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)

To elucidate the possible roles of nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) in the pathophysiology of serogroup A streptococcal (GAS) peritoneal sepsis, we investigated the effects of aminoethylisothiourea (AE-ITU), an inducible NO synthase (iNOS) inhibitor, and a ROS scavenger, and the ET-1 receptor antagonist bosentan. In rats, live GAS inocula, 3 x 10(8) and 1 x 10(9) cfu/kg, entailed a 24-h mortality of 10% and 90%, respectively. GAS caused increases in tissue iNOS activity (9 h), in serum nitrite/nitrate (9-24 h), and in intracellular leukocyte ROS levels (3-6 h). These changes were all prevented by the pre-treatment with AE-ITU. A novel finding was that AE-ITU also prevented the GAS-induced marked increase in plasma ET-1 at 6 h. Short-term (7-h) survival was improved by both AE-ITU and by bosentan. The mechanism(s) for the beneficial effects of AE-ITU may possibly be a combined mode of action; iNOS inhibition, ROS scavenging, and inhibition of the increase in plasma ET-1 caused by GAS.
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PMID:Aminoethyl-isothiourea inhibits the increase in plasma endothelin-1 caused by serogroup A streptococci and prolongs survival in rat peritoneal sepsis. 1138 17

Cytokines play an important role in the lipid disturbances commonly associated with sepsis. Ketogenesis is inhibited during sepsis, and tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) have been suggested to mediate this impairment, irrespective of the ketogenic substrate (fatty acid or branched chain ketoacid). However, the underlying mechanism of cytokine action is still unknown. First we investigated the possible role of the induction of nitric oxide (NO) synthesis, using rat hepatocyte monolayers. Hepatocytes were incubated for 6 h, with either alpha -ketoisocaproate (KIC) (1 mM) or oleic acid (0.5 mM) in the presence or absence of TNF alpha (25 microg/L) and IL-6 (15 microg/L). In some experiments, cells were incubated with NO synthase (NOS) inhibitors. The ketone body (beta -hydroxybutyrate and acetoacetate) production and nitrite production were measured in the incubation medium. Our results indicated no involvement of nitric oxide in the inhibitory action of cytokines on ketogenesis. Secondly, we showed that cycloheximide (10(-4)M) did not counteract the cytokine-mediated ketogenesis decrease; hence, the effects of cytokines on ketogenesis are not protein synthesis-dependent. The cytokine-mediated inhibition of ketogenesis is therefore unrelated to either NO production or protein synthesis.
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PMID:Cytokine-mediated inhibition of ketogenesis is unrelated to nitric oxide or protein synthesis. 1147 28

Our study aimed to characterize the mechanisms underlying the attenuated cardiovascular responsiveness toward the renin-angiotensin system during sepsis. For this purpose, we determined the effects of experimental Gram-negative and Gram-positive sepsis in rats. We found that sepsis led to a ubiquitous upregulation of NO synthase isoform II expression and to pronounced hypotension. Despite increased plasma renin activity and plasma angiotensin (Ang) II levels, plasma aldosterone concentrations were normal, and the blood pressure response to exogenous Ang II was markedly diminished in septic rats. Mimicking the fall of blood pressure during sepsis by short-term infusion of the NO donor sodium nitroprusside in normal rats did not alter their blood pressure response to exogenous Ang II. Therefore, we considered the possibility of an altered expression of Ang II receptors during sepsis. It turned out that Ang II type 1 receptor expression was markedly downregulated in all organs of septic rats. Further in vitro studies with rat renal mesangial cells showed that NO and a combination of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) downregulated Ang II type 1 receptor expression in a synergistic fashion. In summary, our data suggest that sepsis causes a systemic downregulation of Ang II type 1 receptors that is likely mediated by proinflammatory cytokines and NO. We suggest that this downregulation of Ang II type 1 receptors is the main reason for the attenuated responsiveness of blood pressure and of aldosterone formation to Ang II and, therefore, contributes to the characteristic septic shock.
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PMID:Downregulation of angiotensin II type 1 receptors during sepsis. 1150 72

