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 aim of this study was to determine if cyclooxygenase (COX) inhibitors influence immune cell distribution in the small intestinal mucosa and mesenteric lymph nodes (MLNs), the grade of mucosal damage, and the rate of apoptosis in septic rats. The effects induced by a selective COX-2 inhibitor (SC-236) were compared with those of a nonselective COX-1 and -2 inhibitor (indomethacin). Cecal ligation and puncture (CLP), CLP + SC-236 p.o, and CLP + indomethacin p.o, were evaluated. Animals were harvested 6 and 24 h after CLP, respectively. The concentration of proinflammatory cytokines was higher in ascitic fluid than in blood. CLP + SC-236 attenuated IL-6 in plasma and in ascitic fluid and CLP + indomethacin augmented TNF-alpha in ascitic fluid compared with CLP at 6 h. CLP + SC-236 gave a lesser degree of mucosal damage compared with CLP alone or with indomethacin at 6 and 24 h (P < 0.05). Untreated CLP had significant reductions in the number of T lymphocytes in the villi and increases of macrophages in the mucosa and MLNs compared with controls (P < 0.05). CLP + indomethacin decreased T lymphocytes in the villi and MLNs. CLP caused an enhanced apoptosis in the mucosa compared with controls (P < 0.05), pretreatment with COX inhibitors did not significantly change this. Both COX inhibitors enhanced apoptosis in MLNs and attenuated the increase of macrophages in mucosa and MLNs (P < 0.05). It is proposed that the increased apoptosis and the decrease in T cells in the mucosa may be causally related. Apoptosis of lymphocytes may impair the immunologic defense in sepsis. Furthermore, loss of intestinal epithelial cells may compromise bowel wall integrity and facilitate translocation.
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PMID:Influence of cyclooxygenase inhibitors on gut immune cell distribution and apoptosis rate in experimental sepsis. 1652 53

Pyruvic acid, an intermediate metabolite of glucose, an effective scavenger of reactive oxygen species (ROS), inhibits tumor necrosis factor-alpha production and NF-kappaB signaling pathways, reduces circulating levels of HMGB1 (high mobility group B1), decreases COX-2 (cyclo-oxygenase-2), iNOS (inducible nitric oxide synthase), and IL-6 (interleukin-6) mRNA expression in liver, ileal mucosa, and colonic mucosa in animal models with endotoxemia. These studies suggest that pyruvate has potent anti-oxidant and anti-inflammatory actions. Insulin influences the production of pyruvate by its action on glucose metabolism and pyruvate is an insulin secretagogue. This suggests that in metabolic syndrome X, obesity, hypertension, diabetes mellitus, and cancer (where insulin resistance is common due to enhanced TNF-alpha production) pyruvate plays a role. This may have relevance to the use of glucose-insulin-potassium regimen in these clinical conditions, sepsis, and cancer.
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PMID:Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule. 1664 87

This study examined the role of nitric oxide (NO) on the expression of the hepatic vasoregulatory gene during polymicrobial sepsis. Aminoguanidine (AG, 100 mg/kg) or Nomega-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg) was injected intraperitoneally at 0, 3, 6, 10, and 20 h after a cecal ligation and puncture (CLP). The heart rate increased 24 h after the CLP, and this increase was attenuated by L-NAME and further attenuated by AG. The mean arterial pressure in the CLP animals did not change significantly 24 h after the onset of sepsis but was increased after the L-NAME injection. Sepsis increased the serum aminotransferase levels, which were attenuated by AG but augmented by L-NAME. CLP increased the mRNA level of the ET-1 and ETB receptors in the liver. This increase was prevented by AG but augmented by L-NAME. The level of iNOS and HO-1 mRNA expression were increased by CLP, which was prevented by both AG and L-NAME. The level of TNF-alpha and COX-2 mRNA expression increased after CLP, and was attenuated by AG. These results show that iNOS and eNOS are regulated differently in sepsis. While eNOS appears to have a protective role in liver microcirculation, the strong upregulation of iNOS might contribute to a microvascular dysfunction and hepatic injury.
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PMID:Role of nitric oxide in the expression of hepatic vascular stress genes in response to sepsis. 1788 72

