AJP - Regu Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 285: R727-R732, 2003. First published June 26, 2003; doi:10.1152/ajpregu.00175.2003
0363-6119/03 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
285/4/R727    most recent
00175.2003v1
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 ISI Web of Science
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 ISI Web of Science (9)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Frenette, J.
Right arrow Articles by Frenette, P. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Frenette, J.
Right arrow Articles by Frenette, P. S.

INFLAMMATION, CYTOKINES, AND TEMPERATURE REGULATION

Macrophages, not neutrophils, infiltrate skeletal muscle in mice deficient in P/E selectins after mechanical reloading

Jéroôme Frenette,1 Nadia Chbinou,1 Charles Godbout,1 David Marsolais,1 and Paul S. Frenette2

1Department of Rehabilitation, Faculty of Medicine, Laval University, Ste-Foy, Quebec, Canada G1K 7P4; and 2Divisions of Hematology and Clinical Immunology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029

Submitted 3 April 2003 ; accepted in final form 16 June 2003


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Our objective was to test the hypothesis that endothelial selectins, P and E selectins, are necessary for leukocyte migration after muscle injury from unloading/reloading. Mice hindlimbs were suspended for 10 days followed by reloading periods of 6 or 24 h after which the soleus muscle was dissected. Light microscopic observations showed that macrophages, but not neutrophils, were able to invade soleus muscles in mice deficient in P/E selectins (P/E-/-) during reloading periods. The recruitment efficiency of neutrophils after 6 and 24 h of reloading was minimal in P/E-/- mice relative to unloaded animals. The recruitment of macrophages in the soleus muscle was preserved in P/E-/- mice. The concentration of macrophages increased by 8.1-fold compared with unloaded muscles in double-mutant mice after 24 h of reloading. The accumulation of macrophages in reloaded muscles did not lead to fiber necrosis. Together, these findings indicate that macrophages can invade skeletal muscle through cellular mechanisms that do not involve P/E selectins during skeletal muscle reloading.

muscle inflammation; mechanical stress; hindlimb suspension

MODIFICATIONS IN SKELETAL muscle use and muscle injury caused by direct trauma, thermal or mechanical stresses, or muscle reperfusion after periods of ischemia can induce an increase in the concentration of inflammatory cells in muscle (10, 24, 38). Several investigators have speculated that these inflammatory cells can increase muscle fiber injury after modified muscle use (7, 39), which has been supported by experimental evidence showing that neutrophil depletion before muscle reperfusion results in less muscle damage (6, 18). By contrast, macrophages are expected to play a beneficial role in muscle repair. Macrophages can induce apoptosis of neutrophils (30), phagocyte tissue debris (28), and release factors that can regulate cell proliferation and myogenesis (28, 35). Thus the diametrically opposed roles of these leukocyte subsets give credence to the notion that inflammatory cells are a double-edged sword in that they are necessary for efficient tissue healing but responsible for at least part of the secondary damage.

The recruitment of leukocytes from the vasculature into inflammatory sites is a multistep process initiated by rolling of leukocytes along the endothelium, followed by firm adhesion and diapedesis (4). Members of the selectin family, including L/P and E selectins, are thought to be largely responsible for the early rolling of leukocytes in postcapillary venules during the acute phase of inflammation (22). The availability of mice genetically deficient for either L/P or E selectin, as well as mice deficient in two or all selectins, has opened new avenues for dissecting the specific roles of selectins in the recruitment of leukocytes into inflammatory sites. For example, mice deficient in P selectin presented a delay of 2-4 h in the recruitment of leukocytes into inflamed peritoneum, but ultimately the number of inflammatory cells reached near normal levels (29). Mice lacking E selectin displayed a mild phenotype comprising increased leukocyte rolling velocities and reduced leukocyte stable arrest on cytokine-activated endothelium (27, 31). However, the phenotype of animals deficient in both endothelial selectins was much greater than either single knockouts. Indeed, P/E-/- mice exhibited extreme leukocytosis, defects in leukocyte rolling on activated endothelium, and severe reduction in neutrophil accumulation in peritoneum after injection with proinflammatory agents (3, 13). Similar alterations were observed in mice lacking all three selectins (20, 36). Together, these results clearly demonstrate that both endothelial selectins cooperate to recruit neutrophils into inflammatory sites.

