous pyrogen that stimulates the production of other endogenous pyrogens, such as interleukin 1beta (IL-1) (77). Both forms of TNF, TNF-alpha and TNF-beta , share similar inflammatory activities. TNF-beta , first described as "lymphotoxin" (241), is a larger molecule, less potent, not as abundant, and produced mainly by T cells, whereas macrophages are the predominant source of TNF-alpha . For the purposes of this review, TNF refers to TNF-alpha , which is the form associated with septic shock, ischemia-reperfusion injury, and traumatic end organ damage.

Myocardial TNF production. Most cell types do not produce TNF, but the ubiquitous macrophage allows for TNF production in nearly every organ (10, 265). Not surprisingly, the heart contains resident macrophages (137, 200) and is a rich source of several inflammatory cytokines, including TNF (27, 112, 122, 137, 144, 151, 172, 216, 272-274, 285, 291). Levine and associates (161) correlated circulating levels of TNF with the severity of chronic heart failure in patients and postulated that TNF may contribute to the pathogenesis of heart failure. An increase in circulating TNF, soluble TNF receptor, and IL-1 receptor antagonist each follows myocardial infarction (154). In fact, the myocardium produces as much TNF per gram tissue (in response to endotoxin) as either the liver or the spleen, both of which possess large macrophage populations and are major sources of TNF (137). Unexpectedly, cardiac myocytes themselves produce TNF. Kapadia and co-workers (137) demonstrated that production of endotoxin-induced myocardial TNF is nearly evenly distributed between cardiomyocyte and resident cardiac macrophage cell types. Thus local myocardial TNF production is a potential source of TNF affecting myocardial function.

Clinically relevant stimulants of myocardial TNF production. Although infection and endotoxemia are potent stimulants of myocardial TNF production, studies have also documented increases in myocardial TNF and other cytokines following experimental ischemia-reperfusion (112, 122, 258), burn trauma (126), clinical myocardial infarction (27, 154, 216), cardiopulmonary bypass (51, 119, 291), and chronic heart failure (161, 272, 274, 285). Using immunohistochemical localization of TNF, we have recently observed increased TNF in human myocardium following cardiopulmonary bypass (Fig. 1). Increased TNF was observed in both the cardiomyocytes themselves and the interstitial cells. Indeed, locally produced TNF may be an important contributor to postischemic myocardial dysfunction, apoptosis, and/or hypertrophy (93, 149, 151, 168, 213, 222, 245, 303).

    EFFECTS OF TNF ON MYOCARDIUM

Depression of myocardial contractile function. The hemodynamic effects of TNF are characterized by decreased myocardial contractile efficiency and reduced ejection fraction, hypotension, decreased systemic vascular resistance, and biventricular dilatation (50, 84, 135, 228, 229, 295). Before the discovery of TNF, several investigators suspected that sepsis-induced myocardial depression was mediated by a circulating myocardial depressant factor(s) (65, 158, 159). Parillo and colleagues (231) demonstrated that the sera from septic patients with myocardial depression consistently depressed in vitro myocyte performance, whereas sera from septic patients without a compromised ejection fraction did not. The first experimental evidence suggesting that TNF mediates endotoxin-induced myocardial depression was provided by Tracey and associates (275). They observed that TNF administration resulted in hypotension, metabolic acidosis, hemoconcentration, diffuse pulmonary infiltrates, hyperglycemia, hyperkalemia, pulmonary and gastrointestinal petechial hemorrhages, acute tubular necrosis, and death (275). Although myocardial function was not examined, the hypotension and shock suggested myocardial depression. These investigators further substantiated the link between sepsis and TNF by utilizing anti-TNF monoclonal antibodies to neutralize the circulating TNF and thereby prevent its adverse effects (276). Gulick and co-workers (111) demonstrated that TNF (or IL-1) inhibited cardiac myocyte adrenergic responsiveness in vitro. Similarly, TNF (or IL-1)-induced depression of myocardial function in an ex vivo, crystalloid-superfused papillary muscle preparation was observed by Finkel and colleagues (92).

Mechanisms of TNF-induced contractile dysfunction. Because calcium homeostasis is of paramount importance to the normal myocardial contraction-relaxation cycle, several investigators have examined the effects of TNF on myocardial calcium handling. Indeed, coordinated and precise regulation of the oscillating intracellular calcium mediates systolic contraction, diastolic relaxation, enzymatic activity, and mitochondrial function (187, 191). TNF-induced disruption of calcium handling may lead to dysfunctional excitation-contraction coupling and, thereby, systolic and/or diastolic dysfunction. Assessment of myocardial calcium handling can be accomplished in one of four ways: 1) the cardiac contractile state can be assessed as developed force or pressure, 2) sarcolemmal calcium handling is reflected in the action potential, 3) sarcoplasmic reticulum calcium handling is demonstrated by the calcium transient, and 4) the myofilament-regulatory complex is exhibited by the association between the calcium transient and the force of contraction. The calcium transient represents the transition from the resting state to contraction, which occurs when a small amount of calcium enters the cytosol via voltage-gated L-type calcium channels, which in turn results in a much greater release of calcium from sarcoplasmic reticulum ryanodine receptor calcium release channels. These two calcium channels have microarchitectural communication, and calcium entry through one influences the other. Yokoyama and colleagues (304) determined that, soon after TNF administration, the amplitude of the calcium transient was decreased during systole. TNF appears to depress systolic function by disrupting calcium-induced calcium release by the sarcoplasmic reticulum. Indeed, TNF disrupts L-type channel-induced calcium influx and thereby depresses calcium transients (150). Corroborating these findings, Oral et al. (223) demonstrated that TNF's early effects on the calcium transient and systolic function were mediated by sphingosine (Fig. 2). NO does, however, appear to mediate TNF-induced desensitization of myofilaments to intracellular calcium (107). These findings (110, 141, 223) indicate that TNF-induced, sphingosine-mediated disruption of calcium-induced calcium release occurs early and that NO mediates TNF-induced desensitization of myofilaments to increased intracellular calcium (Fig. 2). Although the association between massive calcium influx and myocellular ischemic injury has been established, the source of the elevated intracellular calcium remains controversial and may have important therapeutic significance. The most likely scenarios involve either ineffective sarcolemmal calcium extrusion and/or inadequate sarcoplasmic reticulum calcium sequestration (191). Either seems plausible because both exhibit energy-dependent kinetics, i.e., postischemia, the ATP-hungry sarcolemmal calcium-adenosinetriphosphatase (ATPase) and/or sarcoplasmic reticulum calcium-ATPase would be unable to bring intracellular calcium back to the basal levels required for muscle relaxation (191). This, in turn, would decrease muscle shortening during a contraction, leading to both systolic and diastolic dysfunction.


View larger version (22K):
[in this window]
[in a new window]
 
Fig. 2.   Myocardial TNF production by both cardiac myocytes and resident macrophage contributes to 2 phases of contractile dysfunction. The immediate phase occurs minutes after TNF exposure, is NO independent, and is mediated by sphingosine disruption of calcium transients. The late phase of contractile dysfunction requires hours, is temporally correlated with inducible NO synthase (iNOS) induction, and is due to NO-induced myofilament desensitization to calcium.

In addition to calcium dyshomeostasis, the mechanisms by which TNF causes myocardial dysfunction include direct cytotoxicity, oxidant stress, disruption of excitation-contraction coupling, and myocyte apoptosis, as well as the induction of other cardiac depressants such as IL-1 (72, 75), IL-2 (92, 106, 257), and IL-6 (92, 233). Indeed, IL-1 synergistically enhances TNF-induced myocardial depression (151) and cytotoxicity (153). Finkel and associates (92) demonstrated that NO synthase (NOS) inhibition prevented the myocardial depressive effects of either TNF or IL-1, concluding that the negative inotropic effects were mediated by NO. LPS, TNF, and IL-1 each induce NOS and augment guanosine 3',5'-cyclic monophosphate, which mediates NO's effects in other cell types (55, 98, 100, 167, 218, 255, 261). Nitric oxide has also been implicated in the pathogenesis of myocardial infarction (6), hypoxia-induced cardiomyocyte damage (144), and autoimmune myocarditis (131). Wang and Zweier (293) observed increased NO and peroxynitrite release from the isolated rat heart after 30 min of global ischemia. Pretreatment with a NOS inhibitor resulted in a fourfold increase in the postischemic functional recovery. Nitric oxide also appears to mediate the beta -adrenoceptor unresponsiveness (281) that occurs during sepsis (21).

The biphasic (immediate and delayed) nature of TNF-induced myocardial depression suggests that TNF induces negative inotropic effects by at least two different mechanisms (208, 223). As depicted in Fig. 2, the early phase of TNF-induced functional depression occurs within minutes, whereas the delayed phase appears to require hours of TNF exposure (223). TNF may not induce high levels of NO rapidly enough to account for the early phase of myocardial depression (223). In this regard, sphingolipid metabolites are stress-induced second messengers that participate in intracellular signal transduction after TNF binding to the TNF type 1 receptor (TNFR1) (118). Two important characteristics of sphingolipid metabolites led to the hypothesis (223) that sphingosine mediates TNF-induced myocardial contractile dysfunction: 1) it is rapidly produced by cardiac myocytes (via sphingomyelin degeneration) after TNF's triggering of TNFR1 (148, 300) and 2) sphingosine decreases calcium transients by blocking the ryanodine receptor, which mediates calcium-induced calcium release from the sarcoplasmic reticulum (71, 242). These investigators (223) reported that myocardial sphingosine production occurred within minutes of TNF administration and temporally correlated with myocardial dysfunction and calcium dyshomeostasis in cardiac myocytes. Blockade of sphingosine production abolished TNF-induced contractile dysfunction, and sphingosine administration replicated TNF-induced contractile depression in a dose-dependent fashion. Thus it appears likely that sphingosine mediates the early depression (NO independent) and that NO mediates the late dysfunction induced by TNF (Fig. 2).

Although several investigators have implicated NO in TNF-induced myocardial dysfunction (32, 33, 107, 139, 250), others have been unable to attribute all of TNF's depressive effects to NO (140, 146, 198, 304). In fact, it has been reported that NO can protect the myocardium during ischemia-reperfusion injury (210, 247), possibly by decreasing leukocyte mediated endothelial cell injury (28, 31, 68, 218) or decreasing myocardial oxygen consumption (256). This discrepancy may be due to differences in the quantities of NO produced during injury. The relative contribution of NO production by the calcium-dependent, constitutive form of NOS (cNOS) is at least two orders of magnitude less than the calcium-independent, cytokine-inducible form of NOS (iNOS). The low levels of NO produced by cNOS may serve a protective role, whereas the high levels produced by iNOS may be injurious (167, 218). Thus the role of NO as a mediator of this process remains controversial; however, it is likely that TNF-induced myocardial depression occurs via both NO-dependent and NO-independent mechanisms (141).

TNF-induced myocardial apoptosis. Programmed cell death (apoptosis) is a process by which cells undergo inducible nonnecrotic cellular suicide (263, 268, 287). In contrast with necrotic cell death, programmed cell death is dependent on de novo synthesis of proteins that initiate a cellular suicide program in response to specific stimuli (227, 263, 268, 287). For most cells of hematopoietic lineage, apoptosis is a constitutive process but can also be induced by noxious stimuli (11). Although originally described as a process by which the immune system "quietly" deleted autoreactive cells, it is now apparent that apoptosis contributes to the pathophysiology of neurodegenerative diseases, autoimmune diseases, acquired immunodeficiency syndrome, and cancer, as well as a number of myocardial diseases (52, 263, 268, 287). Cardiac myocyte apoptosis occurs in chronic heart failure, ischemia, arrhythmogenic right ventricular dysplasia (characterized by the replacement of myocardial cells with fat and fibrous tissue), viral myocarditis, and sudden cardiac death (Fig. 3) (44, 109, 132-134, 136, 168, 213, 222, 226, 267, 280).


View larger version (19K):
[in this window]
[in a new window]
 
Fig. 3.   TNF induces myocyte apoptosis by TNF type 1 receptor (TNFR1) and Fas activation (Fas ligand also triggers Fas). Their respective cytoplasmic proteins, TRADD and FADD, serve as death domains that communicate via the receptor interactive protein (RIP). RIP contains a kinase domain that allows communication of the death signal to the nucleus where endonucleases fragment myocyte DNA. TNFR2 activation favors the proliferative pathway to nuclear factor kappa B (NFkappa B) activation. TNF receptor-associated factors (TRAFs) are the TNFR2 cytoplasmic proteins, whose function is unknown. TM, transmembrane portion of receptor. TRAFs contain associated zinc and ring fingers (function unknown).

Cardiac myocyte apoptosis (versus necrosis) is characterized by cell death with the maintenance of cell-membrane integrity (149, 263, 268); therefore, apoptotic cardiac myocytes do not release creatine kinase and do retain their ability to exclude dyes such as Trypan blue (149). This feature likely results in the underestimation of myocyte death during myocardial infarction. Indeed, it has been proposed that the degree of myocardial apoptosis, rather than necrosis, is a more accurate reflection of myocardial infarct size (136). Apoptotic cardiac myocytes also retain their ability to contract in response to calcium ionophores (149). After the high influx of calcium associated with necrosis (191), necrotic myocytes are maximally contracted and are unable to further contract in response to a calcium ionophore; however, apoptotic myocytes maintain myofilament responsiveness when calcium entry is induced (149).

TNF induces apoptosis in many cell types, including the myocardium (11, 219, 220, 245). Krown and colleagues (149) demonstrated that TNF induced cardiac myocyte apoptosis by a sphingosine-dependent mechanism. TNF induces sphingosine formation (220, 223), which also mediates apoptosis in other cell types (220). TNF-induced NO production also may play a role (246).

TNF induces cardiac myocyte apoptosis via TNFR1. The "death domain" of the cytosolic component of TNFR1 has been linked to apoptosis in many cell types and likely mediates TNF-induced cardiac myocyte apoptosis (283). TNF binding to either TNFR1 or Fas activates a pathway favoring apoptosis, whereas the type 2 TNF receptor (TNFR2) activates a pathway leading to nuclear factor kappa B (NFkappa B) induction (Fig. 3). TNFR1 and Fas are linked to cytoplasmic proteins that are referred to as the death domains TRADD (128) and FADD (56), respectively the TNF receptor-associated death domain and the Fas-associated death domain. Interaction between the death domain proteins is accomplished by receptor-interacting protein (RIP) (64). RIP, but not TRADD or FADD, contains a kinase domain that communicates the signal. TNF binding to TNFR1 or Fas may result in conformational changes in TRADD and FADD that allow RIP binding (30). RIP initiates the intranuclear communication that activates endonucleases to destroy the cell's nuclear DNA (Fig. 3). The TNFR2 is linked to the TNF receptor-associated factors (TRAFs) (206). Although their biological function remains unknown, most TRAFs contain two protein motifs called "zinc" and "ring" fingers that likely convey proliferative signals by activating transcription factors such as NFkappa B (17). These pathways are not absolute, however, and cross-activation occurs (17, 227).

    TNF PRODUCTION

Understanding of the intracellular mechanisms that lead to TNF production may allow targeted disruption of TNF-mediated pathological conditions.

LPS-induced macrophage intracellular signaling leading to TNF production. In most cell types, the TNF gene is silenced (24) but can be accessed in cell types that express the signaling mechanisms and transcriptional apparatus required for TNF production. Because macrophages are the main TNF source, mechanisms of TNF production have been studied almost exclusively in these cells. Although there are undoubtedly different cell types and different stimuli, the following signaling mechanisms describe what is presently known concerning LPS-stimulated macrophage TNF production (265).

The mechanisms leading to LPS-stimulated macrophage TNF production appear multiple. Intracellular pathways that participate in the LPS-activated signaling cascade and contribute to the production and release of macrophage-derived proinflammatory mediators are multiple. This section will focus on those therapeutically accessible signaling events known to lead to macrophage TNF production (Fig. 4). LPS binds a variety of serum proteins that either positively or negatively influence the macrophage-mediated proinflammatory response (278). Of these, LPS-binding protein (LBP) is the best characterized. LBP facilitates LPS binding to the macrophage CD14 (Figs. 4 and 5). CD14 is the macrophage-specific surface receptor for LPS. Although not absolutely required for LPS-induced macrophage activation (at high doses LPS can bypass CD14 by triggering the p80 LPS receptor directly), LBP is required for LPS-CD14 interaction. Under normal circumstances, LPS-LBP interaction with CD14 is an obligate trigger of the intracellular signals that transmit LPS-induced TNF production. Indeed, Lee and colleagues (157) demonstrated that anti-CD14 monoclonal antibody abolished LPS-induced macrophage activation and TNF release. Although CD14 is macrophage specific, soluble (shed) CD14 enhances LPS-induced activation of both endothelial cells and epithelial cells (236). Endogenous, shed CD14 acts at distant sites to enhance LPS-induced activation of other cell types, and, seemingly paradoxically, high pharmacological doses of exogenous soluble CD14 decreases LPS interaction with the intact macrophage CD14 receptor. Therefore, using saturating concentrations of soluble CD14, Haziot and associates (120) prevented mortality in LPS-treated mice.


View larger version (33K):
[in this window]
[in a new window]
 
Fig. 4.   Lipopolysaccharide (LPS) interaction with CD14 leads to rapid intracellular tyrosine phosphorylation of Ras [by phosphotyrosine kinase (PTK)], a process that initiates the protein kinase cascade, leading to TNF production. Ras activates Raf-1/mitogen-activated protein kinase kinase, which activate members of the mitogen-activated protein kinase (MAPK) family of protein kinases, extracellular signal-related kinase, stress-activated protein kinase, and Jun nuclear kinase. The P38 MAPK appears to be an important MAPK in the cascade leading to TNF gene induction. NFkappa B is activated by inhibitory kappa B (Ikappa B) phosphorylation (which disengages its inhibitory subunit, Ikappa B) and translocates to the nucleus to activate TNF promoters. At least 2 TNF promoter sites must be occupied by NFkappa B for TNF gene transcription to occur. Once translated to pro-TNF in the cytosol, myristoylation permits membrane insertion, where pro-TNF remains until it is cleaved to its mature form by TNF-alpha -converting enzyme (TACE). Ischemia-reperfusion, oxidant stress, and hydrogen peroxide directly activate P38 MAPK and NFkappa B to induce TNF production. LBP, LPS binding protein.


