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ABSTRACT |
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The following is the abstract of the article discussed in the subsequent letter:
Scammell, Thomas E., John D. Griffin, Joel K. Elmquist, and Clifford B. Saper. Microinjection of a
cyclooxygenase inhibitor into the anteroventral preoptic region
attenuates LPS fever. Am. J. Physiol.
274 (Regulatory Integrative Comp.
Physiol. 43): R933-R935, 1998.
Considerable
evidence supports the role of prostaglandins in fever production, but
the neuroanatomic sites of prostaglandin synthesis that produce fever
remain unknown. With the use of a novel microinjection technique, we
injected the cyclooxygenase inhibitor ketorolac into the preoptic area
(POA) to determine which preoptic regions produce the prostaglandins
required for fever. Initial experiments demonstrated that intravenous
ketorolac blocked the fever normally produced by lipopolysaccharide
(LPS) 5 µg/kg iv. Microinjection of ketorolac into the POA had no
effect on body temperature, and injection of artificial cerebrospinal fluid into the POA did not alter LPS fever. Injection of ketorolac into
the anteroventral POA markedly decreased the fever produced by LPS,
compared with injections into more rostral, caudal, or dorsal
locations. These observations indicate that prostaglandin synthesis in
the anteroventral preoptic region is necessary for the production of
fever.
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LETTER |
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Abstract
Letter
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To the Editor: In their recent article, Scammell and colleagues (5) discuss afferent signals that drive preoptic prostaglandin E2 synthesis and fever after intravenous injection of lipopolysaccharide (LPS). The authors examine the concept of these signals being carried to the brain by the vagus nerve and take a closer look at two studies supporting this concept: a study by Sehic and Blatteis (6) showing a blockade of the biphasic febrile response to intravenous LPS in guinea pigs and our study (3) demonstrating ablation of the monophasic LPS fever in rats. Concurring with our repeated warnings (2-4, 7), the authors caution that alternative interpretations of these vagotomy experiments are conceivable. The possibility of multiple interpretations stems from two facts. First, truncal subdiaphragmatic vagotomy often results in severe complications such as gross emaciation, thermoeffector insufficiency (for review, see Ref. 3), and bacterial translocation from the gut (1), to name a few. Second, these side effects of vagotomy may by themselves decrease the febrile responsiveness. However, many of the side effects are preventable with special care and do not occur in fostered vagotomized animals, whereas the febrile nonresponsiveness does (3). Experiments in well-nourished rats rejected the explanation of the vagotomy-induced febrile nonresponsiveness as being due to either malnutrition (3) or thermoeffector incompetence (2). In their article, Scammell et al. (5) propose a new interpretation of attenuated fevers in vagotomized animals. The authors suggest that slowed motility of the denervated gut promotes translocation of intestinal flora and their constituents into portal circulation, ultimately resulting in tolerance to LPS. However, the existing data allow for rejection of this intriguing hypothesis.
The first sign of tolerance to LPS is attenuation of the second phase of biphasic fever (whether LPS or interleukin-1 induced), without tangible changes in the first phase and without changes in the monophasic response to a low pyrogen dose (8). Yet well-nourished rats with subdiaphragmatic truncal vagotomy do not respond to a monophasic fever-inducing dose of intravenous LPS, but show no abnormality in the second febrile phase when injected with a wide range of higher doses (4). This is exactly the opposite of what is expected in LPS tolerance.
Our recent study with selective subdiaphragmatic vagotomies (7)
provides an even stronger argument against the translocation hypothesis. Indeed, if vagotomy were to result in the proposed sequela
(intestinal dysfunction
subsequent bacterial translocation from the guteventual tolerance to LPS), it would be denervation of the intestine (and/or perhaps stomach) that is responsible for these events. However, the rats with a denervated intestine (selective celiac vagotomy) exhibited no suppression of LPS fever and
neither did the animals with selective gastric vagotomy. In contrast,
the animals with selective hepatic vagotomy displayed drastically
reduced fevers. This is despite the fact that the hepatic branch is a
small, primarily afferent nerve, minimally contributing to efferent
innervation of the gut. Moreover, selective transection of the hepatic
branch does not lead to those devastating changes in gastrointestinal
functions that are common in animals with gastric and, to a lesser
extent, celiac vagotomies. Obviously, subdiaphragmatic vagotomy induces
febrile nonresponsiveness via a mechanism localized in the liver
and/or portal vein, but not in the gut. We conclude that the
hypothesis by Scammell and colleagues (5) does not satisfactorily
explain the published results of vagotomy experiments (3, 4, 6) and,
therefore, does not dismiss the current concept of vagal afferents
conveying peripheral pyrogenic signals to the brain.
