Ibuprofen in canine endotoxin shock.

Jacobs, Elizabeth R.; Soulsby, Michael; Bone, Roger C.; Wilson, Frank J.; Hiller, F. Charles

doi:10.1172/jci110645

Cited by 119 publications

(26 citation statements)

References 20 publications

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“…This is consistent with the previous finding that PGE 2 and EP4 agonists attenuated LPS-induced cytokine production in mice (40). However, a number of studies have provided evidence that COX inhibitors can improve survival after the onset of endotoxic shock and COXdeficient mice are resistant to endotoxin-induced inflammation and death (17,19,41). Thus, the precise pathophysiological role of PGE 2 in microbe infection still remains undefined.…”

Section: Figuresupporting

confidence: 90%

“…In contrast, PGE 2 has several detrimental effects in sepsis, including vasodilation and increased vascular permeability (16). Several previous studies have shown that COX inhibitors can improve the survival of mice after burn infection or administration of a lethal dose of LPS (17)(18)(19). These findings indicate that PGs play an important role in microbial inflammation, including sepsis or endotoxemia.…”

Section: T Riggering Receptor Expressed On Myeloid Cells-1 (Trem-1)mentioning

confidence: 99%

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Lipopolysaccharide-Induced Up-Regulation of Triggering Receptor Expressed on Myeloid Cells-1 Expression on Macrophages Is Regulated by Endogenous Prostaglandin E2

Murakami

Kohsaka

Kitasato

et al. 2007

The Journal of Immunology

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Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified cell surface molecule that is expressed by neutrophils and monocytes. TREM-1 expression is modulated by various ligands for TLRs in vitro and in vivo. However, the influence of PGE2, a potential mediator of inflammation, on TREM-1 expression has not been elucidated. In this study, we examined the effects of PGE2 on LPS-induced TREM-1 expression by resident murine peritoneal macrophages (RPM) and human PBMC. PGE2 significantly induced murine TREM-1 (mTREM-1) expression by RPM. Up-regulation of TREM-1 expression was specific to PGE2 among arachidonic acid metabolites, while ligands for chemoattractant receptor-homologous molecule expressed on Th2 cells and the thomboxane-like prostanoid receptor failed to induce mTREM-1 expression. PGE2 also increased expression of the soluble form of TREM-1 by PBMC. LPS-induced TREM-1 expression was regulated by endogenous PGE2 especially in late phase (>2 h after stimulation), because cyclooxygenase-1 and -2 inhibitors abolished this effect at that points. A synthetic EP4 agonist and 8-Br-cAMP also enhanced mTREM-1 expression by RPM. Furthermore, protein kinase A, PI3K, and p38 MAPK inhibitors prevented PGE2-induced mTREM-1 expression by RPM. Activation of TREM-1 expressed on PGE2-pretreated PBMC by an agonistic TREM-1 mAb significantly enhanced the production of IL-8 and TNF-α. These findings indicate that LPS-induced TREM-1 expression on macrophages is mediated, at least partly, by endogenous PGE2 followed by EP4 and cAMP, protein kinase A, p38 MAPK, and PI3K-mediated signaling. Regulation of TREM-1 and the soluble form of TREM-1 expression by PGE2 may modulate the inflammatory response to microbial pathogens.

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Section: Figuresupporting

confidence: 90%

Section: T Riggering Receptor Expressed On Myeloid Cells-1 (Trem-1)mentioning

confidence: 99%

Lipopolysaccharide-Induced Up-Regulation of Triggering Receptor Expressed on Myeloid Cells-1 Expression on Macrophages Is Regulated by Endogenous Prostaglandin E2

Murakami

Kohsaka

Kitasato

et al. 2007

The Journal of Immunology

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“…The ability of ibuprofen to avert hemodynamic effects supports the notion that IL--and TNF-induced increases in cyclooxygenase products contribute significantly to the hemodynamic changes observed. In a variety of models of septic shock, ibuprofen attenuates the increased levels of TXB, PGI2, and PGE2, as well as hemodynamic changes associated with the shock (43)(44)(45)(46). These latter studies suggest that the AA metabolites mediating endotoxin-and cytokine-induced hypotension are similar.…”

Section: Discussionmentioning

confidence: 86%

Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition.