View larger version (26K):
[in this window]
[in a new window]
 
Fig. 5.   Targets for preventing TNF production and activity. The various pretranscriptional and posttranslational strategies of limiting TNF production include limiting the synthesis of LBP; inhibiting macrophage expression and shedding of CD14 receptors; activation of gp130 subunit-linked receptors with interleukin 6 (IL-6), IL-11, cardiotrophin 1 (CT-1), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), or oncostatin M (OSM); inhibition of P38 MAPK; inhibition of NFkappa B translocation/activation with antioxidants [pyrrolidine dithiocarbamate (PDTC)] and/or heat shock proteins (HSPs); pretranscriptional binding of NFkappa B by HSPs and/or posttranslational binding of TNF by HSPs; TACE inhibition; and postrelease neutralization of TNF with TNF-soluble receptors. Please see Fig. 4 legend for additional enzyme abbreviations.

As shown in Fig. 4, LPS-LBP-CD14 interaction provokes rapid activation of protein tyrosine kinase (PTK) causing tyrosine phosphorylation of several intracellular protein kinases (116, 244, 252, 296-298). PTK activates a pathway involving Ras/Raf-1/mitogen-activated protein kinase kinase (MEK)/MAPKs/NFkappa B (46, 70, 162, 163). Several studies have demonstrated that LPS activates PTK and that PTK inhibition abolishes downstream activation of MAPKs, TNF and IL-1 production, and macrophage-mediated tumoricidal activity (46, 127, 205, 237, 282). Ras is an early target of activated PTK and is able to interact directly with Raf-1 (127, 205, 282). Raf-1 is an important intermediate to MAPK activation (46, 127, 205, 282). Studies by Reimann and colleagues (237) demonstrated that LPS resulted in PTK-dependent rapid phosphorylation and activation of Raf-1. These findings were supported by Geppert and associates (102), who observed that transfection of the dominant-negative repressors of Ras and Raf-1 into macrophages resulted in a suppression of LPS-induced activation of the TNF promoter. However, transfection with a constitutively active form of Raf-1 did not reproduce LPS-induced macrophage activation, suggesting that Raf-1 activation is necessary but not sufficient to induce macrophage TNF production (102).

Raf-1/MEK appears to activate members of the MAPK family of protein kinases; of these the P38 MAPK appears to be a pivotal MAPK in the cascade leading to TNF gene induction (115, 117, 155, 156, 253). Han and colleagues (116) isolated a 38-kDa macrophage protein kinase that was phosphorylated following LPS treatment. Subsequent cloning and sequence analysis (115, 117) revealed that the novel MAPK homologue was closely related to the osmolar-sensitive Hog-1 gene in yeast. During the same period, Lee and co-workers (155) were searching for the target proteins of a novel class of anti-inflammatory drugs (pyridinyl imidazoles) capable of abolishing LPS-induced proinflammatory monokine production. Photoaffinity labeling of drug analogs identified proteins that proved to be the mammalian equivalent of the Hog-1 gene product. The 38-kDa protein was identical to the MAPK cloned by Han and co-workers (115, 117). Pyridinyl imidazoles, which abolish proinflammatory monokine production, are highly selective inhibitors of P38 MAPK and its downstream products, but not of Ras or Raf-1, activation (156). Thus LPS interaction with CD14 leads to rapid intracellular tyrosine phosphorylation of Ras, a process that initiates the protein kinase cascade leading to NFkappa B activation and TNF production.

Ischemia-reperfusion-induced TNF production. Although considerable information exists concerning the mechanisms by which LPS induces TNF production, little is known about the mechanisms of ischemia-reperfusion-induced myocardial TNF production (112). Reperfusion of ischemic myocardium imposes an oxidant burden in which the reduction product of molecular oxygen, hydrogen peroxide, contributes to myocardial injury (41). Hydrogen peroxide-induced activation of P38 MAP kinase may contribute to ischemia-reperfusion-induced TNF production (113, 129). Oxidant stress also activates NFkappa B, which may also play a role in the sequence of ischemia-reperfusion-induced TNF production (Fig. 4).

In most cells, NFkappa B exists in a latent state, unable to induce TNF production (169). In this state, NFkappa B is bound to its inhibitory proteins, collectively called inhibitory kappa B (Ikappa B), which mask its nuclear localization site; however, after activation by ischemia-reperfusion (or LPS), phosphorylation of Ikappa B results in disruption of the NFkappa B-Ikappa B complex and degradation of Ikappa B (165, 265, 277). Once liberated from Ikappa B, NFkappa B translocates from the cytoplasm to the nucleus, where it docks to DNA at one of four NFkappa B binding (TNF promoter) sites (251). Site-directed mutation studies by Shakov et al. (251) demonstrated that at least two of these TNF promoter regions must be bound by NFkappa B for TNF transcription to occur. Deletion of all four NFkappa B binding sites abolished macrophage TNF production(251). Ikappa B may be phosphorylated by MAPKs (169); however, it is noteworthy that Raf-1, a relatively upstream component of this pathway, is also capable of activating NFkappa B (127, 165). Redundant or "skip" activation sequences may be designed to ensure NFkappa B activation following LPS challenge. Thus NFkappa B is activated by either Ikappa B phosphorylation or directly by oxidant stress, after which it translocates to the nucleus to activate TNF gene transcription.

Posttranslational processing of TNF. Once TNF gene transcription occurs, TNF mRNA is translated into the 26-kDa TNF precursor (pro-TNF) in the cytoplasm (80, 177, 203). Myristoylation in the cytoplasm facilitates membrane insertion/association, where it is cleaved by TNF-alpha -converting enzyme (TACE). The mature 17-kDa TNF is then released into the extracellular space. This process is similar to the posttranslational processing of pro-IL-1beta , which is converted to its mature form by IL-1beta -converting enzyme (ICE) (53). Metalloproteinase inhibitors suppress TACE processing of pro-TNF and decrease LPS-stimulated TNF release (80, 177, 203). More importantly, McGeehan et al. (177) and Mohler et al. (203) independently observed that these inhibitors decrease LPS-induced lethality in mice. Metalloproteinase inhibitors are nonspecific and inhibit the enzymatic activity of various collagenases. Interestingly, ICE inhibitors do not prevent the release of the IL-1beta precursor into the extracellular space, whereas TACE inhibitors do prevent the release of pro-TNF(80). This suggests that, in contrast to IL-1beta , only the mature form of TNF is released. Thus TACE may be a rate-limiting step in TNF release.

    THERAPEUTIC STRATEGIES

TNF contributes to myocardial contractile dysfunction and cardiomyocyte death, whether produced as a result of ischemia or sepsis. Future perspectives on blocking transcription and/or biological activity are discussed, as each suggests potentially therapeutic options (1-4, 22-26, 48, 49, 72-80, 85-88, 104, 105, 162, 163, 173-175, 182, 186, 193, 194, 196).

Inhibition of TNF transcription. Selective interference with TNF transcription may be an effective strategy of inhibiting TNF production (47). Although most anticytokine strategies have focused on preventing postrelease activity, agents that prevent TNF synthesis may provide additional benefit when used alone or in combination with postrelease neutralizing agents. Theoretically, disruption of the signaling cascade at any level would inhibit TNF production at the pretranscriptional level. This, however, may not provide selective inhibition of TNF production. Because the signaling cascade "fans out," proximal signaling enzymes also initiate other vital pathways, as well as those for TNF production. For these reasons, more distal inhibition, such as P38 MAPK or NFkappa B inhibition, have theoretical appeal.

The P38 MAPK inhibitors selectively prevent macrophage proinflammatory monokine production (66, 155, 156, 253). P38 MAPK is activated by endotoxin (155, 156), cytokine (66, 156), hyperosmotic (253), hydrogen peroxide (113, 129), and ischemia-reperfusion stress (29). Bogoyevitch and colleagues (29) demonstrated that P38 MAPK is present in heart and that even brief ischemia-reperfusion of isolated rat heart activates P38 MAPK. These investigators also demonstrated that the degree of P38 MAPK activation correlates with the severity of injury. Pyridinyl-imidazole compounds, known as cytokine-suppressive anti-inflammatory drugs, complex with and inhibit P38 MAPK with high potency and specificity (66, 155, 156). Indeed, the half-maximal effective concentration values for P38 MAPK are in the nanomolar range (66, 155, 156, 271). Tong and associates (271) determined the crystal structure of the P38-pyridinyl-imidazole complex and reported that the high specificity of these compounds is due to its unique binding to the ATP pocket in P38 MAPK with a nearly perfect fit.

NFkappa B is a TNF transcription factor (16, 207) that is present in the heart and activated by myocardial oxidant stress (Fig. 4) (193, 196). Pyrrolidine dithiocarbamates (PDTC) are effective NFkappa B antagonists (47, 55, 138, 166, 201, 207, 248, 290); however, they lack specificity and little is known about their bioactivity or side effects. NFkappa B is activated by oxidant stress (160, 201, 207, 248); therefore, powerful antioxidants (e.g., PDTC) prevent NFkappa B activation. Indeed, vitamin E and glutathione also prevent NFkappa B activation via their antioxidant properties (138, 166, 201, 207, 248, 290). Binding NFkappa B with HSP70 should prevent intranuclear translocation of NFkappa B and thereby also accomplish pretranscriptional inhibition of TNF production. Indeed, Feinstein and associates (91) demonstrated that, in astroglial cells, HSP70 binds NFkappa B in the cytosol and prevents its translocation to the nucleus. HSPs also inhibit TNF production at the posttranslational level (see HSPs) (238).

Inhibition of TNF activity. TNF and IL-1 synergistically depress myocardial function (75, 151, 208, 221). Therefore, blocking the activity of either TNF or IL-1 should have a synergistic beneficial effect. Phase I, II, and III clinical studies have examined the safety and efficacy of anti-TNF monoclonal antibodies, soluble TNF receptors, and IL-1 receptor antagonists in the treatment of patients with sepsis (1, 4, 26, 79, 89, 90, 95, 103, 221, 299). Although the overall results of these studies were somewhat disappointing, encouraging information has been obtained in specific subgroups of the patient population at risk. Anticytokine manipulation appears to be safe. Maximal TNF and IL-1 activity occurs within a few hours of insult, most often preceding the administration of anticytokine agents by hours or days in clinical studies (79). Pretreatment of animals with various anti-TNF binding protein strategies prevents endotoxin-induced myocardial dysfunction and lethality (26, 89, 105, 208, 286). Therefore, the most efficacious use of these strategies would be in those clinical settings allowing pretreatment. Because TNF has been implicated as a potential mediator of myocardial ischemia and reperfusion injury, preischemic administration of TNF binding proteins may reduce myocardial damage. Cardiac bypass, heart transplantation, and coronary angioplasty are three clinical scenarios that permit a scheduled myocardial ischemia-reperfusion/inflammatory event. Indeed, these events are more common clinically than sepsis.

TNF undergoes posttranslational myristoylation promoting membrane insertion and interaction within TACE (80, 101). Metalloproteinase inhibitors suppress TACE processing of TNF and decrease LPS-stimulated TNF release (80, 177, 203). These inhibitors decrease LPS-induced lethality in mice and may represent a therapeutic strategy to reduce TNF activity (177, 203). Protease inhibitors such as aprotinin may exert similar beneficial effects (124). Using exhaled NO and lung epithelial iNOS expression as markers of inflammation, Hill and colleagues (124) demonstrated that aprotinin decreased cardiopulmonary bypass-induced inflammation in humans. Indeed, aprotinin may exert its anti-inflammatory effects by decreasing TNF processing by TACE and thereby reduce TNF-induced iNOS expression and NO production.

HSPs. Many animal studies have demonstrated that prior thermal stress reduces myocardial infarct size following prolonged ischemia. Hutter et al. (130) postulated the induction of a class of "housekeeping" (heat shock) proteins that could repair or prevent stress-induced cellular damage. TNF, adrenergic, oxidant, endotoxin, or heat stress can induce the production of HSPs. The tolerance that evolves to the lethal metabolic and pyrogenic effects of endotoxin (12, 288) is temporally correlated with the appearance of the HSPs (43, 78, 96, 114, 307) and antioxidants (36, 38, 39, 41). Indeed, TNF-induced production of HSPs may be a mechanism by which TNF production is regulated (211, 212). LPS or TNF-induced production of HSPs (35, 37) can also provoke cross-tolerance (protective preconditioning) against other forms of injury (188, 197). We noted that LPS (39, 188, 197), TNF, or IL-1 (42) 24-h pretreatment conferred protection against subsequent myocardial ischemia-reperfusion injury. Induction of HSPs by heat, LPS, cytokine, or adrenergic stress results in similar postischemic protection (186). Indeed, Hutter and colleagues (130) demonstrated a direct correlation in the degree of HSP induction (after various degrees of thermal stress) and the volume of myocardial infarct reduction following ischemia and reperfusion. We found that endotoxin (200) or adrenergic stress (199, 239) induced HSP70, which was associated with protection against endotoxemic or ischemic myocardial depression. Furthermore, this protection is cycloheximide inhibitable (188), suggesting that the mechanism of protection requires de novo protein synthesis. A differential effect of HSPs on cardiomyocyte survival following heat stress or ischemia was reported by Cumming and colleagues (67). They demonstrated that transfection of isolated cardiomyocytes with HSP70 increased cell survival following either lethal ischemia or lethal heat stress, that HSP90 protected against heat stress but not ischemia, and that HSP60 offered no protection against either stress. Plumier et al. (235) have convincingly linked HSP70 with infarct size reduction by overexpressing human HSP70 in transgenic mice with a dramatic improvement in postischemic myocardial recovery. Suzuki and colleagues (264) utilized an in vivo HSP70 gene delivery system to decrease myocardial ischemia-reperfusion injury. Liposomes containing the human HSP70 gene were used to facilitate in vivo transfer of HSP70 to rat heart. Furthermore, increased cardiomyocyte susceptibility to hypoxia and reoxygenation was observed when Nakano and associates (212) used antisense to HSP72 (inducible form of HSP70) to block endogenous HSP72 production. Thus HSPs, regardless of how they are induced, appear to decrease subsequent injury in part by downregulating subsequent TNF production (238).

Histological examination of protected hearts has localized the increased HSP70 to myocardial macrophages (200). It is possible that stimuli that induce HSP protect against injury by decreasing macrophage/TNF-mediated tissue injury. Indeed, HSP induction is temporally coincident with the onset of macrophage endotoxin-tolerance (96, 114). Feinstein and associates (91) demonstrated that HSP70 may reduce inflammation by decreasing NFkappa B activation. They demonstrated that HSP70 blocks iNOS expression by binding its transcription factor, NFkappa B, and preventing its translocation to the nucleus. Although not examined, HSP70 binding to NFkappa B may also decrease TNF and IL-1 production by the same mechanism (Fig. 5). In addition to its pretranscriptional effects, Ribeiro and colleagues (238) showed that HSP72 prevents posttranslational release of TNF. They demonstrated physical interaction between cytosolic TNF and HSP72, which was associated with decreased TNF release (Fig. 5). Thus heat shock or endotoxin induces HSPs, which appear to protect against subsequent insults by binding cytosolic NFkappa B and TNF, thereby limiting destructive inflammation. Liposomal delivery or gene transfer (40, 240) of HSPs into cells may allow the induction of HSP-mediated protection without the deleterious physical consequences of heat shock.

gp130 Subunit-linked agonists. The gp130 receptor subunit was first identified as a component of the IL-6 signal transduction pathway (5, 142). Six different cytokines that share gp130 as a receptor subunit downregulate TNF production (Fig. 5) (5, 7, 19, 279, 294). These cytokines are IL-6, IL-11, cardiotrophin-1 (CT-1), leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. Of particular interest are the recent findings of Benigni and colleagues (18) who demonstrated that CT-1 decreases TNF production by the heart. The mechanism by which gp130 agonists decrease TNF production is unknown, but may involve MAPK interaction at a pretranscriptional level (125). In addition to the transduction of anti-inflammatory signals, recent observations suggest that this receptor subunit has important implications in cardiovascular development and disease. Targeted disruption of gp130 (gp130 knockout mice) results in hypoplastic development of the ventricular myocardium and is incompatible with life (305), whereas continuous activation of gp130 leads to ventricular hypertrophy (232). Furthermore, Hirota and associates (125) have recently proposed that CT-1 is released by cardiac myocytes during ischemia to enhance cellular survival by an unknown mechanism. Thus gp130-linked agonists decrease TNF production and may be of therapeutic benefit in decreasing TNF-mediated myocardial injury.

Preconditioning: anti-TNF actions of adenosine, norepinephrine, HSPs, and antioxidants. The heart has intrinsic defense mechanisms against ischemic or endotoxemic injury, which can be elicited by brief periods of ischemia. We (15, 34, 37, 39, 42, 58, 62, 63, 185, 190, 195, 200, 202) and others (147, 164, 176, 209, 234, 259, 260, 269, 270, 289, 306) have termed this protective phenomenon ischemic cardiac preconditioning. Although these findings are paradoxical, recent clinical evidence suggests that the myocardium adapts to the stresses of repeated sublethal ischemia. Indeed, Kloner and Shook (147), Otani et al. (225), and Andreotti et al. (9) have independently observed a protective role for angina, which precedes myocardial infarction by 24-48 h. We have recently confirmed these observations in an ex vivo model of human myocardial ischemia-reperfusion injury (57, 61, 63). These findings suggest that the stress of angina induces an endogenous adaptive mechanism that protects the myocardium. Endogenous myocardial protection against ischemia-reperfusion injury can be induced by early and delayed mechanisms, which have been respectively referred to as first and second window preconditioning (39, 209). The temporal discrepancy between early and delayed preconditioning suggests that different adaptation mechanisms exist (209, 269, 302). Early preconditioning occurs within minutes, is transient, and may be independent of de novo protein synthesis (269). The second window of protection requires hours for complete induction, is more sustained (up to 7 days), and may require de novo protein synthesis (176, 199, 200). Mechanistic examination of early and delayed preconditioning has permitted pharmacological induction of similar, if not identical, endogenous protection. In this regard, components of early preconditioning can be mimicked by preischemic stimulation of either adenosine A1 (121, 301), alpha 1-adrenergic (15, 202), or bradykinin B2 (34, 108) receptor stimulation. This receptor-inducible protection is mediated via the activation of KATP channels (110) and protein kinase C isoforms (145, 202); however, ultimate effectors remain unknown. Delayed myocardial adaptation, or second window preconditioning, has been induced by transient ischemia (302), endotoxemia (39, 176), inflammatory mediators (42), hyperthermia (81), rapid ventricular pacing (266), or alpha 1-adrenoceptor stimulation (199) >= 24 h after stimulation.