Because little is known about the mechanisms through which inflammatory cells invade skeletal muscle and that blocking inflammatory cell invasion may significantly improve the outcome of several inflammatory pathologies, we tested the hypothesis that P/E selectins are necessary for inflammatory cell recruitment in skeletal muscle by modifying mechanical loading to produce muscle dysfunction (12, 40). In this model, weight bearing is removed from the mouse hindlimb muscles followed by a period of normal, weight-bearing ambulation, during which inflammatory cells invade shortened and weakened soleus muscles. This muscle unloading/reloading procedure was applied to wild-type and P/E-/- mice, after which the concentration of invading populations of neutrophils and macrophages and the percentage of injured fibers were assessed.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Experimental protocol. P/E-/- mice were generated by gene targeting (13) and were backcrossed seven generations into the C57BL/6 background, and wild-type C57BL/6 (purchased from Charles River, Quebec, Canada) were used for mechanical unloading and reloading studies. All female mice were aged between 8 and 12 wk and housed at Laval University mouse facility under SPF conditions. Wild-type and P/E-/- mice were subjected to hindlimb unloading for 10 days using an apparatus similar to that described by Morey-Holton and Globus (32). Mice were removed from the suspension apparatus at the end of the unloading period and either immediately killed or allowed to reload their hindlimbs during normal cage activity for periods of 6 or 24 h. Mice were anesthetized with pentobarbital sodium (10 mg/kg), and soleus muscles were excised with the intact tendons, frozen and sectioned as described by St.-Pierre and Tidball (39). All studies and procedures were approved by the Animal Research Committee at Laval University.

Immunohistochemistry. Sections were processed for immunohistochemistry with the following antibodies: 1) F4/80 (rat anti-mouse IgG; diluted 1:100; Bioproducts for Science), which recognizes a plasma membrane component on mature macrophages, and 2) Ly-6G (rat anti-mouse IgG; diluted 1:300; Pharmingen), which binds specifically to peripheral neutrophils. The sections labeled for macrophages or neutrophils were then washed in PBS and incubated with biotinylated anti-rat IgG (diluted 1:200; Vector Laboratories) for 1 h. After rinsing in PBS for 30 min, the sections were incubated with horseradish peroxidase-avidin (1:1,000; Vector Laboratories).

Some sections were also double-labeled for macrophages and the endothelial cell marker platelet endothelial cell adhesion molecule-1 (PECAM-1; rat anti-mouse CD31; diluted 1:100; Pharmingen) to confirm macrophage invasion. Macrophages were labeled with F4/80 as described above, followed by incubation with an alkaline phosphatase-avidin (1:1,000; Vector Laboratories) instead of horseradish peroxidase-conjugated avidin. Sections were then incubated at 37°C and developed with 5-bromo-4-chloro-3-indolyl phosphate and nitroblue tetrazolium for 30 min. The primary antibody was omitted from control sections. The concentration of inflammatory cells labeled with each antibody was measured in duplicate in two mid-belly sections separated by 1 mm from left and right solei. Therefore, eight sections per mouse were examined by light microscopy using Nomarski optics. The number of labeled cells in each section was counted, and the total area of the section was determined manually by moving methodically the quadrant in each area to cover the whole section. Intravascular leukocytes, which represented <2% of counted leukocytes, were excluded during neutrophil and macrophage counting, and the data were normalized relative to unloaded mouse groups.

Blood collection. Blood was collected by cardiac puncture and placed in polypropylene tubes containing EDTA. These samples were analyzed in the Department of Hematology at Centre Hospitalier de l'Université Laval. Complete blood counts were determined using an automic cell counter (Beckman Coulter) and differential counts on Wright-stained smears.

