Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endogenously produced cytokine, tumor necrosis factor-alpha (TNF-alpha), has been shown in adult animal models to be associated with many of the pathophysiologic effects of sepsis, including systemic hypotension and hemorrhagic necrosis. TNF-alpha can induce the release of various vasoactive arachidonic acid metabolites, suggesting that TNF-alpha may act either directly or via intermediary substances in producing its effects. The pathophysiologic role of TNF-alpha in neonatal sepsis, especially its potential effect on pulmonary vascular tone, is presently unknown. To assess the role of TNF-alpha in neonatal sepsis, 19 piglets (19 +/- 5 d old) were anesthetized, intubated, paralyzed, mechanically ventilated, and catheterized to assess pulmonary and systemic vascular hemodynamics and pulmonary gas exchange. The multiple inert gas elimination technique was used to assess ventilation perfusion matching. A 30-min infusion of human recombinant TNF-alpha (250 micrograms/kg total dose) was administered to animals pretreated with either 10 mg/kg dazmegrel, a thromboxane synthase inhibitor (n = 9) or placebo (n = 10). TNF-alpha alone induced a prompt and sustained rise in pulmonary arterial pressure and pulmonary vascular resistance that continued at least for 2 h after onset of the infusion. In contrast, the animals pretreated with dazmegrel demonstrated no rise in pulmonary vascular resistance until 2 h after the onset of the infusion. Neither group of animals demonstrated a significant decline in arterial PO2 or evidence from inert gas analysis of VA/Q mismatching or increase in intrapulmonary shunt.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor-induced neonatal pulmonary hypertension: effects of dazmegrel pretreatment. 234 73

To test the hypothesis that release of endothelium-derived relaxing factor/nitric oxide is inhibited by Gram-negative lipopolysaccharide (LPS; endotoxin), we examined endothelium-independent and endothelium-dependent vasodilator agents in aortic vascular smooth muscle isolated from guinea pigs 4 h after injection of saline (controls) or induction of Escherichia coli endotoxemia. LPS significantly inhibited vasodilator responses to the endothelium-dependent agonists acetylcholine (ACh; 10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). However, LPS did not affect vasodilator responses to the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase (NOS) inhibitor N gamma-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to ACh; whereas, the cyclooxygenase inhibitor indomethacin (INDO) did not reduce vasodilator effects of ACh. Neither L-NAME nor INDO affected the vasodilator effects of nitroprusside in LPS or control vessels. In contrast, L-NAME converted the vasodilator action of ADP to a vasoconstrictor response that was blocked individually by INDO and the thromboxane synthase inhibitor dazoxiben, suggesting that ADP releases NO and also the vasoconstrictor and platelet aggregating eicosanoid thromboxane A2. These findings suggest that acute (4 h) endotoxemia inhibits function of the constitutive isoform of NOS in vascular endothelial cells. Since L-NAME unmasked a vasoconstrictor action of the endogenous purinoceptor agonist ADP, pharmacologic agents that inhibit NOS may exacerbate LPS-induced inhibition of endothelial NOS; this series of events could lead to diminution of vasodilator reserves and perhaps to augmentation of platelet aggregation during Gram-negative sepsis.
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PMID:Inhibition of endothelium-dependent vasodilation by Escherichia coli endotoxemia. 753 38

Increased release of endothelium-derived relaxing factor/nitric oxide has been proposed as the final common pathway for vasodilator responses to gram-negative lipopolysaccharide (endotoxin). To test this hypothesis, we examined endothelium-dependent and endothelium-independent vasodilator agents in vascular smooth muscle isolated from guinea pigs 16 hours after injection of saline (control group) or induction of Escherichia coli endotoxemia; aortic rings (approximately 1 mm in diameter) were studied with standard isometric tension techniques. Endotoxemia resulted in a significant loss of vasodilator responses to the endothelium-dependent receptor agonists acetylcholine (10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). In contrast, endotoxemia did not affect vasodilator responses to either the endothelium-dependent receptor agonist substance P (10(-11)-10(-7) M), the endothelium-dependent and receptor-independent agonist A23187 (10(-9)-10(-6) M), or the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to acetylcholine more in vessels from lipopolysaccharide-injected than control guinea pigs. Unexpectedly, L-NAME converted the endothelium-dependent vasodilator action of ADP to an endothelium-dependent vasoconstrictor response that was blocked individually by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor dazoxiben, and the thromboxane A2 receptor antagonist SQ29548. We conclude that in vivo endotoxemia inhibits the constitutive isoform of nitric oxide synthase in endothelial cells by selectively disrupting receptor-coupled activation mechanisms shared by acetylcholine and ADP. Furthermore, since L-NAME unmasks a thromboxane A2-mediated vasoconstrictor action of the endogenous purinoceptor agonist ADP, drugs that inhibit nitric oxide synthase could exacerbate sepsis-induced vasoconstriction and ischemia by synergizing with lipopolysaccharide-induced inhibition of endothelial nitric oxide synthase.
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PMID:Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia. 767 34