Stress hormones, adenosine and norepinephrine (15, 34, 58-62, 178, 185, 195, 199, 202), are released during transient ischemia and can induce the early phase of preconditioning via intracellular kinases. The induced hydrolysis of phosphatidyl-4,5-bisphosphate by phospholipase C produces inositol trisphosphate and diacylglycerol, the intracellular targets of which have been identified as PKC and calcium-storage organelles (13, 14, 99, 178, 180, 181, 183-185, 188-190, 192, 197, 199, 200, 217, 292). Interrogation of preconditioning's mechanisms has focused on adenosine or norepinephrine signaling within the cardiac myocyte. However, it is possible that these ischemic stress hormones partly contribute to protection by their anti-inflammatory effects (45, 69, 175, 179, 230, 249, 254, 284). Adenosine's anti-inflammatory effects include 1) decreased TNF production in LPS-challenged mice (230), 2) decreased LPS-stimulated iNOS expression (69), 3) inhibition of neutrophil adhesion and injury to cardiac myocytes (45), and 4) decreased intestinal neutrophil accumulation after ischemia-reperfusion of the small intestine (249). Indeed, it has recently been reported that adenosine decreases cardiac TNF levels and bioactivity after ischemia and reperfusion of the isolated rat heart (182). Similarly, adrenergic agents decrease TNF production during human endotoxemia (284), as well as decrease macrophage superoxide and NO release (254). Thus 1) preconditioning induces the release of adenosine and norepinephrine, 2) adenosine and norepinephrine exhibit anti-inflammatory properties, 3) adenosine reduces cardiac TNF following ischemia and reperfusion, and 4) adenosine and norepinephrine pretreatment each protects myocardium against ischemia and reperfusion injury.

The mechanisms of endotoxin-induced delayed myocardial protection (39) and adenosine- or phenylephrine-induced acute myocardial protection (59, 63, 82, 97, 110, 143, 152) have been studied extensively. Endotoxin-induced delayed myocardial protection against the deleterious consequences of ischemia and reperfusion is only one of several noxious stimuli reported to induce protection >24 h after the original insult (39, 176). Indeed, transient ischemia (302), hyperthermia (170), rapid ventricular pacing (266), and norepinephrine each induce delayed myocardial protection against ischemia and reperfusion (199). Additionally, mediators of endotoxin-induced systemic effects, IL-1 and TNF, have been reported to independently induce similar, delayed cardioadaptive effects. The detoxified endotoxin derivative, monophosphoryl lipid-A, also instigates delayed cardioprotection (215). Induction of antioxidant enzymes and HSPs have been implicated in the mechanisms of delayed preconditioning. In this regard, it is known that preischemic oxidant stress induces myocardial adaptation to ischemia and reperfusion (20, 39, 176). It has been hypothesized that the oxidant stress associated with ischemic preconditioning or endotoxin induces antioxidant enzymes that scavenge free radicals and thereby decrease oxidant-induced myocardial damage during subsequent ischemia and reperfusion injury. Induction of antioxidant enzymes may act to limit oxidant-induced activation of NFkappa B or P38 MAPK. Delayed preconditioning may also act to decrease myocardial TNF production via HSPs (see HSPs).

Potential risks of cytokine inhibition: lessons learned from sepsis trials. Anti-TNF therapy should be interpreted with several important caveats. TNF likely plays an important role in the execution of a normal immune response. Effectiveness of antigen presentation is enhanced when the T cell receives a costimulatory signal such as TNF or IL-1 (48, 49, 54). Many of the animal models that have demonstrated beneficial effects of anti-TNF therapy have chosen to use endotoxin, not live bacteria, as the insult. It is likely that in those situations anti-TNF therapy may limit the clearance of live bacteria and thereby increase mortality. The anti-TNF clinical trial that employed anti-TNF therapy in the form of soluble p75 TNFR was associated with increased mortality (94). Studies have demonstrated that TNF may be required to fight intracellular pathogens (Listeria) and fungi (Candida), and to survive abdominal sepsis. It appears that TNF signal transduction through the p55 receptor is necessary to clear Candida infection (262). Likewise, TNF appears to be necessary for survival from sepsis in a murine peritonitis model (83, 123). TNF knockout mice are also unable to clear bacteremia after Listeria monocytogenes infection (8). TNF-deficient mice develop normally but are highly susceptible to Candida albicans infection, have impaired granuloma development, and do not form germinal centers after antigen challenge (171). However, these mice are also resistant to endotoxin challenge (171). Thus anti-TNF therapy may be most useful in those situations that constitute a pure inflammatory insult (e.g., ischemia and reperfusion injury). In this regard, the doses in the phase II p75 TNFR study (94, 214, 243) may have been excessive. The p75 TNFR may act as a TNF carrier and prolong the circulating half-life of TNF in vivo (204). The molecular difference between the p55 and the p75 TNFR may well prove important in that p55 TNFR may allow TNF to exit the circulation while p75 TNFR may prolong TNF circulation, stimulating fixed tissue receptors. This hypothesis is supported by a study in which mice were administered Escherichia coli and then either the p55 or the p75 TNFR. In mice treated with p75 TNFR, there appeared to be a "TNF carrier state" induced by p75 that was absent with p55 TNFR treatment (89). Thus TNF has been implicated in the pathogenesis of myocardial ischemia and reperfusion injury; therefore, employment of anti-TNF strategies during and after inflammatory insults may prove beneficial. However, we must be cognizant of the lessons learned from sepsis trials, which may suggest that we should avoid anti-TNF therapy in those patients with concurrent infection.

    ACKNOWLEDGEMENTS

I am indebted to Dr. Charles A. Dinarello (Professor of Medicine, Division of Infectious Disease, University of Colorado Health Sciences Center) and Dr. Alden H. Harken (Professor and Chairman of Surgery, Division of Cardiothoracic Surgery, University of Colorado Health Sciences Center) for the many days they spent reading and revising this manuscript. Also, thanks to Drs. E. E. Moore, J. M. Brown, D. A. Fullerton, I. H. Chaudry, A. Ayala, X. Meng, J. C. Cleveland, B. S. Cain, R. C. McIntyre, Jr., B. C. Sheridan, R. Meacham, L. Shapiro, D. A. Partrick, F. Gamboni-Robertson, and L. Ao for discussion, support, and encouragement.

    FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute Grants HL-43696 and HL-44186, National Institute of General Medical Sciences Grant GM-08315, and a National Institutes of Health National Research Service Award.

Address for reprint requests: D. R. Meldrum, Univ. of Colorado Health Sciences Center, 4200 East Ninth Ave., Box C-320, Denver, CO 80262.

    REFERENCES
Top
Abstract
Introduction
References

1.  Abraham, E. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. Second Annual Autumnal Sepsis Meeting, Deauville, France, 1995.

2.   Abraham, E., M. P. Glauser, T. Butler, J. Garbino, D. Gelmont, P. F. Laterre, K. Kudsk, H. A. B. Ha, C. Otto, E. Tobin, C. Zwingelstein, W. Lesslauer, and A. Leighton. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group. JAMA 277: 1531-1538, 1997[Abstract/Free Full Text].

3.   Abraham, E., and T. A. Raffin. Sepsis therapy trials: continued disappointment or reason for hope? JAMA 271: 1876-1878, 1994[Abstract/Free Full Text].

4.   Abraham, E., R. Wunderink, H. Silverman, T. M. Perl, S. Nasraway, H. Levy, R. Bone, R. P. Wenzel, R. Balk, R. Allred, J. E. Pennington, and J. C. Wherry. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. JAMA 273: 934-941, 1995[Abstract/Free Full Text].

5.   Aderka, D., J. Le, and J. Vilcek. IL-6 inhibits LPS-induced tumor necrosis factor production in cultured human monocytes, in U937 cells, and in mice. J. Immunol. 143: 3517-3523, 1989[Abstract].

6.   Akiyama, K., H. Suzuki, P. Grant, and R. J. Bing. Oxidation products of nitric oxide, NO2 and NO3, in plasma after experimental myocardial infarction. J. Mol. Cell. Cardiol. 29: 1-9, 1997[Medline].

7.   Alexander, H. R., G. G. H. Wong, G. M. Doherty, D. J. Venzon, D. L. Fraker, and J. A. Norton. Differentiation factor/leukemia inhibitory factor protection against lethal endotoxemia in mice: synergistic effect with IL-1 and TNF. J. Exp. Med. 175: 1139-1142, 1992[Abstract/Free Full Text].

8.   Amiot, F., O. Boussadia, S. Cases, C. Fitting, M. Lebastard, J. M. Cavaillon, G. Milon, and F. Dautry. Mice heterozygous for a deletion of the tumor necrosis factor-alpha and lymphotoxin-alpha genes: biological importance of a nonlinear response of tumor necrosis factor-alpha to gene dosage. Eur. J. Immunol. 27: 1035-1042, 1997[Medline].

9.   Andreotti, F., V. Pasceri, D. R. Hackett, G. J. Davies, A. W. Haider, and A. Maseri. Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N. Engl. J. Med. 334: 7-12, 1996[Abstract/Free Full Text].

10.   Arras, M., A. Hoche, R. Bohle, P. Eckert, W. Riedel, and J. Schaper. Tumor necrosis factor-alpha in macrophages of heart, liver, kidney, and in the pituitary gland. Cell Tissue Res. 285: 39-49, 1996[Medline].

11.   Ayala, A., C. D. Herndon, D. L. Lehman, C. A. Ayala, and I. H. Chaudry. Differential induction of apoptosis in lymphoid tissues during sepsis: variation in onset, frequency, and the nature of the mediators. Blood 87: 4261-4275, 1996[Abstract/Free Full Text].

12.   Ayala, A., J. M. Kisala, J. A. Felt, M. M. Perrin, and I. H. Chaudry. Does endotoxin tolerance prevent the release of inflammatory monokines (interleukin 1, interleukin 6, or tumor necrosis factor) during sepsis? Arch. Surg. 127: 191-197, 1992[Abstract/Free Full Text].

13.   Ayala, A., D. R. Meldrum, M. M. Perrin, and I. H. Chaudry. The release of transforming growth factor beta following hemorrhage: its role as a mediator of host immunosuppression. Immunology 79: 479-484, 1993[Medline].

14.   Ayala, A., M. M. Perrin, D. R. Meldrum, W. Ertel, and I. H. Chaudry. Hemorrhage induces an increase in serum TNF which is not associated with elevated levels of endotoxin. Cytokine 2: 170-174, 1990[Medline].

15.   Banerjee, A., C. Locke-Winter, K. B. Rogers, M. B. Mitchell, D. D. Bensard, E. C. Brew, C. B. Cairns, and A. H. Harken. Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha-1 adrenergic mechanism. Circ. Res. 73: 656-670, 1993[Abstract/Free Full Text].

16.   Barnes, P. J., and M. Karvin. Nuclear factor kappa B: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336: 1066-1071, 1997[Free Full Text].

17.   Bazzoni, F., and B. Beutler. The tumor necrosis factor ligand and receptor families. N. Engl. J. Med. 334: 1717-1725, 1996[Free Full Text].

18.   Benigni, F., S. Sacco, D. Pennica, and P. Ghezzi. Cardiotrophin-1 inhibits tumor necrosis factor production in the heart and serum of LPS-treated mice and in vitro mouse blood cells. Am. J. Pathol. 149: 1847-1850, 1996[Abstract].

19.   Benigni, F., P. Villa, M. T. Dimitri, S. Sacco, J. D. Sipe, L. Lagunowich, N. Panayotatos, and P. Ghezzi. Ciliary neurotrophic factor (CNTF) inhibits brain and peripheral TNF production and, in association with its soluble receptor, protects mice against LPS toxicity. Mol. Med. 1: 568-575, 1995[Medline].

20.   Bensard, D. B., J. M. Brown, B. O. Anderson, A. Banerjee, P. F. Shanley, M. A. Grosso, G. J. R. Whitman, and A. H. Harken. Induction of endogenous tissue antioxidant enzyme activity attenuates myocardial reperfusion injury. J. Surg. Res. 49: 126-131, 1990[Medline].

21.   Bensard, D. D., A. Banerjee, R. C. McIntyre, R. Berens, and A. H. Harken. Endotoxin disrupts beta-adrenergic signal transduction in the heart. Arch. Surg. 129: 198-205, 1994[Abstract/Free Full Text].

22.   Beutler, B., and A. Cerami. Cachectin: more than a tumor necrosis factor. N. Engl. J. Med. 316: 379-385, 1987[Medline].

23.   Beutler, B., D. Greenwald, J. D. Hulmes, M. Chang, Y. C. Pan, J. Mathison, R. Ulevitch, and A Cerami. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316: 552-554, 1985[Medline].

24.   Beutler, B., and V. Kruys. Lipopolysaccharide signal transduction, regulation of tumor necrosis factor biosynthesis, and signaling by tumor necrosis factor itself. J. Cardiovasc. Pharmacol. 25: S1-S8, 1995.

25.   Beutler, B., J. Mahoney, N. L. Trang, P. Pekala, and A. Cerrami. Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J. Exp. Med. 161: 984-995, 1985[Abstract/Free Full Text].

26.   Beutler, B., I. W. Milsark, and A. C. Cerami. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effects of endotoxin. Science 229: 869-871, 1985[Abstract/Free Full Text].

27.   Biasucci, L. M., A. Vitelli, G. Liuzzo, S. Altamura, G. Caligiuri, C. Monaco, A. G. Rebuzzi, G. Ciliberto, and A. Maseri. Elevated levels of interleukin 6 in unstable angina. Circulation 94: 874-877, 1996[Abstract/Free Full Text].

28.   Biffl, W. L., E. E. Moore, F. A. Moore, and C. C. Silliman. Nitric oxide reduces endothelial expression of intracellular adhesion molecule-1. J. Surg. Res. 63: 328-332, 1996[Medline].

29.   Bogoyevitch, M. A., J. Gillespie-Brown, A. J. Ketterman, S. J. Fuller, R. Ben-Levy, A. Ashworth, C. J. Marshall, and P. H. Sugden. Stimulation of the stress-activated mitogen activated protein kinase subfamilies in perfused heart: p38/RK mitogen activated protein kinases and c-Jun N-Terminal kinases are activated by ischemia/reperfusion. Circ. Res. 79: 162-173, 1996[Abstract/Free Full Text].

30.   Boldin, M. P., E. E. Varfolomeev, Z. Pancer, I. L. Mett, J. H. Camonis, and D. Wallach. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J. Biol. Chem. 270: 7795-7798, 1995[Abstract/Free Full Text].

31.   Boyle, E. M., E. D. Verrier, and B. D. Spiess. Endothelial cell injury in cardiovascular surgery. Ann. Thorac. Surg. 62: 1549-1557, 1996[Abstract/Free Full Text].

32.   Brady, A. J. B., P. A. Poole-Wilson, S. E. Harding, and J. B. Warren. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1963-H1966, 1992[Abstract/Free Full Text].

33.   Brady, A. J. B., J. B. Warren, P. A. Poole-Wilson, T. J. Williams, and S. E. Harding. Nitric oxide attenuates cardiac myocyte contraction. Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H176-H182, 1993[Abstract/Free Full Text].

34.   Brew, E. B., M. B. Mitchell, T. F. Rehring, F. Gamboni-Robertson, R. C. Mcintyre, A. H. Harken, and A. Banerjee. The role of bradykinin in cardiac functional protection after global ischemia-reperfusion in the rat heart. Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H1370-H1378, 1995[Abstract/Free Full Text].

35.   Brown, J. M., B. O. Anderson, J. Repine, P. Shanley, C. White, M. A. Grosso, A. Banerjee, D. Bensard, and A. H. Harken. Neutrophils contribute to TNF induced myocardial tolerance to ischemia. J. Mol. Cell. Cardiol. 24: 485-495, 1992[Medline].

36.   Brown, J. M., G. J. Buehler, E. M. Berger, M. A. Grosso, G. J. Whitman, L. S. Terada, J. Leff, A. H. Harken, and J. E. Repine. Albumin decreases hydrogen peroxide and reperfusion injury in isolated rat hearts. Inflammation 13: 583-589, 1989[Medline].

37.   Brown, J. M., M. A. Grosso, L. S. Terada, A. Banerjee, and A. H. Harken. Endotoxin induces in vivo myocyte HSP-70 expression and protection from cardiac ischemic injury (Abstract). J. Cell. Biochem. 195: 17D, 1993.

38.   Brown, J. M., M. A. Grosso, L. S. Terada, C. J. Beehler, K. M. Toth, G. J. Whitman, and A. H. Harken. Erythrocytes decrease myocardial hydrogen peroxide levels and reperfusion injury. Am. J. Physiol. 256 (Heart Circ. Physiol. 25): H584-H588, 1989[Abstract/Free Full Text].

39.   Brown, J. M., M. A. Grosso, L. S. Terada, G. J. Whitman, A. Banerjee, C. W. White, A. H. Harken, and J. E. Repine. Endotoxin pretreatment increases endogenous myocardial catalase activity and decreases ischemia-reperfusion injury of isolated rat hearts. Proc. Natl. Acad. Sci. USA 86: 2516-2520, 1989[Abstract/Free Full Text].

40.   Brown, J. M., A. H. Harken, and J. B. Sharefkin. Recombinant DNA and surgery. Ann. Surg. 212: 178-186, 1990[Medline].

41.   Brown, J. M., L. S. Terada, M. A. Grosso, G. J. Whitman, S. E. Velasco, A. Patt, A. H. Harken, and J. E. Repine. Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic isolated rat hearts. J. Clin. Invest. 81: 1297-1301, 1988.

42.   Brown, J. M., C. W. White, L. S. Terada, M. A. Grosso, P. F. Shanley, D. W. Mulvin, A. Banerjee, G. J. Whitman, A. H. Harken, and J. E. Repine. Interleukin-1 pretreatment decreases ischemia/reperfusion injury. Proc. Natl. Acad. Sci. USA 87: 5026-5030, 1990[Abstract/Free Full Text].