Statistical analysis. All values are reported as means ± SE. The effect of hindlimb suspension on the number of neutrophils and macrophages as well as the peripheral blood counts was assessed by one-way ANOVA to test whether the variation among experimental groups was significant at P < 0.05. When significant F ratio was obtained, post hoc multiple comparison testing was done with a Fisher's protected least-significant differences test to determine where specific differences had occurred.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 DISCLOSURES
 REFERENCES
 
To evaluate the role of endothelial selectins in the inflammatory response after muscle reloading, we subjected mice to a 10-day period of hypogravity followed by a 6- or 24-h reloading challenge. The soleus muscle was dissected, and mid-belly sections were cut and immunolabeled for neutrophil (Gr-1)- or macrophage (F4/80)-specific antigens. Reloading under these conditions leads to the recruitment of inflammatory cells in the challenged skeletal muscles, which can readily be determined by immunohistochemistry (Fig. 1).



View larger version (105K):
[in this window]
[in a new window]
  		Fig. 1. Micrograph of cross sections of soleus muscles from mice deficient in P/E selectins. A: negative controls (no primary antibody) show no staining. B: double-immunolabeling of macrophages (black) and endothelial cells. Soleus muscles were sectioned and labeled with antibodies specific for macrophages and the endothelial cell marker platelet endothelial cell adhesion molecule-1. Macrophages accumulated in the interstitial space between myofibers (arrows). Capillaries were observed around myofibers (arrowheads). Bars, 50 µm.

 

The number of neutrophils in the soleus muscle of wild-type mice was increased by 2.7- and 2.4-fold after 6 and 24 h of reloading, respectively, compared with unloaded animals. In contrast, the number of neutrophils migrated in the soleus muscle of double-mutant mice after 6 and 24 h of reloading was similar to those of unloaded animals (Fig. 2). These results suggest that the recruitment of neutrophils in skeletal muscle challenged with reloading is dependent on endothelial selectins.



View larger version (17K):
[in this window]
[in a new window]
  		Fig. 2. Percent change for neutrophil accumulation in wild-type (WT) and double-mutant [knockout (KO)] mice from ambulatory controls (AMB) and animals reloaded (R) for 6 or 24 h. Results were expressed relative to unloaded animals (UNL); n = 6 for all WT groups, and n = 7 for all KO groups except for 24-h reloaded (n = 5). Values are means ± SE. *Significantly different from unloaded control, P < 0.05. #Significantly different from its WT matched group, P < 0.05.

 

To evaluate the recruitment of macrophages, sections were stained with the F4/80 antibody. We found that the concentration of macrophages in the soleus muscle of wild-type and double-mutant mice decreased during the unloading period and increased by 4.8- and 8.1-fold, respectively, after 24 h of reloading (Fig. 3). The increases of macrophage concentrations in soleus muscles at 24 h of reloading are consistent with the observation that the concentration of monocytes in circulation is more important in P/E-/- mice than wild type. In contrast to the results obtained with neutrophils, the recruitment efficiency of macrophages was not reduced in P/E-/- mice. The concentration of macrophages was in fact significantly higher in P/E-/- mice compared with wild-type after 24 h of reloading, indicating that the mechanisms mediating macrophage recruitment were preserved and efficient in soleus muscles lacking both endothelial selectins.



View larger version (17K):
[in this window]
[in a new window]
  		Fig. 3. Percent change for macrophage accumulation in WT and KO mice from ambulatory controls and animals reloaded for 6 or 24 h. Results were expressed relative to unloaded animals; n = 6 for all WT groups, and n = 7 for all KO groups except 24-h reloaded (n = 5). Values are means ± SE. *Significantly different from unloaded control, P < 0.05. #Significantly different from its WT matched group, P < 0.05.