Both tumor necrosis factor (TNF) and platelet-activating factor (PAF) are released during sepsis and are important mediators of septic lung injury. I investigated the interactions of TNF and PAF on vasoactive responses in the pulmonary circulation. In isolated rat lungs perfused with a cell- and plasma-free physiological salt solution, PAF (0.01- and 0.1-micrograms boluses) caused transient dose-dependent pulmonary arterial and venous constrictions. In vivo pretreatment of the rats with TNF (0.02 or 0.2 mg/kg i.v.) 1 h before lung isolation increased lung myeloperoxidase activity and markedly enhanced PAF-induced pulmonary vasoconstriction without affecting the pressor responses to angiotensin II or hypoxia. In contrast, pretreatment with lipopolysaccharide (10 mg/kg), which increased lung myeloperoxidase to the same extent as TNF, caused only a modest enhancement of PAF-induced vasoconstriction associated with reduced pressor responses to angiotensin II and hypoxia. Ex vivo perfusion of isolated lungs with TNF for 1 h did not affect PAF vasoconstriction. The TNF-induced potentiation of PAF vasoconstriction was not altered by depletion of circulating neutrophils with vinblastine but was blocked by Dazmegrel, a thromboxane synthase inhibitor. Thus, TNF potentiates PAF-induced pulmonary vasoconstriction by an in vivo mechanism that is neutrophil independent but thromboxane dependent. This TNF-PAF interaction likely contributes to the development of pulmonary hypertension during sepsis.
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PMID:TNF potentiates PAF-induced pulmonary vasoconstriction in the rat: role of neutrophils and thromboxane A2. 789 27

In the present study, we have investigated the effects of nitric oxide (NO) synthase inhibition on mortality in lipopolysaccharide (LPS)-induced sepsis in mice. Serum nitrite levels peaked at 15 h after an injection of LPS (10 mg kg-1, i.p.). Aminoguanidine, a selective inducible NO synthase (iNOS) inhibitor, at a dose of 100 mg kg-1 significantly reduced the LPS-induced increase in nitrite levels and improved mortality. Econazole, iNOS inhibitor, calmodulin antagonist, 5-lipoxygenase and a specific thromboxane synthase inhibitor, at a 1 mg kg-1 dose significantly decreased the LPS-induced increase in nitrite levels, but increased mortality 4. 9-fold when compared to the LPS group (control). Indomethacin, a putative iNOS and non-selective cyclo-oxygenase (COX) inhibitor, of 1, 10 and 100 mg kg-1, dose dependently decreased the LPS-induced increase in nitrite levels. This decrease was significantly different from the control at 10 and 100 mg kg-1 dose levels. When indomethacin (100 mg kg-1) was combined with aminoguanidine (100 mg kg-1), LPS-induced nitrite levels were significantly attenuated. NO precursor, L-arginine, was added to this combination in order to test the inhibition of iNOS activity which resulted in no change in nitrite levels. An indomethacin and aminoguanidine combination increased mortality twofold when compared to the control. The addition of L-arginine to the combination enhanced the mortality rate to 1.5-fold. These results suggest that NO appears to play a role in the LPS-induced septic shock model in mice. The improvement in sepsis-induced mortality enhanced by aminoguanidine by the inhibition of iNOS but not with the other agents or combinations should be re-evaluated in order to make an appropriate choice of the therapeutic target. In addition, it may also suggest that other mediators, such as arachidonic acid products and cytokines play a role in septic shock pathogenesis as well. (c) 1998 The Italian Pharmacological Society.
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PMID:Effects of nitric oxide synthase inhibition in lipopolysaccharide-induced sepsis in mice. 980 22