43.   Buchman, T. G. Manipulation of stress gene expression: a novel therapy for the treatment of sepsis? Crit. Care Med. 22: 901-903, 1994[Medline].

44.   Buerke, M., T. Murohara, C. Skurk, C. Nuss, A. M. Tomaselli, and A. M. Lefer. Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. Proc. Natl. Acad. Sci. USA 92: 8031-8035, 1995[Abstract/Free Full Text].

45.   Bullough, D. A., M. J. Magill, G. S. Firestein, and K. M. Mullane. Adenosine activates A2 receptors to inhibit neutrophil adhesion and injury to isolated myocytes. J. Immunol. 155: 2579-2586, 1995[Abstract].

46.   Buscher, D., R. A. Hipskind, S. Krautwald, T. Reimann, and M. Baccarini. Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages. Mol. Cell. Biol. 15: 466-475, 1995[Abstract].

47.   Butt, T. R., and S. K. Karathasis. Transcription factors as drug targets: opportunities for therapeutic selectivity. Gene Expr. 4: 319-336, 1995[Medline].

48.  Cain, B. S., D. R. Meldrum, A. H. Harken, and R. C. McIntyre. Physiologic basis for anti-cytokine clinical trials. J. Am. Coll. Surg. In press.

49.   Cain, B. S., D. R. Meldrum, C. H. Selzman, J. C. Cleveland, X. Meng, B. C. Sheridan, A. Banerjee, and A. H. Harken. Surgical implications of vascular endothelial physiology. Surgery 122: 516-526, 1997[Medline].

50.   Calvin, J. E., A. A. Driedger, and W. J. Sibbald. An assessment of myocardial function in human sepsis utilizing ECG gated cardiac scintigraphy. Chest 38: 579-586, 1981.

51.   Cameron, D. Initiation of white cell activation during cardiopulmonary bypass: cytokines and receptors. J. Cardiovasc. Pharmacol. 27: S1-S5, 1996.

52.   Carson, D. A., and J. M. Ribeiro. Apoptosis and disease. Lancet 341: 1251-1254, 1993[Medline].

53.   Cerretti, D. P., C. J. Klotsky, B. Mosley, N. Nelson, K. VanNess, T. A. Greenstreet, C. J. March, S. R. Kronheim, T. Druck, L. A. Cannizzaro, K. Huebner, and R. A. Black. Molecular cloning of the IL-1beta converting enzyme. Science 256: 97-100, 1992[Abstract/Free Full Text].

54.   Chaudry, I. H., A. Ayala, W. Ertel, and R. N. Stephan. Hemorrhage and resuscitation: immunological aspects. Am. J. Physiol. 259 (Regulatory Integrative Comp. Physiol. 28): R663-R678, 1990[Free Full Text].

55.   Chen, F., D. C. Kuhn, S. C. Sun, L. J. Gaydos, and L. M. Demers. Dependence and reversal of nitric oxide production on NFkappa B in silica and lipopolysaccharide-induced macrophages. Biochem. Biophys. Res. Commun. 214: 839-846, 1995[Medline].

56.   Chinnaiyan, A. M., K. O'Rourke, M. Tewari, and V. M. Dixit. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81: 505-512, 1995[Medline].

57.   Cleveland, J. C., D. R. Meldrum, B. S. Cain, A. Banerjee, and A. H. Harken. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Circulation 96: 29-32, 1997[Abstract/Free Full Text].

58.   Cleveland, J. C., D. R. Meldrum, R. T. Rowland, A. Banerjee, and A. H. Harken. Optimal myocardial preservation: cooling, cardioplegia and conditioning. Ann. Thorac. Surg. 61: 760-768, 1996[Abstract/Free Full Text].

59.   Cleveland, J. C., D. R. Meldrum, R. T. Rowland, A. Banerjee, and A. H. Harken. Adenosine preconditioning of human myocardium is dependent upon the ATP-sensitive potassium channel. J. Mol. Cell. Cardiol. 29: 175-182, 1997[Medline].

60.   Cleveland, J. C., D. R. Meldrum, R. T. Rowland, A. Banerjee, and A. H. Harken. Preconditioning and hypothermic cardioplegia protect human heart equally against ischemia. Ann. Thorac. Surg. 63: 147-152, 1997[Abstract/Free Full Text].

61.   Cleveland, J. C., D. R. Meldrum, R. T. Rowland, B. S. Cain, X. Meng, F. Gamboni-Robertson, A. Banerjee, and A. H. Harken. Ischemic preconditioning of human myocardium: protein kinase C mediates a permissive role for alpha 1-adrenoceptors. Am. J. Physiol. 273 (Heart Circ. Physiol. 42): H902-H908, 1997[Abstract/Free Full Text].

62.   Cleveland, J. C., D. R. Meldrum, R. T. Rowland, B. C. Sheridan, A. Banerjee, and A. H. Harken. The obligate role of protein kinase C in mediating clinically accessible cardiac preconditioning. Surgery 120: 345-353, 1996[Medline].

63.   Cleveland, J. C., M. Wolmering, D. R. Meldrum, R. T. Rowland, T. F. Rehring, B. C. Sheridan, A. H. Harken, and A. Banerjee. Ischemic preconditioning in human and rat ventricle. Am. J. Physiol. 271 (Heart Circ. Physiol. 40): H1786-H1794, 1996[Abstract/Free Full Text].

64.   Cleveland, J. L., and J. N. Ihle. Contenders in FasL/TNF death signaling. Cell 81: 479-482, 1995[Medline].

65.   Clowes, G. H. A., B. C. George, C. A. Villee, and C. A. Saravis. Muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma. N. Engl. J. Med. 308: 545-588, 1983[Abstract].

66.   Cuenda, A., J. Rouse, Y. N. Doza, R. Meier, P. Cohen, T. F. Gallagher, P. R. Young, and J. C. Lee. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin 1. FEBS Lett. 364: 229-233, 1995[Medline].

67.   Cumming, D. V. E., R. J. Heads, A. Watson, D. S. Latchman, and D. M. Yellon. Differential protection of primary rat cardiomyocytes by transfection of specific heat stress proteins. J. Mol. Cell. Cardiol. 28: 2343-2349, 1996[Medline].

68.   DeCaterina, R., P. Libby, H. B. Peng, V. J. Thannickal, T. B. Rajavashisth, M. A. Gimbrone, W. S. Shin, and J. K. Liao. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J. Clin. Invest. 96: 60-68, 1995.

69.   Denlinger, L. C., P. L. Fisette, K. A. Garis, G. Kwon, A. Vasquez-Torres, A. D. Simon, B. Nguyen, R. A. Proctor, P. J. Bertics, and J. A. Corbett. Regulation of inducible nitric oxide synthase expression by macrophage purinoceptors and calcium. J. Biol. Chem. 271: 337-342, 1996[Abstract/Free Full Text].

70.   Derijart, B., J. Raingeaud, T. Barret, I. H. Wu, J. Han, R. J. Ulevitch, and R. J. Davis. Independent human MAP kinase signal transduction pathways defined by MEK and MKK isoforms. Science 267: 682-685, 1995[Abstract/Free Full Text].

71.   Dettbarn, C. A., R. Betto, G. Salviati, P. Palade, G. M. Jenkins, and R. A. Sabbadini. Modulation of cardiac sarcoplasmic reticulum ryanodine receptor by sphingosine. J. Mol. Cell. Cardiol. 26: 229-242, 1994[Medline].

72.   Dinarello, C. A. Interleukin-1 and its biologically related cytokines. Adv. Immunol. 44: 153-205, 1989[Medline].

73.   Dinarello, C. A. Interleukin-1 and interleukin-1 antagonism. Blood 77: 1627-1652, 1991[Abstract/Free Full Text].

74.   Dinarello, C. A. Role of interleukin-1 in infectious disease. Immunol. Rev. 127: 119-146, 1992[Medline].

75.   Dinarello, C. A. Biologic basis for interleukin 1 in disease. Blood 87: 2095-2147, 1996[Abstract/Free Full Text].

76.   Dinarello, C. A., and C. A. Cannon. Cytokine measurements in septic shock. Ann. Intern. Med. 119: 853-854, 1993[Free Full Text].

77.   Dinarello, C. A., J. G. Cannon, S. M. Wolff, H. Bernheim, B. Beutler, A. Cerami, I. S. Figari, M. A. Palladino, and J. V. O'Connor. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of IL-1. J. Exp. Med. 163: 1433-1450, 1986[Abstract/Free Full Text].

78.   Dinarello, C. A., R. A. Dempsey, M. Allegretta, D. R. Parkinson, and J. W. Mier. Inhibitory effects of elevated temperature on human monokine production and natural killer cell activity. Cancer Res. 46: 6236-6241, 1986[Abstract/Free Full Text].

79.   Dinarello, C. A., J. A. Gelfand, and S. M. Wolff. Anticytokine strategies in the treatment of the sytemic inflammatory response syndrome. JAMA 269: 1829-1835, 1993[Abstract/Free Full Text].

80.   Dinarello, C. A., and N. H. Margolis. Stopping the cuts: the recently discovered enzymes that process the precursors of inflammatory cytokines are good targets for the design of new anti-inflammatory therapeutic agents. Curr. Biol. 5: 587-590, 1995[Medline].

81.   Donnelly, T., R. Sievers, F. Vissern, W. Welch, and C. Wolfe. Heat shock protein induction in rat hearts. A role for improved myocardial salvage after ischemia and reperfusion? Circulation 85: 769-778, 1992[Abstract/Free Full Text].

82.   Downey, J. M., M. V. Cohen, K. Ytrehus, and Y. Liu. Cellular mechanisms in ischemic preconditioning: the role of endogenous adenosine and PKC. Ann. NY Acad. Sci. 723: 82-98, 1994[Medline].

83.   Echtenacher, B., W. Falk, D. N. Mannel, and P. H. Krammer. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J. Immunol. 145: 3762-3766, 1990[Abstract].

84.   Ellrodt, A. G., M. S. Riedinger, A. Kimchi, D. S. Berman, J. Maddahi, H. J. C. Swan, and G. H. Murata. Left ventricular performance in septic shock: reversible segmental and global abnormalities. Am. Heart J. 110: 402-409, 1985[Medline].

85.   Ertel, W., J. P. Kremer, J. Kenney, U. Steckholzer, D. Jarrar, O. Trentz, and F. W. Schildberg. Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood 85: 1341-1347, 1995[Abstract/Free Full Text].

86.   Ertel, W., D. R. Meldrum, M. H. Morrison, A. Ayala, and I. H. Chaudry. Immunoprotective effect of a calcium channel blocker on macrophage antigen presentation function, Ia expression, and IL-1 synthesis following hemorrhage. Surgery 108: 154-160, 1990[Medline].

87.   Ertel, W., M. H. Morrison, D. R. Meldrum, A. Ayala, and I. H. Chaudry. Ibuprofen restores cellular immunity and decreases susceptibilty to sepsis following hemorrhage. J. Surg. Res. 53: 55-61, 1992[Medline].

88.   Ertel, W., F. A. Scholl, H. Gallati, M. Bonaccio, and F. W. Schildberg. Increased release of soluble tumor necrosis factor receptors into the blood during clinical sepsis. Arch. Surg. 129: 1330-1337, 1994[Abstract/Free Full Text].

89.   Evans, T. J., D. Moyes, A. Carpenter, R. Martin, H. Loetscher, W. Lesslauer, and J. Cohen. Protective effect of 55- but not 75-kDa soluble tumor necrosis factor receptor-immunoglobin G fusion proteins in an animal model of gram-negative sepsis. J. Exp. Med. 180: 2173-2179, 1994[Abstract/Free Full Text].

90.   Exley, A. R., W. Buurman, M. Bodmer, and J. Bohen. Monoclonal antibody (Mab) to recombinant human tumor necrosis factor (rhTNF) in the prophylaxis and treatment of endotoxic shock in Cynomogus monkeys (Abstract). Clin. Sci. (Colch.) 76: 50, 1989.

91.   Feinstein, D. L., E. Galea, D. A. Aquino, G. C. Li, H. Xu, and D. J. Reis. Heat shock protein 70 suppresses astroglial-inducible nitric oxide synthase expression by decreasing NFkappa B activation. J. Biol. Chem. 271: 17724-17732, 1996[Abstract/Free Full Text].

92.   Finkel, M. S., C. V. Oddis, T. D. Jacob, S. C. Watkins, B. G. Hattler, and R. L. Simmons. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257: 387-389, 1992[Abstract/Free Full Text].

93.   Finkel, T. H., M. J. Pabst, H. Suzuki, L. A. Guthrie, J. R. Forehand, W. A. Phillips, and R. B. Johnston. Priming of neutrophils and macrophage for the enhanced release of superoxide anion by the calcium ionophore ionomycin: implications for regulation of the respiratory burst. J. Biol. Chem. 262: 12589-12596, 1987[Abstract/Free Full Text].

94.   Fisher, C. J. J., J. M. Agosti, S. M. Opal, S. F. Lowry, R. A. Balk, J. C. Sadoff, E. Abraham, R. M. H. Schein, and E. Benjamin. Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. N. Engl. J. Med. 334: 1697-1702, 1996[Abstract/Free Full Text].

95.   Fisher, S. C. J., S. M. Opal, J. F. Dhainaut, S. Stephens, J. L. Zimmerman, P. Nightingale, S. J. Harris, R. M. H. Schein, E. A. Panacek, J. L. Vincent, G. E. Foulke, E. L. Warren, C. Garrard, G. Park, M. W. Bodmer, J. Cohen, C. V. Linden, A. S. Cross, and J. C. Sadoff. Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. Crit. Care Med. 21: 318-327, 1993[Medline].

96.   Fouqueray, B., C. Philippe, A. Amrani, J. Perez, and L. Baud. Heat shock prevents LPS-induced TNF-alpha synthesis by rat mononuclear phagocytes. Eur. J. Immunol. 22: 2983-2987, 1992[Medline].

97.   Fralix, T. A., E. Murphy, R. E. London, and C. Steenbergen. Protective effects of adenosine in the reperfused rat heart: changes in metabolism and intracellular ion homeostasis. Am. J. Physiol. 264 (Cell Physiol. 33): C986-C994, 1993[Abstract/Free Full Text].

98.   Friese, R. S., D. A. Fullerton, R. C. McIntyre, T. F. Rehring, J. A. Agrafojo, A. Banerjee, and A. H. Harken. Nitric oxide prevents neutrophil-mediated pulmonary vasomotor dysfunction in acute lung injury. J. Surg. Res. 63: 23-28, 1996[Medline].

99.   Friese, R. S., T. F. Rehring, M. Wollmering, E. E. Moore, L. L. Ketch, A. Banerjee, and A. H. Harken. Trauma primes cells. Shock 1: 388-394, 1994[Medline].

100.   Fullerton, D. A., R. C. McIntyre, A. R. Hahn, J. Agrafojo, K. Koike, A. Banerjee, and A. H. Harken. Dysfunction of cGMP-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury. Am. J. Physiol. 268 (Lung Cell. Mol. Physiol. 12): L1029-L1035, 1995[Abstract/Free Full Text].

101.   Gearing, A. J. H., P. Beckett, M. Christodoulou, M. Churchill, J. Clements, A. H. Davidson, A. H. Drummond, W. A. Galloway, R. Gilbert, J. L. Gordon, T. M. Leber, M. Mangan, K. Miller, P. Nayee, K. Owen, S. Patel, W. Thomas, G. Wells, L. M. Wood, and K. Woolley. Processing of tumor necrosis factor-alpha precursor by metalloproteinases. Nature 370: 555-557, 1994[Medline].

102.   Geppert, T. D., C. E. Whitehurst, P. Thompson, and B. Beutler. Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis in the rat through the Ras/Raf-1/MEK/MAPK pathway. Mol. Med. 1: 93-103, 1994[Medline].

103.   Gershenwald, J. E., Y. M. Fong, and T. J. I. Fahey. Interleukin 1 receptor blockade attenuates the host inflammatory response. Proc. Natl. Acad. Sci. USA 87: 4966-4970, 1990[Abstract/Free Full Text].

104.   Giroir, B. P., J. H. Johnson, T. Brown, G. L. Allen, and B. Beutler. The tissue distribution of tumor necrosis factor biosynthesis during endotoxemia. J. Clin. Invest. 90: 693-698, 1992.

105.   Giroir, P. B., J. W. Horton, J. White, K. L. McIntyre, and C. Q. Lin. Inhibition of tumor necrosis factor prevents myocardial depression during burn shock. Am. J. Physiol. 267 (Heart Circ. Physiol. 36): H118-H124, 1994[Abstract/Free Full Text].

106.   Glauser, F. L., G. G. DeBlois, D. E. Bechard, R. E. Merchant, A. J. Grant, A. A. Fowler, and R. P. Fairman. Cardiopulmonary effects of recombinant interleukin-2 infusion in sheep. J. Appl. Physiol. 64: 1030-1037, 1988[Abstract/Free Full Text].

107.   Goldhaber, J. L., K. H. Kim, P. D. Natterson, T. Lawrence, P. Yang, and J. N. Weiss. Effects on TNF-alpha on [Ca2+]i and contractility in isolated adult rabbit ventricular myocytes. Am. J. Physiol. 271 (Heart Circ. Physiol. 40): H1449-H1455, 1996[Abstract/Free Full Text].

108.   Goto, M., Y. Liu, X. M. Yang, J. L. Ardell, M. V. Cohen, and J. M. Downey. Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ. Res. 77: 611-621, 1995[Abstract/Free Full Text].

109.   Gottlieb, R. A., K. O. Burleson, R. A. Kloner, B. M. Babior, and R. L. Engler. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J. Clin. Invest. 94: 1621-1628, 1994.

110.   Gross, G. J., and J. Auchampach. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ. Res. 70: 223-233, 1992[Abstract/Free Full Text].

111.   Gulick, T., M. K. Chung, S. J. Pieper, L. G. Lange, and G. F. Schreiner. Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte adrenergic responsiveness. Proc. Natl. Acad. Sci. USA 86: 6753-6757, 1989[Abstract/Free Full Text].

112.   Gurevitch, J., I. Frolkis, Y. Yuhas, Y. Paz, M. Matsa, R. Mohr, and V. Yakirevich. Tumor necrosis factor-alpha is released from the isolated heart undergoing ischemia and reperfusion. J. Am. Coll. Cardiol. 28: 247-252, 1996[Abstract].