 

To ascertain that changes in the concentrations of neutrophils and macrophages in soleus muscle were not caused by alterations in the number of circulating leukocytes, blood cell counts were determined at different periods of unloading and reloading in wild-type and double-mutant mice. These results corroborate previous observations showing that double-mutant mice exhibit severe leukocytosis (13). Importantly, the period of reloading had no impact on leukocyte counts in either wild-type or P/E -/- mice (Table 1).


View this table:
[in this window]
[in a new window]
  		Table 1. Peripheral blood counts

 

To evaluate the severity of muscle necrosis in wild-type and double-mutant mice, we counted the number of macrophages that invaded muscle fibers under different experimental conditions. We found that the proportion of muscle fibers that were invaded by F4/80 macrophages did not exceed 0.36% of the total number of fibers (Fig. 4). Modifications in mechanical loading did not significantly change the number of necrotic fibers in either strains.



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 4. Percentage of necrotic fibers in WT and KO mice from ambulatory controls and animals unloaded for 10 days or reloaded for 6 or 24 h; n = 6 for all WT groups, and n = 7 for all KO groups except for 24-h reloaded (n = 5). Values are means ± SE. No differences were observed between any groups.

 


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
DISCLOSURES
 REFERENCES
 
The sequence and time course of inflammatory cell invasion are believed to be similar and well preserved in all damaged tissues. However, recent results have shown that leukocyte recruitment in skeletal muscle varies depending on type of insult. For example, eccentric contractions (lengthening contractions) induce damage and loss in muscle force (9), but immunohistochemical and myeloperoxidase data indicate that monocyte recruitment occurs without extravasation of neutrophils (25). In contrast, ischemia and reperfusion in skeletal muscle provokes a massive recruitment of neutrophils with a mild invasion of macrophages (23). In addition, hindlimb suspension and reloading or chemical injury with bupivacain lead to a classic infiltration of neutrophils followed by macrophages (11, 12, 33). Several explanations for these variations in the sequences can be proposed, but the most appealing are that 1) neutrophils and macrophages use different adhesion molecules and/or chemokine/chemokine receptors that may be differentially activated for each type of muscle injury, and 2) the response of neutrophils and macrophages to cytokines and chemokines differs in these models of muscle damage. Platelet-derived growth factor is one of the possible cytokines released by injured skeletal muscle that can chemotactically attract neutrophils and macrophages (5). Macrophage inflammatory protein-1 represents another potential candidate because it is a powerful chemoattractant molecule for inflammatory cells (26), and its concentration increases in circulation after strenuous exercise (34). However, we cannot exclude the possibility that nonmuscle cells such as endothelial cells, adipocytes, or endogenous macrophages may also be a source of leukocyte chemoattractants during muscle reloading.

In the present study, we tested the hypothesis that P/E selectins are necessary for leukocyte invasion in a model of muscle dysfunction caused by hindlimb suspension followed by reloading periods. Here we show that P/E selectins are not required for macrophage invasion in skeletal muscle, indicating that other adhesion molecules participate in the recruitment of this leukocyte subset. The most plausible candidate for bypassing P/E selectin function is the {alpha}4-integrin/vascular cell adhesion molecule-1 pathway, because {alpha}4-integrin is highly expressed on eosinophils and monocytes (7, 16) and can mediate the rolling and adhesion of these leukocytes under in vitro and in vivo conditions (1, 19). Interestingly, intravital microscopy observations in a model of IL-4-induced inflammation of the cremaster muscle revealed that {alpha}4-integrin can initiate leukocyte-endothelial cell interactions in the absence of selectins in vivo and that the recruitment of eosinophils and mononuclear cells is preserved (17). This is also consistent with the recent observation by Jung and Ley (21) indicating that mice lacking all three selectins presented dramatic reductions in leukocyte rolling and neutrophil recruitment, but monocyte recruitment on the vessel wall was almost unaffected. Together, these findings provide strong evidence that neutrophil and monocyte recruitment in muscle and nonmuscle tissues appears to operate through distinct mechanisms.

