Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gender-based differences in the incidence and severity of bacterial sepsis render males more susceptible to septic shock than females. However, the mechanisms that underlie this sexual dimorphism remain unclear. In the present study we confirm that males produce significantly higher levels of the inflammatory cytokine IL-6 and the acute phase protein LPS-binding protein (LBP) than females following in vivo lipopolysaccharide (LPS) exposure. It has also been verified that LPS-challenged male-derived macrophages produce higher levels of IL-1beta and lower levels of PGE(2) than similarly treated female-derived cells. Importantly, we demonstrated that male-derived macrophages produce significantly higher levels of the inflammatory chemokine IP-10 following LPS challenge than their female counterparts. It has been demonstrated further that, although resting macrophage levels of mRNA encoding Toll-like receptor 4 (TLR4) and its co-receptor CD14, are not significantly different between genders, male-derived macrophages constitutively express higher levels of these proteins on their cell surface. Elevated circulating levels of LBP and constitutively higher cell surface expression of TLR4 and CD14 on macrophages in males could result in the observed sexual dimorphism in LPS-induced inflammatory mediator production and the greater susceptibility of males to bacterial sepsis.
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PMID:Sexual dimorphism in expression of receptors for bacterial lipopolysaccharides in murine macrophages: a possible mechanism for gender-based differences in endotoxic shock susceptibility. 1657 44

Sepsis and SIRS are affections with major alterations in inflammatory activity. The impact of prostaglandins (PG) and leukotrienes (LT) produced from white blood cells (WBC) in this context is not completely understood. Thirty nine patients with sepsis or SIRS were investigated in comparison to 10 healthy controls. WBC were collected and separately exposed to arachidonic acid (AA) or to nothing else. After centrifugation, the generated PGE(2) and LTCDE(4) with or without stimulation were measured in the supernatant. LT-levels were significantly higher during sepsis/SIRS than in controls whereas PG-levels of patients were decreased to those of controls in basic condition. The relation between the level with and without stimulation showed a significant higher ratio in PG in contrast to LTs. The survivor's ratio in LT levels was significantly higher than that of non-survivors, which did not differ from controls. Generation of LT from WBC is enhanced during sepsis/SIRS, but LT generation after stimulation only in survivors but not in non-survivors. This inability of WBC to generate LT during sepsis in non-survivors could be predictive regarding the outcome of sepsis/SIRS and may be part of the "immunoparalysis" seen during sepsis in association with bad outcome.
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PMID:Functional analysis of eicosanoids from white blood cells in sepsis and SIRS. 1724 52

Brain Natriuretic Peptide (BNP), besides retaining vasodilatory, diuretic and natriuretic properties, is a vasoactive hormone that it is also involved in several cardiac diseases as well as severe sepsis and septic shock. All these conditions are characterized by an ongoing inflammatory response consisting in a complex interaction of pleiotropic mediators derived from plasma or cells, including monocytes and macrophages. However, the relationship between this hormone and inflammation remains to be elucidated. Therefore, the aim of the present study was to evaluate a possible BNP immunomodulatory activity on macrophages. Our results demonstrate that BNP regulates the production of major inflammatory molecules, such as reactive oxygen- and nitrogen species (ROS and RNS), leukotriene B(4) (LTB(4)), prostaglandin E(2) (PGE(2)); modulates the cytokines (TNF-alpha, IL-12 and IL-10) profile, and affects cell motility. These results furnish novel and brand-new proofs on BNP ability of modulating the production of inflammatory mediators in macrophages whose role has broad implications in inflammatory states where increased BNP levels have been reported.
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PMID:Brain Natriuretic Peptide (BNP) regulates the production of inflammatory mediators in human THP-1 macrophages. 1841 Sep 72

Fatal cases of acute shock complicating Clostridium sordellii endometritis following medical abortion with mifepristone (also known as RU-486) used with misoprostol were reported. The pathogenesis of this unexpected complication remains enigmatic. Misoprostol is a pharmacomimetic of PGE(2), an endogenous suppressor of innate immunity. Clinical C. sordellii infections were associated with intravaginal misoprostol administration, suggesting that high misoprostol concentrations within the uterus impair immune responses against C. sordellii. We modeled C. sordellii endometritis in rats to test this hypothesis. The intrauterine but not the intragastric delivery of misoprostol significantly worsened mortality from C. sordellii uterine infection, and impaired bacterial clearance in vivo. Misoprostol also reduced TNF-alpha production within the uterus during infection. The intrauterine injection of misoprostol did not enhance mortality from infection by the vaginal commensal bacterium Lactobacillus crispatus. In vitro, misoprostol suppressed macrophage TNF-alpha and chemokine generation following C. sordellii or peptidoglycan challenge, impaired leukocyte phagocytosis of C. sordellii, and inhibited uterine epithelial cell human beta-defensin expression. These immunosuppressive effects of misoprostol, which were not shared by mifepristone, correlated with the activation of the G(s) protein-coupled E prostanoid (EP) receptors EP2 and EP4 (macrophages) or EP4 alone (uterine epithelial cells). Our data provide a novel explanation for postabortion sepsis leading to death and also suggest that PGE(2), in which production is exaggerated within the reproductive tract during pregnancy, might be an important causal determinant in the pathogenesis of more common infections of the gravid uterus.
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PMID:Misoprostol impairs female reproductive tract innate immunity against Clostridium sordellii. 1868 13