113.   Guyton, K. Z., Y. Liu, M. Gorospe, Q. Xu, and N. J. Holbrook. Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J. Biol. Chem. 271: 4138-4142, 1996[Abstract/Free Full Text].

114.   Hall, T. J. Role of hsp70 in cytokine production. Experientia 50: 1048-1053, 1994[Medline].

115.   Han, J., J. D. Lee, L. Bibbs, and R. J. Ulevitch. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265: 808-811, 1994[Abstract/Free Full Text].

116.   Han, J., J. D. Lee, P. S. Tobias, and R. J. Ulevitch. Endotoxin induces rapid tyrosine phosphorylation in 70Z/3 cells expressing CD14. J. Biol. Chem. 268: 25009-25014, 1993[Abstract/Free Full Text].

117.   Han, J., B. Richter, Z. Li, V. Kravchenko, and R. J. Ulevitch. Molecular cloning of the p38 MAP kinase. Biochim. Biophys. Acta 16: 224-227, 1995.

118.   Hannun, Y. A. Functions of ceramide in coordinating the metabolic response to stress. Science 274: 1855-1859, 1996[Abstract/Free Full Text].

119.   Hattler, B. G., A. Zeevi, C. V. Oddis, and M. S. Finkel. Cytokine induction during cardiac surgery: analysis of TNF-alpha expression pre- and postcardiopulmonary bypass. J. Card. Surg. 10: 418-422, 1995[Medline].

120.   Haziot, A., G. W. Rong, X. Y. Lin, J. Silver, and S. M. Goyert. Recombinant soluble CD14 prevents mortality in mice treated with endotoxin (lipopolysaccharide). J. Immunol. 154: 6529-6532, 1995[Abstract].

121.   Headrick, J. P. Ischemic preconditioning: bioenergetic and metabolic changes and the role of endogenous adenosine. J. Mol. Cell. Cardiol. 28: 1227-1240, 1996[Medline].

122.   Herskovitz, A., S. Choi, A. A. Ansari, and S. Wesselingh. Cytokine mRNA expression in the postischemic/reperfused myocardium. Am. J. Pathol. 146: 419-428, 1995[Abstract].

123.   Heumann, D., D. L. Roy, G. Zanetti, H. P. Eugster, B. Ryffel, M. Hahne, J. Tschopp, and M. P. Glauser. Contribution of TNF/TNF receptor and of Fas ligand to toxicity in murine models of endotoxemia and bacterial peritonitis. J. Inflamm. 47: 173-179, 1995[Medline].

124.   Hill, G. E., D. R. Springall, and R. A. Robbins. Aprotinin is associated with a decrease in nitric oxide production during cardiopulmonary bypass. Surgery 121: 449-455, 1997[Medline].

125.   Hirota, H., K. Yoshida, T. Taga, and T. Kishimoto. gp130 Signaling pathways: recent advances and implications for cardiovascular disease. Trends Cardiovasc. Med. 6: 109-115, 1996.

126.   Horton, J. W. Cellular basis for burn-mediated cardiac dysfunction in adult rabbits. Am. J. Physiol. 271 (Heart Circ. Physiol. 40): H2615-H2621, 1996[Abstract/Free Full Text].

127.   Howe, L. R., S. J. Leevers, N. Gomez, S. Nakielny, P. Cohen, and C. J. Marshall. Activation of the MAP kinase pathway by the protein kinase raf. Cell 71: 335-342, 1992[Medline].

128.   Hsu, H., J. Xiong, and D. V. Goeddel. The TNF receptor 1-associated protein TRADD signals cell death and NFkappa B activation. Cell 81: 495-504, 1995[Medline].

129.   Huot, J., F. Houle, F. Marceau, and J. Landry. Oxidative stress-induced actin reorganization mediated by the p38 mitogen-activated protein kinase/heat shock pathway in vascular endothelial cells. Circ. Res. 80: 383-392, 1997[Abstract/Free Full Text].

130.   Hutter, M. M., R. E. Sievers, V. Barbosa, and C. L. Wolfe. Heat shock protein induction in rat hearts. A direct correlation between the amount of heat shock protein induced and the degree of myocardial protection. Circulation 89: 355-362, 1994[Abstract/Free Full Text].

131.   Ishiyama, S., M. Hiroe, T. Nishikawa, S. Abe, T. Shimojo, H. Ito, S. Ozasa, K. Yamakawa, M. Matsuzaki, M. U. Mohammed, H. Nakazawa, T. Kasajima, and F. Marumo. Nitric oxide contributes to the progression of myocardial damage in experimental autoimmune myocarditis. Circulation 95: 489-496, 1997[Abstract/Free Full Text].

132.   Itoh, G., T. Jie, J. Tamura, M. Suzuki, Y. Suzuki, M. Ikeda, M. Koike, and M. Nomura. Apoptosis and human myocardial ischemic damage, including conduction system. Basic Appl. Myol. 6: 237-240, 1996.

133.   Itoh, G., J. Tamura, M. Suzuki, Y. Suzuki, M. Ikeda, M. Koike, T. Jie, M. Nomura, and K. Ito. DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method of and DNA agarose electrophoresis. Am. J. Pathol. 146: 1235-1331, 1996[Abstract].

134.   James, T. N. Normal and abnormal consequences of apoptosis in the human heart from postnatal morphogenesis to paroxysmal arrhythmias. Circulation 90: 556-573, 1994[Abstract/Free Full Text].

135.   Jha, P., H. Jacobs, D. Bose, R. Wang, J. Yang, R. B. Light, and S. Mink. Effects of E. coli sepsis and myocardial depressant factor on interval-force relations in the dog ventricle. Am. J. Physiol. 264 (Heart Circ. Physiol. 33): H1402-H1410, 1993[Abstract/Free Full Text].

136.   Kajstura, J., W. Cheng, K. Reiss, W. A. Clark, E. H. Sonnenblick, S. Krajewski, J. C. Reed, G. Olivetti, and P. Anversa. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab. Invest. 74: 86-107, 1996[Medline].

137.   Kapadia, S., J. Lee, G. Torre-Amione, H. H. Birdsall, T. S. Ma, and D. L. Mann. Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration. J. Clin. Invest. 96: 1042-1052, 1995.

138.   Kawai, M., R. Nishikomori, E. Y. Jung, G. Tai, C. Yamanaka, M. Mayumi, and T. Heike. Pyrrolidine dithiocarbamate inhibits intracellular adhesion molecule-1 biosynthesis induced by cytokines in human fibroblasts. J. Immunol. 154: 2333-2341, 1995[Abstract].

139.   Keaney, J. F., J. M. Hare, J. L. Balligand, J. Loscalzo, T. W. Smith, and W. S. Colucci. Inhibition of nitric oxide synthase augments myocardial contractile responses to beta-adrenergic stimulation. Am. J. Physiol. 271 (Heart Circ. Physiol. 40): H2646-H2652, 1996[Abstract/Free Full Text].

140.   Keller, R. S., J. J. Jones, K. F. Kim, P. R. Myers, H. R. Adams, J. L. Parker, and L. Rubin. Endotoxin-induced myocardial dysfunction: is there a role for nitric oxide? Shock 4: 338-344, 1995[Medline].

141.   Kelly, R. A., and T. W. Smith. Cytokines and cardiac contractile function. Circulation 95: 778-781, 1997[Free Full Text].

142.   Kishimoto, T., S. Akira, and T. Taga. Interleukin-6 and its receptor: a paradigm for cytokines. Science 258: 593-597, 1992[Abstract/Free Full Text].

143.   Kitakaze, M., M. Hori, and T. Kamada. Role of adenosine and its interaction with alpha-adrenoceptor activity in ischemic and reperfusion injury of the myocardium. Cardiovasc. Res. 27: 18-27, 1993[Medline].

144.   Kitakaze, M., K. Node, K. Komamura, T. Minamino, M. Inoue, M. Hori, and T. Kamada. Evidence for nitric oxide generation in the cardiomyocytes: its augmentation by hypoxia. J. Mol. Cell. Cardiol. 27: 2149-2154, 1995[Medline].

145.   Kitakaze, M., K. Node, T. Minamino, K. Komamura, H. Funaya, Y. Shinozaki, M. Chujo, H. Mori, M. Inoue, M. Hori, and T. Kamada. Role of activation of protein kinase C in the infarct size limiting effect of ischemic preconditioning through the activation of 5'-nucleotidase. Circulation 93: 781-791, 1996[Abstract/Free Full Text].

146.   Klabunde, R. E., and A. F. Coston. Nitric oxide synthase inhibition does not prevent cardiac depression in endotoxin shock. Shock 3: 73-78, 1995[Medline].

147.   Kloner, R. A., and T. Shook. Previous angina alters in-hospital outcome in TIMI-4: a clinical correlate to preconditioning. Circulation 91: 37-45, 1995[Abstract/Free Full Text].

148.   Kolesnick, R. N. Sphingosine and derivatives as cellular signals. Prog. Lipid Res. 30: 1-38, 1991[Medline].

149.   Krown, K. A., M. T. Page, C. Nguyen, D. Zechner, V. Gutierrez, K. L. Comstock, C. G. Glembotski, P. J. E. Quintana, and R. A. Sabbadini. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes: involvement of the sphingolipid signaling cascade in cardiac cell death. J. Clin. Invest. 98: 2854-2865, 1996[Medline].

150.   Krown, K. A., Y. Yasui, M. Brooker, A. Dubin, C. Nguyen, G. Harris, P. McDonough, C. G. Glembotski, P. Palade, and R. A. Sabbadini. TNF-alpha receptor expression in rat cardiac myocytes: TNF inhibition of L-type Ca2+ current and Ca2+ transients. FEBS Lett. 376: 24-30, 1995[Medline].

151.   Kumar, A., V. Thota, L. Dee, J. Olson, E. Uretz, and J. E. Parrillo. Tumor necrosis factor-alpha and interleukin 1-beta are responsible for the in vitro myocardial cell depression induced by human septic shock serum. J. Exp. Med. 183: 949-958, 1996[Abstract/Free Full Text].

152.   Lasley, R. D., J. W. Rhee, D. G. L. V. Wylen, and J. R. M. Mentzer. Adenosine A1 receptor mediated protection of the globally ischemic isolated rat heart. J. Mol. Cell. Cardiol. 22: 39-47, 1990[Medline].

153.   Last-Barney, K., C. A. Homon, R. B. Faanes, and V. J. Merluzzi. Synergistic and overlapping activities of tumor necrosis factor-alpha and IL-1. J. Immunol. 141: 527-530, 1988[Abstract].

154.   Latini, R., M. Bianchi, E. Correale, C. A. Dinarello, G. Fantuzzi, C. Fresco, A. P. Maggoini, M. Mengozzi, S. Romano, and L. Shapiro. Cytokines in acute myocardial infarction: selective increase in circulating tumor necrosis factor, its soluble receptor, and interleukin 1 receptor antagonist. J. Cardiovasc. Pharmacol. 23: 1-6, 1994[Medline].

155.   Lee, J. C., J. T. Laydon, P. C. McDonnel, T. F. Gallagher, S. Kumar, D. Green, D. McNulty, M. J. Blumenthal, J. R. Heys, S. W. Landvatter, J. E. Strickler, M. M. McLaughlin, I. R. Siemens, S. M. Fisher, G. P. Livi, J. R. White, J. L. Adams, and P. R. Young. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739-746, 1994[Medline].

156.   Lee, J. C., and P. R. Young. Role of CSB/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. J. Leukoc. Biol. 59: 152-157, 1996[Abstract].

157.   Lee, J. D., V. Kravchenko, T. N. Kirkland, J. Han, N. Mackman, A. Moriarty, D. Letureq, P. S. Tobias, and R. J. Ulevitch. GPI-anchored or integral membrane forms of CD14 mediate identical cellular responses to endotoxin. Proc. Natl. Acad. Sci. USA 90: 9930-9934, 1993[Abstract/Free Full Text].

158.   Lefer, A. M. Origin of myocardial depressant factor in shock. Am. J. Physiol. 218: 1423-1427, 1970.

159.   Lefer, A. M. Role of a myocardial depressant factor in the pathogenesis of circulatory shock. Federation Proc. 29: 1836-1847, 1970[Medline].

160.   LeTulzo, Y., R. Shenkar, D. Kaneko, P. Moine, G. Fantuzzi, C. A. Dinarello, and E. Abraham. Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor kappa B regulation and cytokine expression. J. Clin. Invest. 99: 1516-1524, 1997[Medline].

161.   Levine, B., J. Kalman, L. Mayer, H. Fillit, and M. Packer. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N. Engl. J. Med. 323: 236-241, 1990[Abstract].

162.   Levitzki, A. Signal transduction interception as a novel approach to disease management. Ann. NY Acad. Sci. 766: 363-368, 1995[Medline].

163.   Levitzki, A., and A. Gazit. Tyrosine kinase inhibition: an approach to drug development. Science 267: 1782-1788, 1995[Abstract/Free Full Text].

164.   Li, G. C., and Z. Werb. Correlation between the synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts. Proc. Natl. Acad. Sci. USA 79: 3218-3226, 1982[Abstract/Free Full Text].

165.   Li, S., and J. M. Sedivy. Raf-1 protein kinase activates the NFkappa B transcription factor by dissociating the cytoplasmic NFkappa B-Ikappa B complex. Proc. Natl. Acad. Sci. USA 90: 9247-9251, 1993[Abstract/Free Full Text].

166.   Liu, S. L., S. D. Esposti, T. Yao, A. M. Diehl, and M. A. Zern. Vitamin E therapy of acute CCl4-induced hepatic injury in mice is associated with inhibition of nuclear factor kappa B binding. Hepatology 22: 1474-1481, 1995[Medline].

167.   Lyons, C. R. The role of nitric oxide in inflammation. Adv. Immunol. 60: 323-371, 1995[Medline].

168.   Mallat, Z., A. Tedgui, F. Fontaliran, R. Frank, M. Durigon, and G. Fontaine. Evidence of apoptosis in arrythmogenic right ventricular dysplasia. N. Engl. J. Med. 335: 1190-1196, 1996[Abstract/Free Full Text].

169.   Mallinin, N. L., M. P. Boldin, A. V. Kovalenko, and D. Wallach. MAP3K-related kinase involved in NFkappa B induction by TNF, CD95 and IL-1. Nature 385: 540-544, 1997[Medline].

170.   Marber, M., D. Latchman, J. Walker, and D. Yellon. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88: 1264-1272, 1993[Abstract/Free Full Text].

171.   Marino, M. W., A. Dunn, D. Grail, M. Inglese, Y. Noguchi, E. Richards, A. Jungbluth, H. Wada, M. Moore, B. Williamson, S. Basu, and L. J. Old. Characterization of tumor necrosis factor-deficient mice. Proc. Natl. Acad. Sci. USA 94: 8093-8098, 1997[Abstract/Free Full Text].

172.   Massey, K. D., R. M. Strieter, S. L. Kunkel, J. M. Danforth, and T. J. Standiford. Cardiac myocytes release leukocyte-stimulating factors. Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H980-H987, 1995[Abstract/Free Full Text].

173.   Matsumori, A., K. Ono, R. Nishio, H. Igata, T. Shioi, S. Matsui, Y. Furukawa, A. Iwasaki, Y. Nose, and S. Sasayama. Modulation of cytokine production and protection against lethal endotoxemia by the cardiac glycoside oubain. Circulation 96: 1501-1506, 1997[Abstract/Free Full Text].

174.   Matsumori, A., K. Ono, R. Nishio, Y. Nose, and S. Sasayama. Amiodarone inhibits production of tumor necrosis factor-alpha by human mononuclear cells: a possible mechanism for its effect in heart failure. Circulation 96: 1386-1389, 1997[Abstract/Free Full Text].

175.   Matsumori, A., K. Ono, Y. Sato, T. Shioi, Y. Nose, and S. Sasayama. Differential modulation of cytokine production by drugs: implications for therapy in heart failure. J. Mol. Cell. Cardiol. 28: 2491-2499, 1996[Medline].

176.   Maulik, N., M. Watanabe, D. Engelman, R. M. Engelman, V. E. Kagan, E. Kisin, V. Tyurin, G. A. Cordis, and D. K. Das. Myocardial adaptation to ischemia by oxidative stress induced by endotoxin. Am. J. Physiol. 269 (Cell Physiol. 38): C907-C916, 1995[Abstract/Free Full Text].

177.   McGeehan, G. M., J. D. Becherer, R. Bast, C. M. Boyer, B. Champion, K. M. Connolly, J. G. Conway, P. Furdon, S. Karp, S. Kidao, A. B. McElroy, J. Nichols, K. M. Pryzwansky, F. Schoenen, L. Sekut, A. Truesdale, M. Verghese, J. Warner, and J. P. Ways. Regulation of TNF-alpha processing by a metalloproteinase inhibitor. Nature 370: 558-561, 1994[Medline].

178.  Meldrum, D. R. Mechanisms of cardiac preconditioning: ten years after the discovery of ischemic preconditioning. J. Surg. Res. In press.

179.   Meldrum, D. R., A. Ayala, and I. H. Chaudry. Energetics of defective macrophage antigen presentation following hemorrhage. Surgery 112: 150-158, 1992[Medline].

180.   Meldrum, D. R., A. Ayala, and I. H. Chaudry. Mechanism of diltiazem's immunomodulatory effects following hemorrhage and resuscitation. Am. J. Physiol. 265 (Cell Physiol. 34): C412-C421, 1993[Abstract/Free Full Text].

181.   Meldrum, D. R., A. Ayala, P. Wang, W. Ertel, and I. H. Chaudry. Association between decreased splenic ATP levels and immunodepression. Am. J. Physiol. 261 (Regulatory Integrative Comp. Physiol. 30): R351-R357, 1991[Abstract/Free Full Text].

182.   Meldrum, D. R., B. S. Cain, J. C. Cleveland, X. Meng, A. Ayala, A. Banerjee, and A. H. Harken. Adenosine decreases post-ischemic myocardial TNF-alpha production: anti-inflammatory implications for preconditioning and transplantation. Immunology 92: 472-477, 1997[Medline].

183.   Meldrum, D. R., J. C. Cleveland, X. Meng, B. C. Sheridan, A. Banerjee, and A. H. Harken. Hemorrhage induces acute cardioadaptation to ischemia reperfusion by an alpha 1-adrenoceptor-mediated, protein synthesis-independent mechanism. Am. J. Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R718-R725, 1997[Abstract/Free Full Text].