Experimental studies on cardiac and skeletal muscles indicate that neutrophil infiltration plays a significant role in some tissue injury (15, 24, 42, 43). For example, an injurious role for inflammatory cells in skeletal muscle has been demonstrated after ischemia and reperfusion where the extent of muscle injury during reperfusion is diminished in animals depleted of circulating neutrophils (6, 18). In addition, the administration of free radical scavengers prevents muscle damage, suggesting that free radicals generated by inflammatory cells may cause injury during reperfusion (37). The present findings indicate that inflammatory cell invasion does not exacerbate muscle damage where only 0.36% of the fibers were necrotic after 24 h of reloading. Previous results have shown that the increase in inflammatory cell concentration was not associated with any detectable reduction in muscle force and that the inability to activate the contractile machinery was the primary mechanism for the loss in force production during the reloading periods (12). The incubation of soleus muscles in physiological solution containing caffeine, which acts directly on Ca2+ release channels of the sarcoplasmic reticulum, revealed that at least 40% of the reduction in maximal force production originated from a failure in the excitation-contraction coupling process at a step preceding the opening of the sarcoplasmic reticulum Ca2+ release channel (12).

Our results also suggest that endogenous macrophage survival is influenced by mechanical stress. The absence of mechanical loading leads to significant reductions of resident macrophage concentration in both wild-type and P/E selectin-deficient mice. A role for mechanical tension in regulating cell survival has been demonstrated in other cell types, such as endothelial cells (8) and fibroblasts (14). For example, fibroblasts in mechanically loaded collagen matrices showed little or no apoptosis, but the release of mechanical conditions led to apoptosis (14). Whether macrophages also undergo apoptosis after an unloading period remains to be defined, but recent observations showed that macrophages can respond to mechanical deformation with selective augmentation of matrix metalloproteinases and induction of immediate early genes (41). Because a phenotypic continuum exists between fibroblasts and macrophages (2), the possibility that muscular unloading induces macrophage apoptosis should be the subject of future studies.

In summary, our results clearly show that P/E selectins were essential for neutrophils but not required for monocytes to infiltrate reloaded soleus muscle. These results raise interesting questions regarding the design of therapies for inflammatory myopathies in which neutrophils can cause secondary damage. Anti-endothelial selectin therapy may therefore serve a dual purpose as it blocks neutrophil invasion but permits the recruitment of monocytes/macrophages, which are likely positive regulators of cell proliferation and myogenesis.


   DISCLOSURES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
REFERENCES
 
We gratefully acknowledge financial support from the Natural Sciences and Engineering Research Council in Canada and the Fonds de la Recherche en Santé du Québec to J. Frenette. This work was also supported by National Institutes of Health Grant HL-69438 to P. S. Frenette.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Frenette, CHUL Research Center, Rm. 9500, 2705 Blvd. Laurier, Ste-Foy, Quebec, G1V 4G2 Canada (E-mail: jerome.frenette{at}crchul.ulaval.ca).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 

