Critical Care Medicine Division, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania 15261
NORTHOVER AND SUBRAMANIAN
(31) reported in 1962 that treating dogs with
aspirin, a prototypical nonsteroidal anti-inflammatory drug (NSAID),
ameliorated the development of arterial hypotension after the injection
of lipopolysaccharide (LPS). Subsequent to this early report, many
other investigators confirmed that treatment with aspirin or other
NSAIDs improved hemodynamic parameters, organ system function, and even
survival in various animal models of endotoxemia (3, 12, 14,
15) or sepsis (7, 11). The primary pharmacological
action of NSAIDs, of course, is to decrease the formation of
prostaglandins (PGs) and thromboxanes (TXs) by inhibiting
cyclooxygenase (COX), a key enzyme in the biochemical pathway leading
to the formation of these potent mediators (46).
Accordingly, products of the COX pathway, sometimes referred to as
"prostanoids," have been implicated in the pathogenesis of the
deleterious systemic consequences of serious infection and/or
endotoxemia. Other lines of evidence also support this concept. For
example, circulating concentrations of 6-keto-PGF1 We now recognize that there are two COX isoforms, COX-1 and COX-2
(28). COX-1 is constitutively expressed in most tissues (5, 39), whereas COX-2 expression can be induced by
various proinflammatory substances, including LPS, TNF, and interleukin (IL)-1, in a wide variety of cell types (6, 17, 22, 27, 30,
32-34). Accumulating data suggest that the inhibition of COX-2 is actually a key mechanism whereby NSAIDs diminish inflammation (18, 26). Because some of the side effects of treatment
with NSAIDs, such as gastric mucosal irritation, are thought to be caused by inhibition of COX-1, isoform-selective COX-2 inhibitors have
been developed and introduced into clinical practice
(4).
Although COX-2 expression can be increased by proinflammatory
cytokines, the predominant effects of PGE2 tend to be
anti-inflammatory. Thus this mediator has been shown to downregulate a
variety of immunologic responses, including the production of IL-2 by T
cells (2, 19), the activation and proliferation of B cells
(21, 44), the expression of Ia on macrophages
(40), and the phagocytosis of particles by macrophages
(1). PGE2 also inhibits a number of neutrophil
functions, including enzyme release, chemotaxis, and oxygen radical
production (10, 16). Moreover, in a form of negative
feedback, E series PGs downregulate the release of TNF from various
inflammatory cells (25). PG-mediated downregulation of TNF
expression, which occurs at the gene level (20, 24), depends on release of the counterregulatory cytokine IL-10
(42). Interruption of this feedback loop with NSAIDs has
been shown to increase cytokine (TNF, IL-6, or IL-8) release by
stimulated mononuclear cells in vitro (8, 9, 45), in
animals challenged with LPS (36, 38), and in human
volunteers infused with small doses of LPS (29, 41).
Important new information regarding the role of prostanoids and COX-2
in the pathophysiology of endotoxemia and sepsis is provided in the
report by Reddy et al. (35) in this issue of the
American Journal of Physiology-Lung Cellular and Molecular Physiology. These investigators evaluated the effect of
pretreatment with NS-398, a highly selective COX-2 inhibitor, on
survival and inflammatory mediator production in two models of sepsis
in mice (LPS challenge and peritonitis induced by cecal ligation and
puncture). Pretreatment with NS-398 failed to improve long-term
survival in either of the models studied, although in the endotoxemia
model, administration of the COX-2 inhibitor had a modest salutary
effect on early mortality. In addition, although treatment with NS-398 blocked LPS-induced increases in the circulating levels of
immunoreactive PGE2, injection of the COX-2 inhibitor did
not modulate plasma concentrations of TNF or the C-X-C chemokine KC.
Thus, in marked contrast to results that have been previously reported
in studies with isoform nonselective COX inhibitors (14,
15), the data obtained by Reddy et al. (35)
indicate that pharmacological inhibition of COX-2 has only very modest effects on the outcome in experimental sepsis or endotoxemia. Because
these results are discrepant with respect to the findings that have
been obtained with isoform nonselective agents, it is regrettable that
Reddy et al. did not include a "positive control" arm in their
studies to evaluate the effects of treatment with an agent such as
indomethacin or ibuprofen in their own laboratory's models of sepsis.
Certainly, the results reported in this issue of the
American Journal of Physiology-Lung Cellular and Molecular Physiology prompt one to wonder whether similar findings would be
obtained in a study with mice with a targeted disruption of the COX-2 gene.
The results reported by Reddy et al. (35) are also
somewhat discrepant with respect to some earlier findings from studies that used NS-398 to block COX-2 in models of experimental infection. For example, Shoup et al. (37) reported that twice daily
treatment with NS-398 improved long-term survival (from 0 to 45.5%) in
mice subjected to a 15% cutaneous scald burn followed by infection with viable Pseudomonas aeruginosa. Similarly, Strong et al.
(43) showed that administration of NS-398 for 24 h
after trauma (femur fracture) improved survival when mice were
subjected to cecal ligation and puncture 7 days later. It is noteworthy
that NS-398 demonstrated protective effects in two models of sepsis
characterized by infection in the setting of trauma-induced
immunosuppression, whereas the drug was largely ineffective when sepsis
was induced in immunocompetent animals. Taken together, these
observations might suggest that COX-2-derived prostanoids (particularly
PGE2) contribute to immunosuppression induced by trauma but
are relatively unimportant in the pathogenesis of sepsis per
se. The results obtained by Reddy et al. (35)
also suggest that the COX-1 pathway (i.e., the pathway that is not
generally regarded as the one involved in inflammation) is actually
more important than the COX-2 pathway with respect to
prostanoid-induced pathophysiological effects in endotoxemia and
sepsis. Clearly, despite almost 40 years of investigation, we still
have a great deal to learn regarding the role of the prostanoids in the
pathogenesis of sepsis and septic shock.
ARTICLE
TOP
ARTICLE
REFERENCES
(prostacyclin metabolite) and TXB2 (TXA2
metabolite) increase after administration of LPS to experimental
animals (3, 12, 14, 15). Furthermore, blocking prostanoid
production by nonpharmacological means, such as by creating a state of
essential fatty acid deficiency, improves survival after administration
of a lethal dose of LPS (3). In addition, the toxic
effects of tumor necrosis factor (TNF), thought to be one of the
primary cytokines responsible for LPS-induced lethality, can be
ameliorated by treating mice or rats with NSAIDs such as indomethacin
or ibuprofen (13, 23).
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. P. Fink, Critical Care Medicine Division, Univ. of Pittsburgh Medical School, 3550 Terrace St., 616 Scaife Hall, Pittsburgh, PA 15261 (E-mail: finkmp{at}anes.upmc.edu).
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