184.   Meldrum, D. R., J. C. Cleveland, M. B. Mitchell, R. T. Rowland, A. Banerjee, and A. H. Harken. Constructive priming of myocardium against ischemia-reperfusion injury. Shock 6: 238-242, 1996[Medline].

185.   Meldrum, D. R., J. C. Cleveland, M. B. Mitchell, B. C. Sheridan, F. Robertson, A. H. Harken, and A. Banerjee. Protein kinase C mediates Ca2+ induced cardioadaptation to ischemia-reperfusion injury. Am. J. Physiol. 271 (Regulatory Integrative Comp. Physiol. 40): R1718-R1726, 1996.

186.   Meldrum, D. R., J. C. Cleveland, E. E. Moore, D. A. Partrick, A. Banerjee, and A. H. Harken. Adaptive and maladaptive mechanisms of cellular priming. Ann. Surg. 226: 587-598, 1997[Medline].

187.   Meldrum, D. R., J. C. Cleveland, R. T. Rowland, A. Banerjee, and A. H. Harken. Calcium induced inotropy is in part mediated by protein kinase C. J. Surg. Res. 63: 400-405, 1996[Medline].

188.   Meldrum, D. R., J. C. Cleveland, R. T. Rowland, A. Banerjee, A. H. Harken, and X. Meng. Early and delayed preconditioning: differential mechanisms and additive protection. Am. J. Physiol. 273 (Heart Circ. Physiol. 42): H725-H733, 1997[Abstract/Free Full Text].

189.   Meldrum, D. R., J. C. Cleveland, B. C. Sheridan, X. Meng, F. Robertson, B. S. Cain, A. H. Harken, and A. Banerjee. Protein kinase C isoform diversity in preconditioning. J. Surg. Res. 69: 183-187, 1997[Medline].

190.   Meldrum, D. R., J. C. Cleveland, B. C. Sheridan, R. T. Rowland, A. Banerjee, and A. H. Harken. Cardiac preconditioning with calcium: clinically accessible myocardial protection. J. Thorac. Cardiovasc. Surg. 112: 778-786, 1996[Abstract/Free Full Text].

191.   Meldrum, D. R., J. C. Cleveland, B. C. Sheridan, R. T. Rowland, A. Banerjee, and A. H. Harken. Cardiac surgical implications of calcium dyshomeostasis in the heart. Ann. Thorac. Surg. 61: 1273-1280, 1996[Abstract/Free Full Text].

192.   Meldrum, D. R., J. C. Cleveland, B. C. Sheridan, R. T. Rowland, A. Banerjee, and A. H. Harken. Differential effects of adenosine preconditioning on the post-ischemic rat myocardium. J. Surg. Res. 65: 156-164, 1996.

193.   Meldrum, D. R., J. C. Cleveland, B. C. Sheridan, R. T. Rowland, C. H. Selzman, A. Banerjee, and A. H. Harken. Alpha-adrenergic activation of myocardial NFkappa B during hemorrhage. J. Surg. Res. 69: 268-276, 1997[Medline].

194.   Meldrum, D. R., C. A. Dinarello, J. C. Cleveland, L. Shapiro, B. C. Sheridan, and A. H. Harken. P38 MAP kinase-mediated myocardial TNF-alpha production contributes to post-ischemic cardiac dysfunction (Abstract). Circulation 96: I-556, 1997.

195.   Meldrum, D. R., M. B. Mitchell, A. Banerjee, and A. H. Harken. Cardiac preconditioning: induction of endogenous tolerance to ischemia-reperfusion injury. Arch. Surg. 128: 1208-1211, 1993[Abstract/Free Full Text].

196.   Meldrum, D. R., R. Shenkar, B. C. Sheridan, B. S. Cain, E. Abraham, and A. H. Harken. Hemorrhage activates myocardial NFkappa B and increases tumor necrosis factor in the heart. J. Mol. Cell. Cardiol. 29: 2849-2854, 1997[Medline].

197.   Meldrum, D. R., B. C. Sheridan, J. C. Cleveland, D. A. Fullerton, A. Banerjee, and A. H. Harken. Neutrophils are required for endotoxin induced myocardial cross-tolerance to ischemia-reperfusion injury. Arch. Surg. 131: 1203-1208, 1996[Abstract/Free Full Text].

198.   Meng, X., L. Ao, J. M. Brown, D. A. Fullerton, A. Banerjee, and A. H. Harken. Nitric oxide synthase is not involved in cardiac contractile dysfunction in a rat model of endotoxemia without shock. Shock 7: 111-118, 1997[Medline].

199.   Meng, X., J. M. Brown, L. Ao, A. Banerjee, and A. H. Harken. Norepinephrine induces cardiac heat shock protein and delayed cardioprotection in the rat through alpha 1-adrenoceptors. Cardiovasc. Res. 32: 374-383, 1996[Abstract/Free Full Text].

200.   Meng, X., J. M. Brown, L. Ao, W. Franklin, A. Banerjee, and A. H. Harken. Heat shock protein 70 contributes to the induced cardiac resistance to bacterial lipopolysaccharide in the rat. Am. J. Physiol. 271 (Cell Physiol. 40): C1316-C1324, 1996[Abstract/Free Full Text].

201.   Mihm, S., D. Galter, and W. Droge. Modulation of transcription factor NFkappa B activity by intracellular glutathione levels and by variations of the extracellular cysteine supply. FASEB J. 9: 246-252, 1995[Abstract].

202.   Mitchell, M. B., X. Meng, C. G. Parker, A. H. Harken, and A. Banerjee. Preconditioning of isolated rat heart is mediated by protein kinase C. Circ. Res. 76: 73-81, 1995[Abstract/Free Full Text].

203.   Mohler, K. M., P. R. Sleath, J. N. Fitzner, D. P. Cerretti, M. Alderson, S. S. Kerwar, D. S. Tolerance, C. Otten-Evans, T. Greenstreet, and K. Weerawarna. Protection against a lethal dose of endotoxin by an inhibitor of TNF processing. Nature 370: 218-220, 1994[Medline].

204.   Mohler, K. M., D. S. Torrance, C. A. Smith, R. G. Goodwin, K. E. Stremler, V. P. Fung, H. Madani, and M. B. Widmer. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J. Immunol. 151: 1548-1561, 1993[Abstract].

205.   Moodie, S. A., B. M. Willumsen, M. J. Weber, and A. Wolfman. Complexes of Ras.GTP with Raf-1 and mitogen activated protein kinase kinase. Science 260: 1658-1661, 1993[Abstract/Free Full Text].

206.   Mosialos, G., M. Birkenbach, R. Yalamanchili, T. VanArsdale, C. Ware, and E. Kieff. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80: 389-399, 1995[Medline].

207.   Muller, J. M., H. W. Ziegler-Heitbrock, and P. A. Baeuerle. Nuclear factor kappa B, a mediator of LPS effects. Immunobiology 187: 233-256, 1993[Medline].

208.   Murray, D. R., and G. L. Freeman. Tumor necrosis factor-alpha induces a biphasic effect on myocardial contractility in conscous dogs. Circ. Res. 78: 154-160, 1995[Abstract/Free Full Text].

209.   Murry, C., R. Jennings, and K. Reimer. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124-1136, 1986[Abstract/Free Full Text].

210.   Nakanishi, K., J. Vinten-Johansen, D. J. Lefer, Z. Zhao, W. C. Fowler, D. S. McGee, and W. E. Johnston. Intracoronary L-arginine during reperfusion improves endothelial function and reduces infarct size. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1650-H1658, 1992[Abstract/Free Full Text].

211.   Nakano, M., A. A. Knowlton, T. Yokoyama, W. Lesslauer, and D. L. Mann. Tumor necrosis factor-alpha -induced expression of heat shock protein 72 in adult feline cardiac myocytes. Am. J. Physiol. 270 (Heart Circ. Physiol. 39): H1231-H1239, 1996[Abstract/Free Full Text].

212.   Nakano, M., D. L. Mann, and A. A. Knowlton. Blocking the endogenous increase in HSP72 increases susceptibility to hypoxia and reoxygenation in isolated adult feline cardiomyocytes. Circulation 95: 1523-1531, 1997[Abstract/Free Full Text].

213.   Narula, J., N. Haider, R. Virmani, T. G. DiSalvo, F. D. Kolodgie, R. J. Hajjar, U. Schmidt, M. J. Semigran, G. W. Dec, and B. A. Khaw. Apoptosis in myocytes in end-stage heart failure. N. Engl. J. Med. 335: 1182-1189, 1996[Abstract/Free Full Text].

214.   Natanson, C., W. D. Hoffman, A. F. Suffredini, P. Q. Eichacker, and R. L. Dranner. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann. Intern. Med. 120: 771-783, 1994[Abstract/Free Full Text].

215.   Nelson, D. W., J. M. Brown, A. Banerjee, D. D. Bensard, K. B. Rogers, C. R. Locke-Winter, B. O. Anderson, and A. H. Harken. Pretreatment with a nontoxic derivative of endotoxin (MPL) induces functional protection against cardiac ischemia reperfusion injury. Surgery 110: 365-369, 1991[Medline].

216.   Neumann, F. J., I. Ott, M. Gawaz, G. Richardt, H. Holzapfel, M. Jochum, and A. Schomig. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 92: 748-755, 1995[Abstract/Free Full Text].

217.   Nishizuka, Y. Intracellular signalling by hydrolysis of phospholipids and activation of protein kinase C. Science 258: 607-613, 1992[Abstract/Free Full Text].

218.   Nussler, A. K., and T. R. Billiar. Inflammation, immunoregulation, and inducible nitric oxide synthase. J. Leukoc. Biol. 54: 171-178, 1993[Abstract].

219.   Obeid, L. M., C. M. Linardie, L. A. Karolak, and Y. A. Hannun. Programmed cell death induced by ceramide. Science 259: 1769-1771, 1993[Abstract/Free Full Text].

220.   Ohta, H., Y. Yatomi, E. A. Sweeney, S. I. Hakomori, and Y. Igarashi. A possible role of sphingosine in induction of apoptosis by tumor necrosis factor-alpha in human neutrophils. FEBS Lett. 355: 267-270, 1994[Medline].

221.   Okusawa, S., J. A. Gelfand, T. Ikejima, R. J. Conolly, and C. A. Dinarello. Interleukin 1 induces a shock-like state in rabbits: synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J. Clin. Invest. 81: 1162-1172, 1988.

222.   Olivetti, G., R. Abbi, F. Quaini, J. Kajstura, W. Cheng, J. A. Nitahara, E. Quaini, C. DiLoreto, C. A. Beltrami, S. Krajewski, J. C. Reed, and P. Anversa. Apoptosis in the failing human heart. N. Engl. J. Med. 336: 1131-1141, 1997[Abstract/Free Full Text].

223.   Oral, H., G. W. Dorn, and D. L. Mann. Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J. Biol. Chem. 272: 4836-4842, 1997[Abstract/Free Full Text].

224.   Oral, H., S. Kapadia, M. Nakano, G. Torre-Amione, J. Lee, D. Lee-Jackson, J. B. Young, and D. L. Mann. Tumor necrosis factor-alpha and the failing human heart. Clin. Cardiol. 18: S20-S27, 1995.

225.   Ottani, F., M. Galvani, D. Ferrini, F. Sorbello, P. Limonetti, D. Pantoli, and F. Rusticali. Prodromal angina limits infarct size. Circulation 91: 291-297, 1995[Abstract/Free Full Text].

226.   Packer, M. Is tumor necrosis factor an important neurohormoral mechanism in chronic heart failure? Circulation 92: 1379-1382, 1995[Free Full Text].

227.   Pan, G., K. O'Rourke, A. M. Chinnaiyan, R. Gentz, R. Ebner, J. Ni, and V. M. Dixit. The receptor for the cytotoxic ligand TRAIL. Science 276: 111-113, 1997[Abstract/Free Full Text].

228.   Parker, M. M., K. E. McCarthy, F. P. Ognibene, and J. E. Parillo. Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest 97: 126-131, 1990[Abstract/Free Full Text].

229.   Parker, M. M., J. H. Shelhammer, S. L. Bacharach, M. V. Green, C. Natanson, T. M. Frederick, B. A. Damske, and J. E. Parillo. Profound but reversible myocardial depression in patients with septic shock. Ann. Intern. Med. 100: 483-490, 1984.

230.   Parmely, M. J., W. W. Zhou, C. K. Edwards, D. R. Borcherding, R. S. Silverstein, and D. C. Morrison. Adenosine and a related carbocyclic nucleoside analogue selectively inhibit tumor necrosis factor-alpha production and protect mice against endotoxin challenge. J. Immunol. 151: 389-396, 1993[Abstract].

231.   Parrillo, J. E., C. Burch, J. H. Shelhammer, M. M. Parker, C. Natanson, and W. Schuette. A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial performance. J. Clin. Invest. 76: 1539-1553, 1985.

232.   Pennica, D., K. L. King, and K. J. Shaw. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc. Natl. Acad. Sci. USA 92: 1142-1146, 1995[Abstract/Free Full Text].

233.   Peterson, S. M., C. T. Strzalka, J. A. Johnkoski, B. Noble, J. Gorfien, E. L. Hoover, and H. Bergsland. Combination of cyclosporine and splenectomy suppresses interleukin-6 production and major histocombatibility complex class II expression and prolongs cardiac xenograft survival. J. Thorac. Cardiovasc. Surg. 107: 1001-1005, 1994[Abstract/Free Full Text].

234.   Piot, C. P., D. Padmanaban, P. C. Ursell, R. E. Sievers, and C. L. Wolfe. Ischemic preconditioning decreases apoptosis in rat hearts in vivo. Circulation 96: 1598-1604, 1997[Abstract/Free Full Text].

235.   Plumier, J. L., B. M. Ross, R. W. Currie, C. E. Angelidis, H. Kazlaris, G. Kollias, and G. N. Pagoulatos. Transgenic mice expressing the human heat shock protein 70 have improved post-ischemic myocardial recovery. J. Clin. Invest. 95: 1854-1860, 1995.

236.   Pugin, J., C. C. Schurer-Maly, D. Leureq, A. Moriarty, R. J. Ulevitch, and P. S. Tobias. Lipopolysaccharide (LPS) activation of human endothelial and epithelial cells is mediated by LPS binding protein and soluble CD14. Proc. Natl. Acad. Sci. USA 90: 2744-2748, 1993[Abstract/Free Full Text].

237.   Reimann, T., D. Buscher, R. A. Hipskind, S. Krautwald, M. M. Lohmann, and M. Baccarini. Lipopolysaccharide induces activation of of the Raf-1/MAP kinase pathway. A putative role for Raf-1 in the induction of the IL-1 beta and TNF-alpha genes. J. Immunol. 153: 5740-5749, 1994[Abstract].

238.   Ribeiro, S. P., J. Villar, G. P. Downey, J. D. Edelson, and A. S. Slutsky. Effects of the stress response in septic rats and LPS-stimulated alveolar macrophages: evidence for TNF-alpha posttranslational regulation. Am. J. Respir. Crit. Care Med. 154: 1843-1850, 1996[Abstract].

239.   Rowland, R. T., J. M. Brown, X. Meng, L. S. Terada, and A. H. Harken. The mechanism of immature myocardial tolerance to ischemia: phenotypic differences in antioxidants, stress proteins and oxidases. Surgery 118: 446-452, 1995[Medline].

240.   Rowland, R. T., J. C. Cleveland, X. Meng, A. H. Harken, and J. M. Brown. Potential gene therapy strategies in the treatment of cardiovascular disease. Ann. Thorac. Surg. 60: 721-728, 1995[Abstract/Free Full Text].

241.   Ruddle, N. H., and B. H. Waksman. Cytotoxic effect of lymphocyte-antigen interaction in delayed hypersensitivity. Science 157: 1060-1062, 1967[Abstract/Free Full Text].

242.   Sabbadini, R. A., R. Betto, A. Teresi, G. Fachechi-Cassano, and G. Salviati. The effects of sphingosine on sarcoplasmic reticulum membrane calcium release. J. Biol. Chem. 267: 15475-15484, 1992[Abstract/Free Full Text].

243.  Sadoff, J. Soluble TNF receptors. Third International Congress of the Immune Consequences of Trauma, Shock, and Sepsis. Munich, Germany, 1994.

244.   Sanghera, J. S., S. L. Weinstein, M. Aluwalia, J. Girn, and S. L. Pelech. Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages. J. Immunol. 156: 4457-4465, 1996[Abstract].

245.   Saraste, A., K. Pulkki, M. Kallajoki, K. Henriksen, M. Parvinen, and L. M. Voipio-Pulkki. Apoptosis in human acute myocardial infarction. Circulation 95: 320-323, 1997[Abstract/Free Full Text].

246.   Sarih, M., V. Souvannavong, and A. Adam. Nitric oxide synthase induces macrophage death by apoptosis. Biochem. Biophys. Res. Commun. 191: 503-509, 1993[Medline].

247.   Schluter, K. D., M. Weber, E. Schraven, and H. M. Piper. NO donor SIN-1 protects against reoxygenation-induced cardiomyocyte injury by a dual action. Am. J. Physiol. 267 (Heart Circ. Physiol. 36): H1461-H1466, 1994[Abstract/Free Full Text].

248.   Schmidt, K. N., E. B. Traenckner, B. Meier, and P. A. Baeuerle. Induction of oxidative stress by okadaic acid is required for activation of transcription factor NFkappa B. J. Biol. Chem. 270: 27136-27142, 1995[Abstract/Free Full Text].

249.   Schoenberg, M. H., B. Poch, D. Moch, M. Marzinzig, E. Marzinzig, T. Mattfeldt, H. Gruber, and H. G. Beger. Effect of acadesine treatment on postischemic damage to the small intestine. Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H1752-H1759, 1995[Abstract/Free Full Text].

250.   Schulz, R., D. L. Panas, R. Catena, S. Moncada, P. M. Olley, and G. D. Lopaschuk. The role of nitric oxide in cardiac depression induced by interleukin-1beta and tumor necrosis factor-alpha . Br. J. Pharmacol. 114: 27-34, 1995[Medline].

251.   Shakov, A. N., M. A. Collart, P. Vassalli, S. A. Nedospasov, and C. V. Jongeneel. Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor-alpha gene in primary macrophages. J. Exp. Med. 171: 35-47, 1990[Abstract/Free Full Text].