Okusawa¹,

Gelfand²,

Ikejima³

et al. 1988

J. Clin. Invest.

934

298

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In addition to activating T and B lymphocytes, interleukin 1 (IL-1) induces several hematologic and metabolic changes typical of host responses to infection and injury. We now report a new biological property, namely, the induction of hypotension. Rabbits given a single intravenous injection of recombinant human IL-I-beta (5 isg/kg) rapidly developed decreased systemic arterial pressure, which reached the lowest levels after 50-60 min and slowly returned to pre-IL-I values after 3 h. Associated with the hypotension, systemic vascular resistance and central venous pressure fell, while cardiac output and heart rate increased. These responses were prevented by ibuprofen given 15 min before the IL-i. A bolus injection of IL-I followed by a 2-h infusion sustained the hypotension and was associated with leukopenia and thrombocytopenia. Ibuprofen given at the mid-point of the infusion reversed the changes in all hemodynamic parameters, but had no effect on the leukopenia or thrombocytopenia. Tumor necrosis factor (TNF) also induced a shock-like state in rabbits. When the dose of IL-1 or TNF was reduced to 1 ,ug/kg, no hemodynamic changes were observed; however, the combination of these low doses of both cytokines resulted in a profound shock-like state including histological evidence of severe pulmonary edema and hemorrhage. Pretreatment with ibuprofen prevented the hemodynamic, leukocyte, and platelet changes induced by the low-dose cytokine combination, and ameliorated the pulmonary tissue damage.These results demonstrate that IL-1, like TNF, possesses the ability to induce hemodynamic and hematological changes typical of septic shock, and that the combination of IL-I and TNF is more potent than either agent alone. These effects seem to require cyclooxygenase products, and suggest that intravenous cyclooxygenase inhibitors may be of therapeutic value in patients with IL-i/TNF-mediated shock.

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“…In both human and animal studies, nonspecific inhibitors of COX, such as indomethacin or ibuprofen, showed improvement in either the morbidity or mortality associated with sepsis or endotoxin shock. [37][38][39][40][41] However, a recent randomized, double-blind, placebo-controlled trial 42 including 455 septic patients revealed no improved survival in the ibuprofen group. The fact that adverse effects of nonselective COX inhibitors (eg, on renal function) are reportedly pronounced in states of sepsis may be of relevance for the outcome in this context.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 Inhibition Attenuates Lipopolysaccharide-Induced Cardiovascular Failure

et al. 2002

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Abstract-The present study aimed to determine the relevance of cyclooxygenase-2 (COX-2)-derived prostanoids for the adverse effects of lipopolysaccharides (LPSs) on cardiovascular function. For this goal, male Sprague-Dawley rats received a single intravenous dose of LPS (10 mg/kg) and were treated with different cyclooxygenase inhibitors. Injection of LPS caused a marked decrease of systolic arterial pressure, from 128 to 79 mm Hg, and a concomitant increase of heart rate, from 380 to 530 minutes Ϫ1 . Both the decrease of systemic arterial pressure and the increase of heart rate induced by LPS were almost absent if the animals also received the COX-2 blocker rofecoxib (20 mg/kg), regardless whether the drug was given 1 hour before or 1 hour after LPS. Although plasma and organ levels of prostanoids were lowered by rofecoxib, the characteristic LPS-induced increases of NO synthase II and COX-2 gene expression, as well as of plasma and tissue nitrate/nitrite concentrations, were not affected by rofecoxib. Although rofecoxib treatment did also not change LPS-induced tissue cytokine concentrations, it markedly improved LPS-induced liver damage, as indicated by the decrease of transaminases. Moreover, the overall well-being of the LPS-injected animals improved on concomitant treatment with the COX-2 inhibitor. Taken together, our data suggest that COX-2-derived prostanoids are major mediators for the detrimental effects of LPS on cardiovascular and organ function. Key Words: shock Ⅲ cyclooxygenase Ⅲ hemodynamics Ⅲ prostaglandins Ⅲ nitric oxide I t is well known that the release of lipopolysaccharides (LPS) from Gram-negative bacteria into the blood stream (eg, in the course of an infection) causes a number of serious adverse effects, such as an increase of body temperature, decrease of blood pressure, and multiorgan failure. [1][2][3] There is consensus that the first mediators in the cascade of LPSinduced events are cytokines. 1,2 These, in turn, induce the expression of a number of enzymes, generating a second class of mediators, which are meant to support the body's defense against bacterial invaders but also mediate adverse effects. Characteristic cytokine-induced enzymes in this context are the inducible isoforms of NO synthase (NOS-II) and cyclooxygenase-2 (COX-2). 2,4,5 Thus, it is clear that the increase of body temperature and local inflammatory reactions are triggered by COX-2-derived prostanoids. [5][6][7] LPS septicemia leads to cardiovascular failure, as reflected by a strong decrease of arterial blood pressure that is resistant to vasoconstrictor hormones. 8 -12 The mechanisms leading to LPSinduced hypotension have not yet been clearly identified. In view of the ubiquitous and strong stimulation of NO formation through NOS-II, it has been assumed that this particular vasodilator plays the major role for the decrease of arterial resistance. 1,2,4 Moreover, it has been observed that inhibitors of NOS-II such as L-canavanine, S-methylisothiourea, or aminoguanidine attenuate LPS-induced decrease of blood ...

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Ibuprofen in canine endotoxin shock.

Cited by 119 publications

References 20 publications

Lipopolysaccharide-Induced Up-Regulation of Triggering Receptor Expressed on Myeloid Cells-1 Expression on Macrophages Is Regulated by Endogenous Prostaglandin E2

Lipopolysaccharide-Induced Up-Regulation of Triggering Receptor Expressed on Myeloid Cells-1 Expression on Macrophages Is Regulated by Endogenous Prostaglandin E2

Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition.

Cyclooxygenase-2 Inhibition Attenuates Lipopolysaccharide-Induced Cardiovascular Failure

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