In sepsis-induced acute renal failure, actin cytoskeletal alterations result in shedding of proximal tubule epithelial cells (PTEC) and tubular obstruction. This study examined the hypothesis that inflammatory cytokines, released early in sepsis, cause PTEC cytoskeletal damage and alter integrin-dependent cell-matrix adhesion. The question of whether the intermediate nitric oxide (NO) modulates these cytokine effects was also examined. After exposure of human PTEC to tumor necrosis factor-alpha, interleukin-1 alpha, and interferon-gamma, the actin cytoskeleton was disrupted and cells became elongated, with extension of long filopodial processes. Cytokines induced shedding of viable, apoptotic, and necrotic PTEC, which was dependent on NO synthesized by inducible NO synthase (iNOS) produced as a result of cytokine actions on PTEC. Basolateral exposure of polarized PTEC monolayers to cytokines induced maximal NO-dependent cell shedding, mediated in part through NO effects on cGMP. Cell shedding was accompanied by dispersal of basolateral beta(1) integrins and E-cadherin, with corresponding upregulation of integrin expression in clusters of cells elevated above the epithelial monolayer. These cells demonstrated coexpression of iNOS and apically redistributed beta(1) integrins. Attachment studies demonstrated that the major ligand involved in cell anchorage was laminin, probably through interactions with the integrin alpha(3)beta(1). This interaction was downregulated by cytokines but was not dependent on NO. These studies provide a mechanism by which inflammatory cytokines induce PTEC damage in sepsis, in the absence of hypotension and ischemia. Future therapeutic strategies aimed at specific iNOS inhibition might inhibit PTEC shedding after cytokine-induced injury and delay the onset of acute renal failure in sepsis.
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PMID:Coexpressed nitric oxide synthase and apical beta(1) integrins influence tubule cell adhesion after cytokine-induced injury. 1167 13

Sepsis, resistant to therapy, results in the development of septic (endotoxin) shock. The latter is caused by the endotoxins of different Gram-negative bacteria. Endotoxin (bacterial lipopdisacharide--LPS) interacts with cells through specific membrane or plasma soluble endotoxin receptors (sCD14, mlD14, LBP, CD13/CD14, CD16, CD116/CD18, L-selectin, etc.). Endotoxin interaction with the mCD14 receptor of the monocytes, macrophages and the neutrophils results in the production of a number of proinflammatory cytokines--tumor necrosis factor alpha (TNF alpha), interleukines 1 and 6 (IL-1 and IL-6, etc), antiinflammatory cytokines--interleukines 10 and 12 (IL-10 and IL-12), cell adhesion molecules (P-selectin, E-selectin, ICAM-1, VCAM-1, etc.) and inducible enzymes: inducible NO synthase (iNOS), inducible phospholipase A2 (cPL-A2), inducible cyclooxygenase (COX-2). All pathologic processes in the structure and function of human body during endotoxin shock are a result of the disbalance of a number of mediators with a proinflammatory and antiinflammatory effects.
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PMID:[The role of bacterial endotoxins, receptors and cytokines in the pathogenesis of septic (endotoxin) shock]. 1168 28

Incubation of rat aortas with endotoxin and interferon-gamma for 24 h resulted in an aortic oxygen consumption that was substantially inhibited and strongly oxygen dependent (37% inhibition at 160 microM O(2) and 62% inhibition at 80 microM O(2) relative to untreated aortas). This respiratory inhibition was reversed by a nitric oxide (NO) scavenger (oxyhemoglobin) or by an inhibitor of inducible NO synthase [N-(3-(aminomethyl)benzyl)acetamide x 2HCl, 1400W], but not by an inhibitor of soluble guanylate cyclase (1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one). Addition of 1 microM NO to untreated aortas caused rapid and reversible inhibition of oxygen consumption that was greater at lower oxygen concentrations. Incubation of endothelial cells isolated from rat aortas with endotoxin and interferon-gamma for 24 h resulted in a steady-state NO concentration of approximately 0.5 microM and 90% inhibition of cellular oxygen consumption that was immediately reversed by an NO scavenger (oxyhemoglobin). These results suggest that during inflammation and sepsis, tissue respiration may be substantially reduced due to inhibition by NO of cytochrome oxidase.
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PMID:Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation. 1170 90

Impaired response to catecholamines contributes to the altered hemodynamics in sepsis, which has been attributed to excessive NO formation. We have studied the systemic hemodynamic and local forearm responses and inducible NO synthase (iNOS) expression during experimental endotoxemia in humans. Escherichia coli endotoxin (lipopolysaccharide [LPS]) was administered at doses of 1 or 2 ng/kg to healthy volunteers. In 10 subjects, the systemic pressor effect of phenylephrine was assessed before and after the administration of LPS. In 9 further subjects, forearm blood flow responses to intra-arterial noradrenaline, acetylcholine, glyceryl trinitrate, and N(G)-monomethyl-L-arginine (L-NMMA) were studied at baseline and after LPS administration. Peripheral blood was collected and analyzed for iNOS mRNA and protein. Four hours after LPS, the response of systolic blood pressure (P<0.0005) and heart rate (P<0.05) to phenylephrine was significantly reduced. In the forearm, noradrenaline-induced vasoconstriction was also reduced by approximately 50% (P<0.01), but L-NMMA responsiveness was unchanged. iNOS mRNA or protein was not increased. Marked vascular adrenoceptor hyporeactivity is detectable in the absence of increased NO activity or iNOS expression in endotoxemia, arguing against major involvement of vascular iNOS activity in the acute systemic vasodilation to LPS.
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PMID:Adrenoceptor hyporeactivity is responsible for Escherichia coli endotoxin-induced acute vascular dysfunction in humans. 1178 67