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REFERENCES |
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Top
Abstract
Letter
References
Reply
References
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1.
Do
anay, M.,
N. A. Kama,
A. Yazgan,
M. Aksoy,
G. Ergül,
and
A. Tekeli.
The effects of vagotomy on bacterial translocation: an experimental study.
J. Surg. Res.
71:
166-171,
1997[Medline].
2.
Romanovsky, A. A.,
V. A. Kulchitsky,
C. T. Simons,
N. Sugimoto,
and
M. Székely.
Cold defense mechanisms in vagotomized rats.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R784-R789,
1997
3.
Romanovsky, A. A.,
V. A. Kulchitsky,
C. T. Simons,
N. Sugimoto,
and
M. Székely.
Febrile responsiveness of vagotomized rats is suppressed even in the absence of malnutrition.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R777-R783,
1997
4.
Romanovsky, A. A.,
C. T. Simons,
M. Székely,
and
V. Kulchitsky.
The vagus nerve in the thermoregulatory response to systemic inflammation.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R407-R413,
1997
5.
Scammell, T. E.,
J. D. Griffin,
J. K. Elmquist,
and
C. B. Saper.
Microinjection of a cyclooxygenase inhibitor into the anteroventral preoptic region attenuates LPS fever.
Am. J. Physiol.
274 (Regulatory Integrative Comp. Physiol. 43):
R783-R789,
1998
6.
Sehic, E.,
and
C. M. Blatteis.
Blockade of lipopolysaccharide-induced fever by subdiaphragmatic vagotomy in guinea pigs.
Brain Res.
726:
160-166,
1996[Medline].
7.
Simons, C. T.,
V. A. Kulchitsky,
N. Sugimoto,
L. D. Homer,
M. Székely,
and
A. A. Romanovsky.
Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis?
Am. J. Physiol.
275 (Regulatory Integrative Comp. Physiol. 44):
R63-R68,
1998
8.
Yamashiro, O.,
A. Morimoto,
Y. Sakata,
T. Watanabe,
and
N. Murakami.
Febrile and metabolic tolerance to endotoxin in human recombinant interleukin-1
in rabbits.
Am. J. Physiol.
264 (Regulatory Integrative Comp. Physiol. 33):
R1180-R1185,
1993
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Andrej A. Romanovsky Thermoregulation Laboratory Legacy Holladay Park Medical Center Portland, Oregon 97208-3950 |
To the Editor: In our recent article (9), we described the
attenuation of lipopolysaccharide (LPS) fever by inhibition of
prostaglandin synthesis in the preoptic area. We and others have
proposed that LPS and circulating cytokines may activate perivascular
and meningeal cells, which then release prostaglandin E2 into the preoptic area to
initiate fever. As a small point in our discussion, we suggested that
febrile unresponsiveness to LPS after vagotomy could be due to the
development of tolerance to LPS. Specifically, bacterial translocation
can occur after gastric or truncal vagotomies (2) and an increased
portal bacterial load could produce LPS tolerance. Romanovsky presents
well-reasoned arguments against this idea and in support of the vagal
hypothesis, but we feel this perspective cannot account for many
observations.
Romanovsky argues that LPS tolerance results in attenuation of the
second phase of fever but has little effect on the first phase. This
phenomenon has been shown in several studies in which animals were
treated with LPS for several days, but we are unaware of any in
which a low dose of LPS or bacteria was administered over several
weeks, modeling the tolerance that may occur with vagotomy. Direct
evidence such as measurements of portal LPS, Kupffer cell reactivity,
and cytokine concentrations and bioactivity after vagotomy may help
clarify this important concern.
The strongest evidence in support of the vagal hypothesis is Simons and
colleagues (10) recent study that demonstrated an attenuation of fever
to a very low dose of intravenous LPS (1 µg/kg) after hepatic but not
celiac or gastric vagotomy. The authors effectively demonstrate that
the hepatic branch of the vagus nerve accounts for much of the effect
of subdiaphragmatic vagotomy. Still, it is important to point out that
after LPS these hepatic vagotomy rats had persistently higher rectal
temperatures than the vehicle controls. Restraint stress can increase
portal concentrations of LPS and interleukin-6 (11), and it
is possible that subtle stress fevers could be masking small LPS
fevers. More importantly, these researchers have shown
that slightly higher doses of LPS (10 µg/kg iv) produce normal
fevers in vagotomized rats (8), indicating the existence of other,
nonvagal signaling pathways
Several lines of evidence suggest an important signaling role for
barrier cells at the blood-brain interface. Low doses of systemic LPS
or interleukin-1 induce production of interleukin-1 and
cyclooxygenase-2 (COX-2) on central nervous system (CNS) endothelial cells, perivascular microglia, and meningeal macrophages, indicating that these cells can respond to blood-borne pyrogens (1, 3, 7). In
addition, LPS-induced activation of autonomic regulatory neurons as
indicated by expression of c-Fos and corticotropin-releasing factor
(CRF) is not blocked by vagotomy (5).