252.   Shapira, L., S. Takashiba, C. Champagne, S. Amar, and T. E. V. Dyke. Involvement of protein kinase C and protein tyrosine kinase in the lipopolysaccharide-induced TNF-alpha and IL-1 beta production by human moncytes. J. Immunol. 153: 1818-1824, 1994[Abstract].

253.   Shapiro, L., and C. A. Dinarello. Osmotic regulation of cytokine synthesis in vitro. Proc. Natl. Acad. Sci. USA 92: 12230-12234, 1995[Abstract/Free Full Text].

254.   Shen, H. M., L. X. Sha, J. L. Kennedy, and D. W. Ou. Adrenergic receptors regulate macrophage secretion. Int. J. Immunopharmacol. 16: 905-910, 1994[Medline].

255.   Sheridan, B. C., R. C. McIntyre, D. R. Meldrum, J. C. Cleveland, J. Agrafojo, J. H. Eisenach, A. H. Harken, and D. A. Fullerton. Antibody-mediated neutrophil depletion preserves pulmonary vasomotor function. J. Surg. Res. 62: 74-78, 1996[Medline].

256.   Sherman, A. J., C. A. Davis, F. J. Klocke, K. R. Harris, G. Srinivasan, A. S. Yaacoub, D. A. Quinn, K. A. Ahlin, and J. J. Jang. Blockade of nitric oxide synthesis reduces myocardial oxygen consumption in vivo. Circulation 95: 1328-1334, 1997[Abstract/Free Full Text].

257.   Sobotka, P. A., J. McMannis, R. I. Fisher, D. G. Stein, and J. X. Thomas. Effects of interleukin 2 on cardiac function in the isolated rat heart. J. Clin. Invest. 86: 845-850, 1990.

258.   Squadrito, F., D. Altavilla, B. Zingarelli, M. Ioculano, G. Calapai, G. M. Campo, A. Miceli, and A. P. Caputi. Tumor necrosis factor involvement in myocadial ischaemia-reperfusion injury. Eur. J. Pharmacol. 237: 223-230, 1993[Medline].

259.   Steenbergen, C., T. Fralix, and E. Murphy. Role of increased cytosolic calcium concentration in myocardial ischemic injury. Basic Res. Cardiol. 88: 456-470, 1993[Medline].

260.   Steenbergen, C., M. E. Perlman, R. E. London, and E. Murphy. Mechanism of preconditioning: ionic alterations. Circ. Res. 72: 112-125, 1993[Abstract/Free Full Text].

261.   Stein, B., P. Frank, W. Schmitz, H. Scholz, and M. Thoenes. Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J. Mol. Cell. Cardiol. 28: 1631-1639, 1996[Medline].

262.   Steinshamn, S., M. H. Bemelmans, L. J. vanTits, K. Bergh, W. A. Buurman, and A. Waage. TNF receptors in murine Candida albicans infection: evidence for an important role of TNF receptor p55 in antifungal defense. J. Immunol. 157: 2155-2159, 1996[Abstract].

263.   Steller, H. Mechanisms and genes of cellular suicide. Science 267: 1445-1449, 1995[Abstract/Free Full Text].

264.   Suzuki, K., Y. Sawa, Y. Kaneda, H. Ichikawa, R. Shirakura, and H. Matsuda. In vivo gene transfection with heat shock protein 70 enhances myocardial tolerance to ischemia-reperfusion injury in the rat. J. Clin. Invest. 99: 1645-1650, 1997[Medline].

265.   Sweet, M. J., and D. A. Hume. Endotoxin signal transduction in macrophages. J. Leukoc. Biol. 60: 8-26, 1996[Abstract].

266.   Szekeres, L., J. G. Papp, Z. Szilvássy, E. Udvary, and A. Vegh. Moderate stress by cardiac pacing may induce both short term and long term cardioprotection. Cardiovasc. Res. 27: 593-596, 1993[Medline].

267.   Tanaka, M., H. Ito, S. Adachi, T. Akimoto, T. Nishikawa, T. Kasajima, F. Marumo, and M. Hiroe. Hypoxia induces apoptosis with enhanced expression of fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ. Res. 75: 426-433, 1994[Abstract/Free Full Text].

268.   Thompson, C. B. Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456-1462, 1995[Abstract/Free Full Text].

269.   Thornton, J., S. Striplin, G. S. Liu, A. Swafford, A. W. H. Stanley, D. M. Van Winkle, and J. M. Downey. Inhibition of protein synthesis does not block myocardial protection afforded by preconditioning. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H1822-H1825, 1990[Abstract/Free Full Text].

270.   Thornton, J. D., G. S. Liu, R. A. Olsson, and J. M. Downey. Intravenous pretreatment with A1 selective adenosine analogues protects the heart against infarction. Circulation 85: 659-665, 1992[Abstract/Free Full Text].

271.   Tong, L., S. Pav, D. M. White, S. Rogers, K. M. Crane, C. L. Cywin, M. L. Brown, and C. A. Pargellis. A highly specific inhibitor of human p38 kinase binds in the ATP pocket. Nat. Struct. Biol. 4: 311-316, 1997[Medline].

272.   Torre-Amione, G., S. Kapadia, C. Benedict, H. Oral, J. B. Young, and D. L. Mann. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the studies of left ventricular dysfunction (SOLVD). J. Am. Coll. Cardiol. 27: 1201-1206, 1996[Abstract].

273.   Torre-Amione, G., S. Kapadia, J. Lee, R. D. Bies, R. Lebovitz, and D. L. Mann. Expression and functional significance of tumor necrosis factor receptors in human myocardium. Circulation 92: 1487-1493, 1995[Abstract/Free Full Text].

274.   Torre-Amione, G., S. Kapadia, J. Lee, J. B. Durand, R. D. Bies, J. B. Young, and D. L. Mann. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 93: 704-711, 1996[Abstract/Free Full Text].

275.   Tracey, K. J., B. Beutler, S. F. Lowry, J. Merryweather, S. Wolpe, I. W. Milsark, R. J. Hariri, T. J. Fahey, A. Zentella, J. D. Albert, G. T. Shires, and A. Cerami. Shock and tissue injury induced by recombinant human cachectin. Science 234: 470-474, 1986[Abstract/Free Full Text].

276.   Tracey, K. J., Y. Fong, D. G. Hesse, K. R. Manogue, A. T. Lee, G. C. Kuo, S. F. Lowry, and A. Cerami. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 330: 662-664, 1987[Medline].

277.   Trede, N. S., A. V. Tsytsykova, T. Chatila, A. E. Goldfeld, and R. S. Gehas. Transcriptional activation of the human TNF-alpha promoter by superantigen in human monocytic cells: role of NFkappa B. J. Immunol. 155: 902-908, 1995[Abstract].

278.   Ulevitch, R. J., and P. S. Tobias. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol. 13: 437-457, 1995[Medline].

279.   Ulich, T. R., M. J. Fann, P. H. Patterson, J. H. Williams, B. Samal, J. DelCastillo, S. Yin, K. Guo, and D. G. Remick. Intratracheal injection of LPS and cytokines. V. LPS induces expression of LIF and LIF inhibits acute inflammation. Am. J. Physiol. 267 (Lung Cell. Mol. Physiol. 11): L442-L446, 1994[Abstract/Free Full Text].

280.   Umansky, S. R., O. Pisarenko, L. Serebryakova, I. Studneva, O. Tsktishvilli, S. Khutzian, T. Sukhova, A. Lichtenstein, N. Ossina, and M. Kiefer. Dog cardiomyocyte death induced in vivo by ischemia and reperfusion. Basic Appl. Myol. 6: 227-235, 1996.

281.   Ungureanu-Longrois, D., J. L. Balligand, I. Okada, W. W. Simmons, L. Kobzik, C. J. Lowenstein, S. L. Kunkel, T. Michel, R. A. Kelly, and T. W. Smith. Induction of nitric oxide synthase activity by cytokines in ventricular myocytes is necessary but not sufficient to decrease contractile responsiveness to beta -adrenergic agonists. Circ. Res. 77: 494-502, 1995[Abstract/Free Full Text].

282.   Van, A. L., M. Barr, S. Marcus, A. Polverino, and M. Wigler. Complex formation between Ras and Raf and other protein kinases. Proc. Natl. Acad. Sci. USA 90: 6213-6217, 1993[Abstract/Free Full Text].

283.   Vanderabeele, P., W. Deelereq, R. Beyaert, and W. Fiers. Two tumor necrosis factor receptors: structure and function. Trends Cell Biol. 5: 392-399, 1995.[Medline]

284.   VanderPoll, T., S. M. Coyle, K. Barbosa, C. C. Braxton, and S. F. Lowry. Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J. Clin. Invest. 97: 713-719, 1996[Medline].

285.   VanHoffen, E., D. VanWichen, I. Stuij, N. DeJonge, C. Klopping, and J. Lahpor. In situ expression of cytokines in human heart allografts. Am. J. Pathol. 149: 1991-2003, 1996[Abstract].

286.   VanZee, K. J., T. Kohno, E. Fisher, C. S. Rock, L. L. Moldawer, and S. F. Lowry. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor-alpha in vivo and in vitro. Proc. Natl. Acad. Sci. USA 89: 4845-4849, 1992[Abstract/Free Full Text].

287.   Vaux, D. L., and A. Strasser. The molecular biology of apoptosis. Proc. Natl. Acad. Sci. USA 93: 2239-2244, 1996[Abstract/Free Full Text].

288.   Wakabayashi, G., J. G. Cannon, J. A. Gelfand, B. D. Clark, K. Aiura, J. F. Burke, S. M. Wolffe, and C. A. Dinarello. Altered IL-1 and TNF production and secretion during pyrogenic tolerance to LPS in rabbits. Am. J. Physiol. 267 (Regulatory Integrative Comp. Physiol. 36): R329-R336, 1994[Abstract/Free Full Text].

289.   Walker, D. M., and D. M. Yellon. Ischemic preconditioning: from mechanisms to exploitation. Cardiovasc. Res. 26: 734-739, 1992[Free Full Text].

290.   Walker, G., D. Kunz, W. Pignat, H. vandenBosch, and J. Pfeilshifter. Pyrrolidine dithiocarbamate differentially affects cytokine- and cAMP-induced expression of group II phospholipase A2 in rat renal mesangial cells. FEBS Lett. 8: 218-222, 1995.

291.   Wan, S., J. M. DeSmet, L. Barvais, M. Golstein, J. L. Vincent, and J. L. LeClerc. Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. 112: 806-811, 1996[Abstract/Free Full Text].

292.   Wang, P., Z. Ba, D. R. Meldrum, and I. H. Chaudry. Diltiazem restores cardiac output and improves renal function following hemorrhage and resuscitation. Am. J. Physiol. 262 (Heart Circ. Physiol. 31): H1435-H1440, 1992[Abstract/Free Full Text].

293.   Wang, P., and J. L. Zweier. Measurement of nitric oxide and peroxynitrite generation in the postischemic heart: evidence for peroxynitrite-mediated reperfusion injury. J. Biol. Chem. 271: 29223-29230, 1996[Abstract/Free Full Text].

294.   Waring, P. M., L. J. Waring, T. Billington, and D. Metcalf. Leukemia inhibitory factor protects against experimental lethal Escherichia coli septic shock in mice. Proc. Natl. Acad. Sci. USA 92: 1337-1341, 1995[Abstract/Free Full Text].

295.   Weil, M. H., L. D. MacLean, M. B. Visscher, and W. W. Spink. Studies on the circulatory changes in the dog produced by endotoxin from gram-negative microorganisms. J. Clin. Invest. 35: 1191-1198, 1956.

296.   Weinstein, S. L., M. R. Gold, and A. L. DeFranco. Bacterial lipopolysaccharide stimulates protein tyrosine phosphorylation in macrophages. Proc. Natl. Acad. Sci. USA 88: 4148-4152, 1991[Abstract/Free Full Text].

297.   Weinstein, S. L., C. H. June, and A. L. DeFranco. Lipopolysaccharide-induced protein tyrosine phosphorylation in human macrophages is mediated by CD14. J. Immunol. 151: 3829-3838, 1993[Abstract].

298.   Weinstein, S. L., J. S. Sanghera, K. Lemke, A. L. DeFranco, and S. L. Pelech. Bacterial lipopolysaccharide induces tyrosine phosphorylation and activation of mitogen-activated protein kinases in macrophages. J. Biol. Chem. 267: 14955-14962, 1992[Abstract/Free Full Text].

299.  Wherry, J., R. Wenzel, R. Wunderink, H. Silverman, T. Perl, and S. Nasraway. Monoclonal antibody to human tumor necrosis factor (TNF MAb): multicenter efficacy and safety study in patients with the sepsis syndrome. Thirty-Third Interscience Conference on Antimicrobial Agents and Chemotherapy. New Orleans, LA, 1993.

300.   Wiegman, K., S. Schutze, E. Kampen, A. Himmler, T. Machleidt, and M. Kronke. Human 55-kDa receptor for tumor necrosis factor coupled to signal transduction cascades. J. Biol. Chem. 267: 17997-18001, 1992[Abstract/Free Full Text].

301.   Winter, C. B., J. C. Cleveland, K. L. Butler, D. B. Bensard, M. B. Mitchell, A. H. Harken, and A. Banerjee. Facilitative interactions between noradrenergic and purinergic signaling during preconditioning of the rat heart. J. Mol. Cell. Cardiol. 29: 163-173, 1997[Medline].

302.   Yellon, D. M., and G. F. Baxter. A second window of protection or delayed preconditioning: future horizons for myocardial protection? J. Mol. Cell. Cardiol. 27: 1023-1034, 1995[Medline].

303.   Yokoyama, T., M. Nakano, J. L. Bednarczyk, B. W. McIntyre, M. Entman, and D. L. Mann. Tumor necrosis factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes. Circulation 95: 1247-1252, 1997[Abstract/Free Full Text].

304.   Yokoyama, T., L. Vaca, R. D. Rossen, W. Durante, P. Hazarika, and D. L. Mann. Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J. Clin. Invest. 92: 2303-2312, 1993.

305.   Yoshida, K., T. Taga, M. Saito, S. Suematsu, A. Kumanogoh, T. Tanaka, H. Fujiwara, M. Hirata, T. Yamagami, T. Nakahata, T. Hirabayashi, Y. Yoneda, K. Tanaka, W. Z. Wang, C. Mori, K. Shiota, N. Yoshida, and T. Kishimoto. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematologic disorders. Proc. Natl. Acad. Sci. USA 93: 407-411, 1996[Abstract/Free Full Text].

306.   Zucchi, R., S. Ronca-Testoni, Y. Gongyuan, P. Galbani, G. Ronca, and M. Mariani. Postischemic changes in cardiac sarcoplasmic reticulum calcium channels: a possible mechanism of ischemic preconditioning. Circ. Res. 76: 1049-1056, 1995[Abstract/Free Full Text].

307.   Zuckerman, S. H., G. F. Evans, and L. D. Butler. Endotoxin tolerance: Independent regulation of IL-1 and TNF expression. Infect. Immun. 41: 2774-2780, 1991.


AJP Regul Integr Compar Physiol 274(3):R577-R595
0363-6119/98 $5.00 Copyright © 1998 the American Physiological Society



This article has been cited by other articles:


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
L. J. Jobe, G. C. Melendez, S. P. Levick, Y. Du, G. L. Brower, and J. S. Janicki
TNF-{alpha} inhibition attenuates adverse myocardial remodeling in a rat model of volume overload
Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1462 - H1468.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
D. B. Murray, R. McMillan, G. L. Brower, and J. S. Janicki
ETA selective receptor antagonism prevents ventricular remodeling in volume-overloaded rats
Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H109 - H116.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
B. R. Weil, A. M. Abarbanell, J. L. Herrmann, Y. Wang, and D. R. Meldrum
High glucose concentration in cell culture medium does not acutely affect human mesenchymal stem cell growth factor production or proliferation
Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2009; 296(6): R1735 - R1743.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. Wang, Y. Wang, B. Weil, A. Abarbanell, J. Herrmann, J. Tan, M. Kelly, and D. R. Meldrum
Estrogen receptor {beta} mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia
Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2009; 296(4): R972 - R978.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
L. Zou, S. Yang, V. Champattanachai, S. Hu, I. H. Chaudry, R. B. Marchase, and J. C. Chatham
Glucosamine improves cardiac function following trauma-hemorrhage by increased protein O-GlcNAcylation and attenuation of NF-{kappa}B signaling
Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H515 - H523.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
H. Ishii, T. Amano, T. Matsubara, and T. Murohara
Pharmacological Intervention for Prevention of Left Ventricular Remodeling and Improving Prognosis in Myocardial Infarction
Circulation, December 16, 2008; 118(25): 2710 - 2718.
[Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
Z. Yang, J. Linden, S. S. Berr, I. L. Kron, G. A. Beller, and B. A. French
Timing of adenosine 2A receptor stimulation relative to reperfusion has differential effects on infarct size and cardiac function as assessed in mice by MRI
Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2328 - H2335.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
T. A. Markel, Y. Wang, J. L. Herrmann, P. R. Crisostomo, M. Wang, N. M. Novotny, C. M. Herring, J. Tan, T. Lahm, and D. R. Meldrum
VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function
Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2308 - H2314.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
W. N. Duran
The double-edge sword of TNF-{alpha} in ischemia-reperfusion injury
Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2221 - H2222.
[Full Text] [PDF]