  1. Alon R, Kassner PD, Carr MW, Finger EB, Hemler ME, and Springer TA. The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol 128: 1243-5123, 1995.[Abstract/Free Full Text]
  2. Arlein WJ, Shearer JD, and Caldwell MD. Continuity between wound macrophage and fibroblast phenotype: analysis of wound fibroblast phagocytosis. Am J Physiol Regul Integr Comp Physiol 275: R1041-R1048, 1998.[Abstract/Free Full Text]
  3. Bullard DC, Kunkel EJ, Kubo H, Hicks MJ, Lorenzo I, Doyle NA, Doerschuk CM, Ley K, and Beaudet AL. Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice. J Exp Med 183: 2329-2336, 1996.[Abstract/Free Full Text]
  4. Butcher EC. Leukocyte-endothelial cell recognition-three (or more) steps to specificity and diversity. Cell 67: 1033-1036, 1991.[ISI][Medline]
  5. Chen G and Quinn LS. Partial characterization of skeletal myoblast mitogens in mouse crushed muscle extract. J Cell Physiol 153: 563-574, 1992.[ISI][Medline]
  6. Crinnion JN, Homer-Vanniasinkam S, Hatton R, Parkin SM, and Gough MJ. Role of neutrophil depletion and elastase inhibition in modifying skeletal muscle reperfusion injury. Cardiovasc Surg 6: 749-753, 1994.
  7. Davenpeck KL, Sterbinsky SA, and Bochner BS. Rat neutrophils express {alpha}4 and {beta}1 integrins and bind to vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Blood 91: 2341-2346, 1998.[Abstract/Free Full Text]
  8. Dimmeler S, Haendeler J, Rippmann V, Nehls M, and Zeiher AM. Shear stress inhibits apoptosis of human endothelial cells. FEBS Lett 399: 71-74, 1996.[ISI][Medline]
  9. Faulkner JA, Jones DA, and Round JM. Injury to skeletal muscles of mice by forced lengthening during contraction. J Exp Physiol 74: 661-670, 1989.[Abstract/Free Full Text]
  10. Ferguson MK, Seifert FC, and Replogle RL. Leukocyte adherence in venules of rat skeletal muscle following thermal injury. Microvasc Res 24: 34-41, 1982.[ISI][Medline]
  11. Frenette J, Cai B, and Tidball JG. Complement activation promotes muscle inflammation during modified muscle use. Am J Pathol 156: 2103-2110, 2000.[Abstract/Free Full Text]
  12. Frenette J, St-Pierre M, Coôté CH, Mylona E, and Pizza FX. Muscle impairment occurs rapidly and precedes inflammatory cell accumulation following modified mechanical loading. Am J Physiol Regul Integr Comp Physiol 282: R351-R357, 2002.[Abstract/Free Full Text]
  13. Frenette PS, Mayadas TN, Rayburn H, Hynes RO, and Wagner DD. Susceptibility to infection and altered hematopoiesis in mice deficient in both P-and E-selectins. Cell 84: 563-574, 1996.[ISI][Medline]
  14. Grinnell F, Zhu M, Carlson MA, and Abrams JM. Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue. Exp Cell Res 248: 608-619, 1999.[ISI][Medline]
  15. Hawkins HK, Entman ML, Zhu JY, Youker KA, Berens K, Dore M, and Smith CW. Acute inflammatory reaction after myocardial ischemic injury and reperfusion. Am J Pathol 148: 1957-1969, 1996.[Abstract]
  16. Hemler ME. VLA proteins in the integrin family: structures, functions and their role on leukocytes. Annu Rev Immunol 8: 365-400, 1990.[ISI][Medline]
  17. Hickey MJ, Granger DN, and Kubes P. Molecular mechanisms underlying IL-4 induced leukocyte recruitment in vivo: a critical role for the {alpha}4 integrin. J Immunol 163: 3441-3448, 1999.[Abstract/Free Full Text]
  18. Iwahori Y, Ishiguro N, Shimizu T, Kondo S, Yabe Y, Oshima T, Iwata H, and Sendo F. Selective neutrophil depletion with monoclonal antibodies attenuates ischemia/reperfusion injury in skeletal muscle. J Reconstr Microsurg 14: 109-116, 1998.[ISI][Medline]
  19. Johnston B, Issekutz TB, and Kubes P. The {alpha}4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo. J Exp Med 183: 1995-2006, 1996.[Abstract/Free Full Text]
  20. Jung TM and Dailey MO. Rapid modulation of homing receptors (gp90MEL-14) induced by activators of protein kinase C. Receptor shedding due to accelerated proteolytic cleavage at the cell surface. J Immunol 144: 3130-3136, 1990.[Abstract]
  21. Jung U and Ley K. Mice lacking two or all three selectins demonstrate overlapping and distinct functions for each selectin. J Immunol 162: 6755-6762, 1999.[Abstract/Free Full Text]
  22. Kansas GS. Selectins and their ligands: current concepts and controversies. Blood 88: 3259-3287, 1996.[Free Full Text]