As we, Romanovsky, and others have previously suggested (4, 6, 8),
pyrogens may signal the brain through multiple routes, depending on the
site and intensity of inflammation. It is possible that the hepatic
branch of the vagus may be one of the most sensitive signaling
pathways. However, LPS-induced COX-2 expression in CNS barrier cells
and the persistence of c-Fos and CRF after vagotomy indicates that
nonvagal, vascular pathways also play an essential role in the febrile
response. Future experiments may help clarify the relative
contributions and interactions of these vagal and vascular mechanisms.
REPLY
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Abstract
Letter
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REFERENCES |
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Top
Abstract
Letter
References
Reply
References
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1.
Cao, C.,
K. Matsumura,
K. Yamagata,
and
Y. Watanabe.
Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever.
Brain Res.
733:
263-272,
1996[Medline].
2.
Do, M.,
N. A. Kama,
A. Yazgan,
M. Aksoy,
G. Ergul,
and
A. Tekeli.
The effects of vagotomy on bacterial translocation: an experimental study.
J. Surg. Res.
71:
166-171,
1997.
3.
Elmquist, J. K.,
C. D. Breder,
J. E. Sherin,
T. E. Scammell,
W. F. Hickey,
D. Dewitt,
and
C. B. Saper.
Intravenous lipopolysaccharide induces cyclooxygenase-2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages.
J. Comp. Neurol.
380:
1-11,
1997[Medline].
4.
Elmquist, J. K.,
T. E. Scammell,
and
C. B. Saper.
Mechanisms of CNS response to systemic immune challenge: the febrile response.
Trends Neurosci.
20:
565-570,
1997[Medline].
5.
Ericsson, A.,
C. Arias,
and
P. E. Sawchenko.
Evidence for an intramedullary prostaglandin-dependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1.
J. Neurosci.
17:
7166-7179,
1997
6.
Licinio, J.,
and
M. L. Wong.
Pathways and mechanisms for cytokine signaling of the central nervous system.
J. Clin. Invest.
100:
2941-2947,
1997[Medline].
7.
Nakamori, T.,
A. Morimoto,
K. Yamaguchi,
T. Watanabe,
and
N. Murakami.
Interleukin-1 beta production in the rabbit brain during endotoxin-induced fever.
J. Physiol. (Lond.)
476:
177-186,
1994
8.
Romanovsky, A. A.,
C. T. Simons,
M. Szekely,
and
V. A. Kulchitsky.
The vagus nerve in the thermoregulatory response to systemic inflammation.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R407-R413,
1997.
9.
Scammell, T. E.,
J. D. Griffin,
J. K. Elmquist,
and
C. B. Saper.
Microinjection of a cyclooxygenase inhibitor into the anteroventral preoptic region attenuates LPS fever.
Am. J. Physiol.
274 (Regulatory Integrative Comp. Physiol. 43):
R783-R789,
1998.
10.
Simons, C. T.,
V. A. Kulchitsky,
N. Sugimoto,
L. D. Homer,
M. Szekely,
and
A. A. Romanovsky.
Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis?
Am. J. Physiol.
275 (Regulatory Integrative Comp. Physiol. 44):
R63-R68,
1998.
11.
Yagi, S., A. Takakaki, K. Ito, M. Maeda, and T. Hori.
Changes in IL-6 and LPS levels in the hepatoportal vein during
non-inflammatory stress in rats. Ann. Mtg. Soc.
Neurosci. New Orleans 1997, p. 713.
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Thomas E. Scammell Joel K. Elmquist Clifford B. Saper Department of Neurology and Program in Neuroscience Harvard Medical School Beth Israel Deaconess Hospital Boston, Massachusetts 02115 |
This article has been cited by other articles:
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  M. K. Hansen, K. T. Nguyen, M. Fleshner, L. E. Goehler, R. P. A. Gaykema, S. F. Maier, and L. R. Watkins Effects of vagotomy on serum endotoxin, cytokines, and corticosterone after intraperitoneal lipopolysaccharide Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2000; 278(2): R331 - R336. [Abstract] [Full Text] [PDF]
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