Bacterial lipopolysaccharide (LPS) is a major inducer of systemic inflammatory reactions and oxidative stress in response to microbial infections and may cause sepsis. In the present study, we demonstrate that retinoic acid inhibits LPS-induced activation in transgenic reporter mice and human monoblasts through inhibition of nuclear factor kappaB (NF-kappaB). By using noninvasive molecular imaging of NF-kappaB luciferase reporter mice, we showed that administration of retinoic acid repressed LPS-induced whole-body luminescence, demonstrating in vivo the dynamics of retinoic acid's ability to repress physiologic response to LPS. Retinoic acid also inhibited LPS-induced NF-kappaB activity in the human myeloblastic cell line U937. Retinoic-acid-receptor-selective agonists mimicked - while specific antagonists inhibited - the effects of retinoic acid, suggesting the involvement of nuclear retinoic acid receptors. Retinoic acid also repressed LPS-induced transcription of NF-kappaB target genes such as IL-6, MCP-1 and COX-2. The effect of retinoic acid was dependent on new protein synthesis, was obstructed by a deacetylase inhibitor and was partly eliminated by a signal transducer and activator of transcription-1 (STAT1)/methyltransferase inhibitor, indicating that retinoic acid induces a new protein, possibly STAT1, that is involved in inhibiting NF-kappaB. This provides more evidence for retinoic acid's anti-inflammatory potential, which may have clinical implications in terms of fighting microbial infections.
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PMID:Retinoic acid dampens LPS-induced NF-kappaB activity: results from human monoblasts and in vivo imaging of NF-kappaB reporter mice. 1892 86

Renal excretion of organic anions such as para-aminohippurate is reduced during severe sepsis and following ischemia/reperfusion injury. In order to better define the pathophysiology of sepsis-associated renal tubular dysfunction we measured the effect of lipopolysaccharide on renocortical organic anion transporter (OAT) expression in the rat. Prostaglandin E2 (PGE2) downregulates OATs in vitro, therefore, we also evaluated the effect of the cyclooxygenase (COX)-2 inhibitor parecoxib on this process. Endotoxemia caused a time- and dose-dependent decrease of OAT1 and OAT3 expression that paralleled increased renocortical COX-2 expression and PGE2 formation. Pretreatment with parecoxib decreased endotoxin-stimulated PGE(2) formation. Parecoxib attenuated OAT1 and OAT3 gene repression in the rat kidney following endotoxin treatment and during ischemia/reperfusion-induced acute renal injury. COX-2 inhibition improved the creatinine clearance in lipopolysaccharide-treated rats but not after ischemia/reperfusion-induced acute renal injury. The decreased clearance of para-aminohippurate in rats following endotoxin- or ischemia/reperfusion-induced renal injury was improved by parecoxib. Our findings show that COX-2 derived prostanoids downregulate OATs during lipopolysaccharide-induced acute renal injury.
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PMID:COX-2 inhibition attenuates endotoxin-induced downregulation of organic anion transporters in the rat renal cortex. 1894 99

The liver and lung are not only described as "target organs" in sepsis in most species, but are purported to be sources of circulating inflammatory mediators central to the systemic inflammatory response syndrome (SIRS). As we have recently reported an inflammatory response in the laminar tissue in laminitis similar to that described in "target organs" in human sepsis, we investigated the inflammatory response of the lung and liver in the black walnut extract (BWE) model of equine laminitis to determine (1) if a similar systemic inflammatory response occurs in this laminitis model as described for these organs in human sepsis, and (2) if these organs may be an important source of the inflammatory mediators leading to laminar inflammation. Real-time quantitative PCR (RT-qPCR) was used to measure hepatic and pulmonary mRNA concentrations of IL-1beta, IL-4, IL-6, IL-8, IL-10, TNF-alpha, COX-1 and COX-2. Hepatic samples were assessed from two time points in the developmental/prodromal period: (1) 1.5h post-BWE administration (BWE-1.5H, n = 5), and (2) the "developmental time point" (onset of leukopenia, approximately 3h post-BWE administration, BWE-DEV, n = 5). Pulmonary samples were only assessed for the BWE-DEV group. One control group (CON-3H, n = 5) was used for both the 1.5H and DEV groups. Finally, CD13 immunohistochemistry was performed to assess leukocyte emigration into hepatic and pulmonary parenchyma. Hepatic and pulmonary mRNA concentrations of the proinflammatory cytokines IL-6, IL-8 and TNF-alpha were significantly increased (P < 0.05) in BWE-1.5H and BWE-DEV groups compared to the control group; IL-1beta mRNA concentrations were only increased in the lung. The "anti-inflammatory" cytokines, IL-10 and IL-4, underwent transient decreases at different time points. Significant increases in parenchymal leukocyte numbers occurred in both the lung and liver at the BWE-DEV time point. Hepatic and pulmonary proinflammatory cytokine expression differ from that previously reported for the laminae in that TNF-alpha was increased in the hepatic and pulmonary tissues, the increases in expression of IL-6 and IL-8 are dramatically smaller for the liver and lung compared to those reported for the laminae, and the peak changes appear to occur later in the disease process in the liver than in the laminae (BWE-DEV in liver vs. 1.5H in the laminae).
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PMID:Indices of inflammation in the lung and liver in the early stages of the black walnut extract model of equine laminitis. 1912 60