Sepsis may lead to deranged thromboxane-prostacyclin ratio with consecutive organ dysfunction. Because of the suggested role of the gut in the pathogenesis of septic shock and multiple organ failure, we investigated the effects of the novel dual thromboxane synthase inhibitor and receptor antagonist DTTX-30 (TRASI) on intestinal tissue perfusion, O2 kinetics, and energy metabolism over 24 h of hyperdynamic, normotensive porcine endotoxemia. Before, 12, 18, and 24 h after starting continuous i.v. endotoxin (LPS), we measured portal venous (PV) blood flow, intestinal oxygen extraction (iO2ER), intracapillary hemoglobin O2 saturation (HbO2%) of the ileal wall, intramucosal ileal PCO2, PV lactate-pyruvate (L-P) ratio, and plasma levels of thromboxane and prostacyclin. Treatment with TRASI (0.12 mg/kg i.v. bolus injection followed by an infusion of 0.29 mg/kg/h) initiated after 12 h of LPS infusion markedly reduced the plasma thromboxane levels and attenuated the LPS-induced fall in systemic vascular resistance, resulting in hemodynamic stabilization. TRASI did not influence the LPS-induced increase in PV blood flow nor intracapillary HbO2%, thus reflecting unchanged microcirculatory O2 availability and decreased iO2ER, possibly because of reduced O2 requirements. Nevertheless, TRASI prevented the LPS-induced increase in the PV L-P ratio, attenuated the progression of the ileal mucosal-arterial PCO2 gap, and tended to attenuate the gradual fall of PV pH. Hence, compounds like TRASI may beneficially influence LPS-related derangements of gut energy metabolism.
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PMID:Effects of the combined thromboxane receptor antagonist and synthase inhibitor DTTX-30 on intestinal O2-exchange and energy metabolism during hyperdynamic porcine endotoxemia. 1077 20

Enhanced prostanoid generation has been implicated in vascular abnormalities occurring during endotoxemia and sepsis, and the lung is particularly prone to such events. Prostanoids are generated from arachidonic acid (AA) via cyclooxygenase (COX)-1 or -2, both isoenzymes recently demonstrated to be expressed in different lung cell types. Upregulation of COX may underlie the phenomenon that endotoxin [lipopolysaccharide (LPS)]-exposed lungs show markedly enhanced vasoconstrictor responses to secondarily applied stimuli (priming). Isolated rat lungs were perfused with a physiological salt buffer solution in the absence and presence of 1.5% rat plasma and exposed to different concentrations of LPS (1,000 or 10,000 ng/ml) during a 2-h priming period. No change in physiological variables was noted during this period, although enhanced baseline liberation of both thromboxane (Tx) A(2) and PGI(2) as well as of tumor necrosis factor (TNF)-alpha was evident compared with that in control lungs in the absence of LPS. LPS priming caused a significant elevation in AA-induced pulmonary arterial pressure, ventilation pressure, and lung weight gain. Concomitant increased levels of TxA(2) were found in the buffer perfusate. All changes were largely suppressed by three selective, structurally unrelated COX-2 inhibitors (NS-398, DUP-697, and SC-236) in both buffer- and buffer-plasma-perfused lungs. Anti-TNF-alpha neutralizing antibodies were ineffective under conditions of buffer perfusion. In the presence of plasma components, manyfold augmented TNF-alpha generation was noted, and anti-TNF-alpha antibodies significantly suppressed the increase in ventilation pressure but not in the vascular pressor response and lung edema formation. We conclude that the propensity of LPS-primed lungs to respond with enhanced vasoconstriction, edema formation, and bronchoconstriction to a secondarily applied stimulus proceeds nearly exclusively via COX-2 and increased Tx formation, with TNF-alpha generation being involved in the change in bronchomotor reactivity in the presence of plasma constituents. In context with recent immunohistological investigations, LPS-induced upregulation of the COX-2-thromboxane synthase axis in vascular and bronchial smooth muscle cells is suggested to underlie these events.
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PMID:Endotoxin priming of the cyclooxygenase-2-thromboxane axis in isolated rat lungs. 1083 25

Group B streptococci (GBS) cause fatal sepsis in newborns. Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension. In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP-3 receptor gene expression. Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP-3 receptor in infected lung tissue, parecoxib did not suppress urine levels of thromboxane like indometacin. We presume that COX-2 inhibition in GBS sepsis is associated with enhanced thrombogenicity.
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PMID:Parecoxib does not suppress thromboxane synthesis in newborn piglets with group B streptococcal sepsis. 1952 95