Home page
Circ. Res.Home page
F. R. Heinzel, P. Gres, K. Boengler, A. Duschin, I. Konietzka, T. Rassaf, J. Snedovskaya, S. Meyer, A. Skyschally, M. Kelm, et al.
Inducible Nitric Oxide Synthase Expression and Cardiomyocyte Dysfunction During Sustained Moderate Ischemia in Pigs
Circ. Res., November 7, 2008; 103(10): 1120 - 1127.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. Lahm, P. R. Crisostomo, T. A. Markel, M. Wang, Y. Wang, J. Tan, and D. R. Meldrum
Selective estrogen receptor-{alpha} and estrogen receptor-{beta} agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1486 - R1493.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
Y. Wang, P. R. Crisostomo, M. Wang, T. A. Markel, N. M. Novotny, and D. R. Meldrum
TGF-{alpha} increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1115 - R1123.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. A. Markel, P. R. Crisostomo, M. Wang, Y. Wang, T. Lahm, N. M. Novotny, J. Tan, and D. R. Meldrum
TNFR1 signaling resistance associated with female stem cell cytokine production is independent of TNFR2-mediated pathways
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1124 - R1130.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
P. R. Crisostomo, A. M. Abarbanell, M. Wang, T. Lahm, Y. Wang, and D. R. Meldrum
Embryonic stem cells attenuate myocardial dysfunction and inflammation after surgical global ischemia via paracrine actions
Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1726 - H1735.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
K. Shivakumar, S. J. Sollott, M. Sangeetha, S. Sapna, B. Ziman, S. Wang, and E. G. Lakatta
Paracrine effects of hypoxic fibroblast-derived factors on the MPT-ROS threshold and viability of adult rat cardiac myocytes
Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2653 - H2658.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. A. Markel, M. Wang, P. R. Crisostomo, M. C. Manukyan, J. A. Poynter, and D. R. Meldrum
Neonatal stem cells exhibit specific characteristics in function, proliferation, and cellular signaling that distinguish them from their adult counterparts
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1491 - R1497.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Cell Physiol.Home page
D. Shan, R. B. Marchase, and J. C. Chatham
Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes
Am J Physiol Cell Physiol, March 1, 2008; 294(3): C833 - C841.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
M. Gomaraschi, L. Calabresi, G. Rossoni, S. Iametti, G. Franceschini, J. A. Stonik, and A. T. Remaley
Anti-Inflammatory and Cardioprotective Activities of Synthetic High-Density Lipoprotein Containing Apolipoprotein A-I Mimetic Peptides
J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 776 - 783.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. A. Markel, P. R. Crisostomo, M. Wang, J. L. Herrmann, A. M. Abarbanell, and D. R. Meldrum
Right ventricular TNF resistance during endotoxemia: the differential effects on ventricular function
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R1893 - R1897.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
R. Jiang, A. Zatta, H. Kin, N. Wang, J. G. Reeves, J. Mykytenko, J. Deneve, Z.-Q. Zhao, R. A. Guyton, and J. Vinten-Johansen
PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in in vivo rat hearts
Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2845 - H2852.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
A. H. Harken
The world of inhibitory {kappa}B
Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2624 - H2625.
[Full Text] [PDF]


Home page
Am. J. Physiol. Gastrointest. Liver Physiol.Home page
T. A. Markel, P. R. Crisostomo, M. Wang, C. M. Herring, and D. R. Meldrum
Activation of individual tumor necrosis factor receptors differentially affects stem cell growth factor and cytokine production
Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G657 - G662.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
M. Wang, W. Zhang, P. Crisostomo, T. Markel, K. K. Meldrum, X. Y. Fu, and D. R. Meldrum
Endothelial STAT3 plays a critical role in generalized myocardial proinflammatory and proapoptotic signaling
Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2101 - H2108.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
N. C. Moss, W. E. Stansfield, M. S. Willis, R.-H. Tang, and C. H. Selzman
IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury
Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2248 - H2253.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Endocrinol. Metab.Home page
M. Wang, W. Zhang, P. Crisostomo, T. Markel, K. K. Meldrum, X. Y. Fu, and D. R. Meldrum
Sex differences in endothelial STAT3 mediate sex differences in myocardial inflammation
Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E872 - E877.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
S. Li, X. Jiao, L. Tao, H. Liu, Y. Cao, B. L. Lopez, T. A. Christopher, and X. L. Ma
Tumor necrosis factor-{alpha} in mechanic trauma plasma mediates cardiomyocyte apoptosis
Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1847 - H1852.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Cell Physiol.Home page
W. Schoner and G. Scheiner-Bobis
Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth
Am J Physiol Cell Physiol, August 1, 2007; 293(2): C509 - C536.
[Abstract] [Full Text] [PDF]


Home page
J. Appl. Physiol.Home page
D. L. Carlson, D. L. Maass, J. White, P. Sikes, and J. W. Horton
Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury
J Appl Physiol, July 1, 2007; 103(1): 323 - 330.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
M. Fernandez-Velasco, G. Ruiz-Hurtado, O. Hurtado, M. A. Moro, and C. Delgado
TNF-{alpha} downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation
Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H238 - H245.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
D. K. Glover, M. Ruiz, K. Takehana, F. D. Petruzella, J. M. Rieger, T. L. Macdonald, D. D. Watson, J. Linden, and G. A. Beller
Cardioprotection by adenosine A2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia
Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3164 - H3171.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Gastrointest. Liver Physiol.Home page
T. A. Markel, P. R. Crisostomo, M. Wang, C. M. Herring, T. Lahm, K. K. Meldrum, K. D. Lillemoe, F. J. Rescorla, and D. R. Meldrum
Iron chelation acutely stimulates fetal human intestinal cell production of IL-6 and VEGF while decreasing HGF: the roles of p38, ERK, and JNK MAPK signaling
Am J Physiol Gastrointest Liver Physiol, April 1, 2007; 292(4): G958 - G963.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
M. Wang, T. Markel, P. Crisostomo, C. Herring, K. K. Meldrum, K. D. Lillemoe, and D. R. Meldrum
Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta
Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1694 - H1699.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. Tan, D. L. Maass, D. J. White, and J. W. Horton
Effects of burn injury on myocardial signaling and cytokine secretion: possible role of PKC
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R887 - R896.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. Wang, P. R. Crisostomo, C. Herring, K. K. Meldrum, and D. R. Meldrum
Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R880 - R884.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
M. Wang, P. Crisostomo, G. M. Wairiuko, and D. R. Meldrum
Estrogen receptor-{alpha} mediates acute myocardial protection in females
Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2204 - H2209.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
P. R. Crisostomo, M. Wang, G. M. Wairiuko, E. D. Morrell, and D. R. Meldrum
Brief exposure to exogenous testosterone increases death signaling and adversely affects myocardial function after ischemia
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2006; 290(5): R1168 - R1174.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
J. W. Horton, D. L. Maass, and D. J. White
Hypertonic saline dextran after burn injury decreases inflammatory cytokine responses to subsequent pneumonia-related sepsis
Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1642 - H1650.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
D. R. Meldrum
Estrogen increases protective proteins following trauma and hemorrhage
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R809 - R811.
[Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. M. Pitcher, M. Wang, B. M. Tsai, A. Kher, N. T. Nelson, and D. R. Meldrum
Endogenous estrogen mediates a higher threshold for endotoxin-induced myocardial protection in females
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R27 - R33.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
J. Tan, Z. Ma, L. Han, R. Du, L. Zhao, X. Wei, D. Hou, B. H. Johnstone, M. R. Farlow, and Y. Du
Caffeic acid phenethyl ester possesses potent cardioprotective effects in a rabbit model of acute myocardial ischemia-reperfusion injury
Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2265 - H2271.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
G. Hall, I. S. Singh, L. Hester, J. D. Hasday, and T. B. Rogers
Inhibitor-{kappa}B kinase-{beta} regulates LPS-induced TNF-{alpha} production in cardiac myocytes through modulation of NF-{kappa}B p65 subunit phosphorylation
Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2103 - H2111.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
L. Gomez, N. Chavanis, L. Argaud, L. Chalabreysse, O. Gateau-Roesch, J. Ninet, and M. Ovize
Fas-independent mitochondrial damage triggers cardiomyocyte death after ischemia-reperfusion
Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2153 - H2158.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
M. Zhang, Y.-J. Xu, H. K. Saini, B. Turan, P. P. Liu, and N. S. Dhalla
Pentoxifylline attenuates cardiac dysfunction and reduces TNF-{alpha} level in ischemic-reperfused heart
Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H832 - H839.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Endocrinol. Metab.Home page
M. Wang, L. Baker, B. M. Tsai, K. K. Meldrum, and D. R. Meldrum
Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury
Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E321 - E326.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Renal Physiol.Home page
R. Misseri, D. R. Meldrum, C. A. Dinarello, P. Dagher, K. L. Hile, R. C. Rink, and K. K. Meldrum
TNF-{alpha} mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling
Am J Physiol Renal Physiol, February 1, 2005; 288(2): F406 - F411.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
M. Wang, B. M. Tsai, A. Kher, L. B. Baker, G. M. Wairiuko, and D. R. Meldrum
Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion
Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H221 - H226.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
B. M. Tsai, M. Wang, J. M. Pitcher, K. K. Meldrum, and D. R. Meldrum
Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C
Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1215 - L1219.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
B. M. Tsai, M. Wang, M. Clauss, P. Sun, and D. R. Meldrum
Endothelial monocyte-activating polypeptide II causes NOS-dependent pulmonary artery vasodilation: a novel effect for a proinflammatory cytokine
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2004; 287(4): R767 - R771.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
G. W. Moe, J. Marin-Garcia, A. Konig, M. Goldenthal, X. Lu, and Q. Feng
In vivo TNF-{alpha} inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure
Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1813 - H1820.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Endocrinol. Metab.Home page
P. Wang and J. C. Chatham
Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart
Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E725 - E736.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
J. White, D. L. Carlson, M. Thompson, D. L. Maass, B. Sanders, B. Giroir, and J. W. Horton
Molecular and pharmacological approaches to inhibiting nitric oxide after burn trauma
Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1616 - H1625.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
P. D. Constable, G. W. Smith, G. E. Rottinghaus, M. E. Tumbleson, and W. M. Haschek
Fumonisin-induced blockade of ceramide synthase in sphingolipid biosynthetic pathway alters aortic input impedance spectrum of pigs
Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2034 - H2044.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
U. Hofmann, E. Domeier, S. Frantz, M. Laser, B. Weckler, P. Kuhlencordt, S. Heuer, B. Keweloh, G. Ertl, and A. W. Bonz
Increased myocardial oxygen consumption by TNF-alpha is mediated by a sphingosine signaling pathway
Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2100 - H2105.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
S. Belosjorow, I. Bolle, A. Duschin, G. Heusch, and R. Schulz
TNF-alpha antibodies are as effective as ischemic preconditioning in reducing infarct size in rabbits
Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H927 - H930.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. B. Felder, J. Francis, Z.-H. Zhang, S.-G. Wei, R. M. Weiss, and A. K. Johnson
Heart failure and the brain: new perspectives
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R259 - R276.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
R. M. Gomez, O. A. Levander, and L. Sterin-Borda
Reduced inotropic heart response in selenium-deficient mice relates with inducible nitric oxide synthase
Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H442 - H448.
[Abstract] [Full Text] [PDF]


Home page
J. Appl. Physiol.Home page
M. Fujita, R. J. Mason, C. Cool, J. M. Shannon, N. Hara, and K. A. Fagan
Pulmonary hypertension in TNF-alpha -overexpressing mice is associated with decreased VEGF gene expression
J Appl Physiol, December 1, 2002; 93(6): 2162 - 2170.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
D. X. Zhang, F.-X. Yi, A.-P. Zou, and P.-L. Li
Role of ceramide in TNF-alpha -induced impairment of endothelium-dependent vasorelaxation in coronary arteries
Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1785 - H1794.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
C. D. Raeburn, C. M. Calkins, M. A. Zimmerman, Y. Song, L. Ao, A. Banerjee, A. H. Harken, and X. Meng
ICAM-1 and VCAM-1 mediate endotoxemic myocardial dysfunction independent of neutrophil accumulation
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R477 - R486.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. A. Zimmerman, C. H. Selzman, L. L. Reznikov, S. A. Miller, C. D. Raeburn, J. Emmick, X. Meng, and A. H. Harken
Lack of TNF-alpha attenuates intimal hyperplasia after mouse carotid artery injury
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R505 - R512.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
G. Wright, I. S. Singh, J. D. Hasday, I. K. Farrance, G. Hall, A. S. Cross, and T. B. Rogers
Endotoxin stress-response in cardiomyocytes: NF-kappa B activation and tumor necrosis factor-alpha expression
Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H872 - H879.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Respir. Crit. Care Med.Home page
H. FAUVEL, P. MARCHETTI, G. OBERT, O. JOULAIN, C. CHOPIN, P. FORMSTECHER, and R. NEVIERE
Protective Effects of Cyclosporin A from Endotoxin-induced Myocardial Dysfunction and Apoptosis in Rats
Am. J. Respir. Crit. Care Med., February 15, 2002; 165(4): 449 - 455.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
K. K. Meldrum, D. R. Meldrum, X. Meng, L. Ao, and A. H. Harken
TNF-alpha -dependent bilateral renal injury is induced by unilateral renal ischemia-reperfusion
Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H540 - H546.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Cell Physiol.Home page
K. K. Meldrum, D. R. Meldrum, K. L. Hile, E. B. Yerkes, A. Ayala, M. P. Cain, R. C. Rink, A. J. Casale, and M. A. Kaefer
p38 MAPK mediates renal tubular cell TNF-{alpha} production and TNF-{alpha}-dependent apoptosis during simulated ischemia
Am J Physiol Cell Physiol, August 1, 2001; 281(2): C563 - C570.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
K. Detmer, Z. Wang, D. Warejcka, S. K. Leeper-Woodford, and W. H. Newman
Endotoxin stimulated cytokine production in rat vascular smooth muscle cells
Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H661 - H668.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
R. Shahani, L. V. Klein, J. G. Marshall, S. Nicholson, B. B. Rubin, P. M. Walker, and T. F. Lindsay
Hemorrhage-induced {alpha}-adrenergic signaling results in myocardial TNF-{alpha} expression and contractile dysfunction
Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H84 - H92.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
K. K. Meldrum, D. R. Meldrum, S. F. Sezen, J. K. Crone, and A. L. Burnett
Heat shock prevents simulated ischemia-induced apoptosis in renal tubular cells via a PKC-dependent mechanism
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R359 - R364.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
C. Ballard-Croft, D. J. White, D. L. Maass, D. P. Hybki, and J. W. Horton
Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-{alpha}
Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H1970 - H1981.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
B. Chandrasekar, J. F. Nelson, J. T. Colston, and G. L. Freeman
Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury
Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2094 - H2102.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
J. W. Horton, D. L. Maass, J. White, and B. Sanders
Hypertonic saline-dextran suppresses burn-related cytokine secretion by cardiomyocytes
Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1591 - H1601.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
E. Hiraoka, S. Kawashima, T. Takahashi, Y. Rikitake, T. Kitamura, W. Ogawa, and M. Yokoyama
TNF-{alpha} induces protein synthesis through PI3-kinase-Akt/PKB pathway in cardiac myocytes
Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1861 - H1868.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
S. B. Haudek, E. Spencer, D. D. Bryant, D. J. White, D. Maass, J. W. Horton, Z. J. Chen, and B. P. Giroir
Overexpression of cardiac I-{kappa}B{alpha} prevents endotoxin-induced myocardial dysfunction
Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H962 - H968.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
M. Fujita, J. M. Shannon, C. G. Irvin, K. A. Fagan, C. Cool, A. Augustin, and R. J. Mason
Overexpression of tumor necrosis factor-{alpha} produces an increase in lung volumes and pulmonary hypertension
Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L39 - L49.
[Abstract] [Full Text] [PDF]


Home page
Pharmacol. Rev.Home page
I. J. Elenkov, R. L. Wilder, G. P. Chrousos, and E. S. Vizi
The Sympathetic Nerve---An Integrative Interface between Two Supersystems: The Brain and the Immune System
Pharmacol. Rev., December 1, 2000; 52(4): 595 - 638.
[Abstract] [Full Text] [PDF]


Home page
Hum Mol GenetHome page
C. L. Glenn, W. Y.S. Wang, A. V. Benjafield, and B. J. Morris
Linkage and association of tumor necrosis factor receptor 2 locus with hypertension, hypercholesterolemia and plasma shed receptor
Hum. Mol. Genet., August 12, 2000; 9(13): 1943 - 1949.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
D. B. Cowan, D. N. Poutias, P. J. Del Nido, and F. X. McGowan Jr
CD14-independent activation of cardiomyocyte signal transduction by bacterial endotoxin
Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H619 - H629.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Respir. Crit. Care Med.Home page
I. F. AFULUKWE, R. I. COHEN, G. A. ZEBALLOS, M. IQBAL, and S. M. SCHARF
Selective NOS Inhibition Restores Myocardial Contractility in Endotoxemic Rats; However, Myocardial NO Content Does Not Correlate with Myocardial Dysfunction
Am. J. Respir. Crit. Care Med., July 1, 2000; 162(1): 21 - 26.
[Abstract] [Full Text]


Home page
FASEB J.Home page
I. H. C. VOS, R. GOVERS, H.-J. GRÖNE, L. KLEIJ, M. SCHURINK, R. A. DE WEGER, R. GOLDSCHMEDING, and T. J. RABELINK
NF{kappa}B decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts
FASEB J, April 1, 2000; 14(5): 815 - 822.
[Abstract] [Full Text]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
S. Belosjorow, R. Schulz, H. Dorge, F. U. Schade, and G. Heusch
Endotoxin and ischemic preconditioning: TNF-alpha concentration and myocardial infarct development in rabbits
Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2470 - H2475.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
H. Kan, Z. Xie, and M. S. Finkel
TNF-alpha enhances cardiac myocyte NO production through MAP kinase-mediated NF-kappa B activation
Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1641 - H1646.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
K. K. Donnahoo, X. Meng, A. Ayala, M. P. Cain, A. H. Harken, and D. R. Meldrum
Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 1999; 277(3): R922 - R929.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
C. Li, W. Browder, and R. L. Kao
Early activation of transcription factor NF-kappa B during ischemia in perfused rat heart
Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H543 - H552.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
B. D. Shames, D. R. Meldrum, C. H. Selzman, E. J. Pulido, B. S. Cain, A. Banerjee, A. H. Harken, and X. Meng
Increased levels of myocardial Ikappa B-alpha protein promote tolerance to endotoxin
Am J Physiol Heart Circ Physiol, September 1, 1998; 275(3): H1084 - H1091.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
D. L. Carlson, E. Lightfoot Jr., D. D. Bryant, S. B. Haudek, D. Maass, J. Horton, and B. P. Giroir
Burn plasma mediates cardiac myocyte apoptosis via endotoxin
Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1907 - H1914.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
D. X. Zhang, A.-P. Zou, and P.-L. Li
Ceramide Reduces Endothelium-Dependent Vasodilation by Increasing Superoxide Production in Small Bovine Coronary Arteries
Circ. Res., April 27, 2001; 88(8): 824 - 831.
[Abstract] [Full Text] [PDF]


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Meldrum, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Meldrum, D. R.


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online