  23. Kanwar S, Smith CW, and Kubes P. An absolute requirement for P-selectin in ischemia/reperfusion-induced leukocyte recruitment in cremaster muscle. Microcirculation 5: 281-287, 1998.[ISI][Medline]
  24. Korthuis RJ, Grisham MB, and Granger N. Leukocyte depletion attenuates vascular injury in postischemic skeletal muscle. Am J Physiol Heart Circ Physiol 254: H823-H827, 1988.[Abstract/Free Full Text]
  25. Lapointe BM, Frenette J, and Cote CH. Lengthening contraction-induced inflammation is linked to secondary damage but devoid of neutrophil invasion. J Appl Physiol 92: 1995-2004, 2002.[Abstract/Free Full Text]
  26. Lee SC, Brummet ME, Shahabuddin S, Woodworth TG, Georas SN, Leiferman KM, Gilman SC, Stellato C, Gladue RP, Schleimer RP, and Beck LA. Cutaneous injection of human subjects with macrophage inflammatory protein-1 {alpha} induces significant recruitment of neutrophils and monocytes. J Immunol 164: 3392-3401, 2000.[Abstract/Free Full Text]
  27. Ley K, Allietta M, Bullard DC, and Morgan S. Importance of E-selectin for firm leukocyte adhesion in vivo. Circ Res 83: 287-294, 1998.[Abstract/Free Full Text]
  28. Massimino ML, Rapizzi E, Cantini M, Libera LD, Mazzoleni F, Arslan P, and Carraro U. ED2+ macrophages increase selectively myoblast proliferation in muscle cultures. Biochem Biophys Res Commun 235: 754-759, 1997.[ISI][Medline]
  29. Mayadas TN, Johnson RC, Rayburn H, Hynes RO, and Wagner DD. Leukocyte rolling and extravasation are severely compromised in P selectin deficient mice. Cell 74: 541-554, 1993.[ISI][Medline]
  30. Meszaros AJ, Reichner JS, and Albina JE. Macrophage-induced neutrophil apoptosis. J Immunol 165: 435-441, 2000.[Abstract/Free Full Text]
  31. Milstone DS, Fukumura D, Padgett RC, O'Donnell PE, Davis VM, Benavidez OJ, Monsky WL, Melder RJ, Jain RK, and Gimbrone MA Jr. Mice lacking E-selectin show normal numbers of rolling leukocytes but reduced leukocyte stable arrest on cytokine-activated microvascular endothelium. Microcirculation 5: 153-171, 1998.[ISI][Medline]
  32. Morey-Holton ER and Globus RK. Hindlimb unloading rodent model: technical aspects. J Appl Physiol 92: 1367-1377, 2002.[Abstract/Free Full Text]
  33. Orimo S, Hiyamuta E, Arahata K, and Sugita H. Analysis of inflammatory cells and complement C3 in bupivacaine-induced myonecrosis. Muscle Nerve 14: 515-520, 1991.[ISI][Medline]
  34. Ostrowski K, Rohde T, Asp S, Schjerling P, and Pedersen BK. Chemokines are elevated in plasma after strenuous exercise in humans. Eur J Appl Physiol 84: 244-245, 2001.[ISI][Medline]
  35. Robertson TA, Maley MA, Grounds MD, and Papadimitriou JM. The role of macrophages in skeletal muscle regeneration with particular reference to chemotaxis. Exp Cell Res 207: 321-331, 1993.[ISI][Medline]
  36. Robinson SD, Frenette PS, Rayburn H, Cummiskey M, Ullman-Culleré M, Wagner DD, and Hynes RO. Multiple, targeted deficiencies in selectins reveal a predominant role for P-selectin in leukocyte recruitment. Proc Natl Acad Sci USA 96: 11452-11457, 1999.[Abstract/Free Full Text]
  37. Seyama A. The role of oxygen-derived free radicals and the effect of free radical scavengers on skeletal muscle ischemia/reperfusion injury. Surg Today 12: 1060-1067, 1993.
  38. Stauber WT, Fritz VK, Vogelbach DW, and Dahlmann B. Characterization of muscles injured by forced lengthening. I. Cellular infiltrates. Med Sci Sports Exerc 20: 345-353, 1988.[ISI][Medline]
  39. St-Pierre BA and Tidball JG. Differential response of macrophages subpopulations to soleus muscle reloading after rat hindlimb suspension. J Appl Physiol 77: 290-297, 1994.[Abstract/Free Full Text]
  40. Tidball JG, Berchenko E, and Frenette J. Macrophage invasion does not contribute to muscle membrane injury during inflammation. J Leukoc Biol 65: 492-498, 1999.[Abstract]
  41. Yang JH, Sakamoto H, Xu EC, and Lee RT. Biomechanical regulation of human monocyte/macrophage molecular function. Am J Pathol 156: 1797-1804, 2000.[Abstract/Free Full Text]
  42. Yokota J, Minei JP, Fantini GA, and Tom Shire G. Role of leukocytes in reperfusion injury of skeletal muscle after partial ischemia. Am J Physiol Heart Circ Physiol 257: H1068-H1075, 1989.[Abstract/Free Full Text]
  43. Zhao ZQ, Lefer DJ, Sato H, Hart KK, Jefforda PR, and Vinten-Johansen J. Monoclonal antibody to ICAM-1 preserves postischemic blood flow and reduces infarct size after ischemiareperfusion in rabbit. J Leukoc Biol 62: 292-300, 1997.[Abstract]