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

The morphological and functional integrity of the microcirculation is compromised in many cardiovascular diseases such as hypertension, diabetes, stroke, and sepsis. Angiotensin converting enzyme inhibitors (ACEi), which are known to favor bradykinin (BK) bioactivity by reducing its metabolism, may have a positive impact on preventing the microvascular structural rarefaction that occurs in these diseases. Our study was designed to test the hypothesis that BK, via B2 receptors (B2R), protects the viability of the microvascular endothelium exposed to the necrotic and apoptotic cell death inducers H(2)O(2) and LPS independently of hemodynamics. Expression (RT-PCR and radioligand binding) and functional (calcium mobilization with fura-2AM, and p42/p44MAPK and Akt phosphorylation assays) experiments revealed the presence of functional B2R in pig cerebral microvascular endothelial cells (pCMVEC). In vitro results showed that the cytocidal effects of H(2)O(2) and LPS on pCMVEC were significantly decreased by a BK pretreatment (MTT and crystal violet tests, annexin-V staining/FACS analysis), which was countered by the B2R antagonist HOE 140. BK treatment coincided with enhanced expression of the cytoprotective proteins COX-2, Bcl-2, and (Cu/Zn)SOD. Ex vivo assays on rat brain explants showed that BK impeded (by approximately 40%) H(2)O(2)-induced microvascular degeneration (lectin-FITC staining). The present study proposes a novel role for BK in microvascular endothelial protection, which may be pertinent to the complex mechanism of action of ACEi explaining their long-term beneficial effects in maintaining vascular integrity.
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PMID:Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli. 1978 24

Acute endotoxemia is associated with excessive production of proinflammatory mediators by hepatic macrophages and endothelial cells, which have been implicated in liver injury and sepsis. In these studies, we analyzed the role of MSP and its receptor STK in regulating the activity of these cells. Acute endotoxemia, induced by administration of LPS (3 mg/kg) to mice, resulted in increased expression of STK mRNA and protein in liver macrophages and endothelial cells, an effect that was dependent on TLR-4. This was correlated with decreased MSP and increased pro-MSP in serum. In Kupffer cells, but not endothelial cells, MSP suppressed LPS-induced NOS-2 expression, with no effect on COX-2. LPS treatment of mice caused a rapid (within 3 h) increase in the proinflammatory proteins NOS-2, IL-1beta, and TNF-alpha, as well as TREM-1 and TREM-3 and the anti-inflammatory cytokine IL-10 in liver macrophages and endothelial cells. Whereas LPS-induced expression of proinflammatory proteins was unchanged in STK-/- mice, IL-10 expression was reduced significantly. Enzymes mediating eicosanoid biosynthesis including COX-2 and mPGES-1 also increased in macrophages and endothelial cells after LPS administration. In STK-/- mice treated with LPS, mPGES-1 expression increased, although COX-2 expression was reduced. LPS-induced up-regulation of SOD was also reduced in STK-/- mice in liver macrophages and endothelial cells. These data suggest that MSP/STK signaling plays a role in up-regulating macrophage and endothelial cell anti-inflammatory activity during hepatic inflammatory responses. This may be important in protecting the liver from tissue injury.
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PMID:Role of STK in mouse liver macrophage and endothelial cell responsiveness during acute endotoxemia. 2045 8

Nitric oxide (NO) produced by the NO synthase type 2 (NOS-2) is known to have a prominent role in the course of the inflammatory response but less is known concerning the role of NO derived from the constitutive NOS isoforms. We have examined the role of NO derived from NOS-1 in the initiation of the systemic inflammatory response using sepsis models. Injection of LPS in rats induced an early hypotension, NOS-2 expression, increased lung myeloperoxidase activity and increased NO metabolite (NOx) levels in the skeletal muscle. Pre-treatment with 7-nitroindazol (7-NI) prevented all these changes, but its administration after LPS injection was ineffective. Septic (cecal ligation and puncture method, CLP) rats exhibited signs of organ failure, hyporesponsiveness to vasoconstrictors and 75% mortality over 3 days after surgery. Pre-treatment with 7-NI prevented or significantly reduced these alterations. Injection of 7-NI after sepsis onset was without effect. Wild type mice injected with LPS exhibited increased plasma NOx, NOS-2 and COX-2 expression and 80% mortality. NOS-1(-/-) mice injected with LPS exhibited smaller increase in plasma NOx, no NOS-2 and COX-2 expression and reduced mortality. Injection of an NO donor in CLP rats pre-treated with 7-NI or in NOS-1(-/-) mice returned the mortality rate to those of CLP in rats and LPS in mice. Our results demonstrate that NOS-1-derived NO acts as a signaling element and it is essential for the initiation of systemic inflammation as demonstrated by the reduction of the inflammatory response and mortality by both pharmacological inhibition and genetic deletion of NOS-1.
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PMID:NOS-1-derived NO is an essential triggering signal for the development of systemic inflammatory responses. 2165 2


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