Overproduction of nitric oxide (NO) with attendant oxidative and nitrosative stress has been implicated in sepsis-induced diaphragm dysfunction. Here we determined the impact of controlled mechanical ventilation (MV) on rat diaphragm sarcolemmal injury, inducible NO synthase (iNOS) expression, and oxidative stress during endotoxemia. At 4 h after injection of endotoxin, impaired sarcolemmal integrity and decreased force production by the diaphragm were observed in spontaneously breathing rats. The use of MV during endotoxemia largely eliminated sarcolemmal damage and significantly improved diaphragm force production. These benefits were not associated with alterations in either iNOS expression or protein carbonyls (marker of oxidation), which remained abnormally elevated in septic diaphragms despite MV. Therefore, we hypothesized that the protection afforded by MV was due to its ability to decrease the level of mechanical stress placed on the sarcolemma, because the latter could be hyperfragile in the setting of increased oxidative stress. Using an in vitro system to independently modulate oxidative and mechanical stresses, we confirmed that these two factors act together in a synergistic fashion to favor sarcolemmal injury. Accordingly, our data suggest that MV protects the diaphragm during sepsis by abrogating an injurious interaction between oxidative and biomechanical stresses imposed on the sarcolemma.
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PMID:Mechanical ventilation protects against diaphragm injury in sepsis: interaction of oxidative and mechanical stresses. 1179 Jun 43

The pore-forming cytolysin of Vibrio vulnificus (VVC) causes severe hypotension and vasodilatation in vivo. Under the condition of bacterial sepsis, large amounts of nitric oxide (NO) produced by inducible NO synthase (iNOS) can contribute to host-induced tissue damage causing hypotension and septic shock. In this study, we investigated the effect of purified VVC on NO production in mouse peritoneal macrophages. VVC induced NO production in the presence of interferon-gamma. Increased NO production was not affected by polymyxin B, and heat inactivation of cytolysin abolished the NO-inducing capability. NO production was induced at the same concentration range of cytolysin for pore formation, as evidenced by the release of preloaded 2-deoxy-d-[(3)H]glucose. At the higher concentrations of cytolysin causing the depletion of cellular ATP, no NO production was observed. Increased expression of iNOS and activation of NFkappaB by VVC were confirmed by Western blotting and gel shift assay, respectively. These results suggest the role of cytolysin as an inducer of iNOS and NO production in macrophage and as a possible virulence determinant in V. vulnificus infection.
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PMID:Induction of nitric oxide synthase expression by Vibrio vulnificus cytolysin. 1179 87

Nitric oxide (NO) produced by NO synthase (NOS) serves as a ubiquitous mediator molecule involved in many physiologic lung functions, including regulation of vascular and bronchial tone, immunocompetence, and neuronal signaling. On the other hand, excessive and inappropriate NO synthesis in inflammation and sepsis has been implicated in vascular abnormalities and cell injury. At least three different NOS isoforms (neuronal/brain [bNOS], inducible [iNOS], and endothelial [eNOS]) have been described, which are all expressed in normal lung tissue. We investigated the cell-specific expression of bNOS, iNOS, and eNOS in perfused control rat lungs and lungs undergoing stimulation with endotoxin in the presence and absence of plasma constituents. Lung immunohistochemistry and quantitative evaluation of staining intensity showed endotoxin-induced increase in iNOS expression in particular in bronchial epithelial cells, cells of the bronchus-associated lymphoid tissue (BALT), alveolar macrophages, and vascular smooth muscle cells in a time- and dose-dependent fashion. In endothelial cells, which did not express iNOS at baseline, newly induced iNOS was found in response to endotoxin. In contrast, expression of eNOS was markedly suppressed under endotoxin challenge, particularly in bronchial epithelium, BALT, and alveolar macrophages but also in vascular smooth muscle cells and endothelial cells. eNOS expression in bronchial smooth muscle cells was not altered. In contrast to iNOS and eNOS, cellular expression of bNOS in epithelial cells, nerve fibers, BALT, and endothelial cells did not change in response to endotoxin. All changes in NOS regulation were found to be independent of plasma constituents. We conclude that endotoxin exerts a profound impact on the cell-specific NOS regulation in a large number of lung cell types. Prominent features include de novo synthesis or up-regulation of iNOS, in contrast to down-regulation of eNOS, which may well contribute to vascular abnormalities, inflammatory sequelae, and loss of physiologic functions in septic lung failure.
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PMID:Cell-specific nitric oxide synthase-isoenzyme expression and regulation in response to endotoxin in intact rat lungs. 1195 Sep


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