This article has been cited by other articles:


Home page
 J. Appl. Physiol.Home page
N. Dumont, K. Lepage, C. H. Cote, and J. Frenette
Mast cells can modulate leukocyte accumulation and skeletal muscle function following hindlimb unloading
J Appl Physiol, July 1, 2007; 103(1): 97 - 104.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
Z. Yuan, A. Tie, M. Tarnopolsky, and M. Bakovic
Genomic organization, promoter activity, and expression of the human choline transporter-like protein 1
Physiol Genomics, September 14, 2006; 26(1): 76 - 90.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. M. McClung, J. M. Davis, M. A. Wilson, E. C. Goldsmith, and J. A. Carson
Estrogen status and skeletal muscle recovery from disuse atrophy
J Appl Physiol, June 1, 2006; 100(6): 2012 - 2023.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
V. Michel, Z. Yuan, S. Ramsubir, and M. Bakovic
Choline Transport for Phospholipid Synthesis.
Experimental Biology and Medicine, May 1, 2006; 231(5): 490 - 504.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. Khandoga, J. S. Kessler, H. Meissner, M. Hanschen, M. Corada, T. Motoike, G. Enders, E. Dejana, and F. Krombach
Junctional adhesion molecule-A deficiency increases hepatic ischemia-reperfusion injury despite reduction of neutrophil transendothelial migration
Blood, July 15, 2005; 106(2): 725 - 733.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
F. X Pizza, J. M Peterson, J. H Baas, and T. J Koh
Neutrophils contribute to muscle injury and impair its resolution after lengthening contractions in mice
J. Physiol., February 1, 2005; 562(3): 899 - 913.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
W. Baker, B. A. St. P. Schneider, A. Kulkarni, G. Sloan, R. Schaub, J. Sypek, and J. G. Cannon
P-selectin inhibition suppresses muscle regeneration following injury
J. Leukoc. Biol., August 1, 2004; 76(2): 352 - 358.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
K. Ley
Healing without inflammation?
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2003; 285(4): R718 - R719.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
285/4/R727    most recent
00175.2003v1
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 ISI Web of Science
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 ISI Web of Science (9)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Frenette, J.
Right arrow Articles by Frenette, P. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Frenette, J.
Right arrow Articles by Frenette, P. S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the American Physiological Society.