Schisandrin is the main active ingredient isolated from the fruit of Schisandra chinensis Baill. Recent studies have demonstrated that schisandrin exhibits anti-oxidative effects in vivo. In the present study, the effect of schisandrin on plasma nitrite concentration in lipopolysaccharide (LPS)-treated mice was evaluated. It also significantly inhibited carrageenan-induced paw edema and acetic acid-induced vascular permeability in mice. Furthermore, schisandrin had a protective effect on lipopolysaccharide (LPS)-induced sepsis. In vitro, our results are the first that show that the anti-inflammatory properties of schisandrin result from the inhibition of nitric oxide (NO) production, prostaglandin E(2) (PGE(2)) release, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, which in turn results from the inhibition of nuclear factor-kappaB (NF-kappaB), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activities in a RAW 264.7 macrophage cell line.
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PMID:Anti-inflammatory effects of schisandrin isolated from the fruit of Schisandra chinensis Baill. 1862 16

PGE(2), an arachidonic acid metabolite produced by various type of cells regulates a broad range of physiological activities in the endocrine, cardiovascular, gastrointestinal, and immune systems, and is involved in maintaining the local homeostasis. In the immune system, PGE(2) is mainly produced by APCs and it can suppress the Th1-mediated immune responses. The aim of this study was to develop PGE(2)-loaded biodegradable MS that prolong and sustain the in vivo release of this mediator. An o/w emulsion solvent extraction-evaporation method was chosen to prepare the MS. We determined their diameters, evaluated the in vitro release of PGE(2), using enzyme immunoassay and MS uptake by peritoneal macrophages. To assess the preservation of biological activities of this mediator, we determined the effect of PGE(2) released from MS on LPS-induced TNF-alpha release by murine peritoneal macrophages. We also analyzed the effect of encapsulated PGE(2) on inflammatory mediators release from HUVECs. Finally, we studied the effect of PGE(2) released from biodegradable MS in sepsis animal model. The use of this formulation can provide an alternative strategy for treating infections, by modulating or inhibiting inflammatory responses, especially when they constitute an exacerbated profile.
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PMID:Prostaglandin E(2)-loaded microspheres as strategy to inhibit phagocytosis and modulate inflammatory mediators release. 1864 Feb 69

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

Triggering receptor expressed on myeloid cells (TREM)-1 is inducible on monocyte/macrophages and neutrophils and accelerates tissue destruction by propagating inflammatory responses in diseases related to bacterial infection. Its blockade suppressed fatal immune responses in mice models of sepsis without impairing the host defense. However, the influence of TREM-1 on non-bacterial diseases was not elucidated. We describe here that TREM-1 expression was up-regulated by prostaglandin (PG) E(2) as well as lipopolysaccharide. Activation of TREM-1 expressed on PGE(2)-pretreated peripheral blood mononuclear cells by an agonistic TREM-1 mAb significantly enhanced the production of TNFalpha. Indeed, monosodium urate monohydrate (MSU) crystals induced TREM-1 expression in vitro and in vivo. MSU crystals and an anti-TREM-1 agonistic antibody synergistically increased the production of interleukin-1beta compared with stimulation with the crystals alone. Furthermore, TREM-1 was expressed on CD14+ cells in rheumatoid synovial tissue and synovial macrophages from mice with collagen-induced arthritis (CIA). Blockade of TREM-1 ameliorated CIA without affecting T cell and B cell immune responses to the inducing antigen. These results provide evidence that TREM-1 may contribute the development of non-microbial inflammatory diseases through the enhancement of inflammatory responses.
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PMID:[Triggering receptor expressed on myeloid cells-1 as an inflammation amplifier]. 1972 44

Thrombin levels increase at sites of vascular injury and during acute coronary syndromes. It is also increased several fold by sepsis with a reciprocal decrease in the anti-thrombin III levels. In this study we investigate the effects of thrombin on the induction of cyclooxygenase-2 (COX-2) and prostaglandin (PG) production in macrophages. Thrombin-induced COX-2 protein and mRNA expression in RAW264.7 and primary cultured peritoneal macrophages. A serine proteinase, trypsin, also exerted a similar effect. The inducing effect by thrombin in macrophages was not affected by a lipopolysaccharide (LPS)-binding antibiotic, polymyxin B, excluding the possibility of LPS contamination. The increase of COX-2 expression by thrombin was functionally linked to release of PGE(2) and PGI(2) but not thromboxane A(2) into macrophage culture medium. Thrombin-induced COX-2 expression and PGE(2) production were significantly attenuated by PD98059 and SB202190 but not by SP600125, suggesting that ERK1/2 and p38 MAPK activation were involved in this process. This was supported by the observation that thrombin could directly activate ERK1/2 and p38 MAPK in macrophages. A further analysis indicated that the proteinase-activated receptor 1 (PAR1)-activating agonist induced effects similar to those induced by thrombin in macrophages and the PAR1 antagonist-SCH79797 could attenuate thrombin-induced COX-2 expression and PGE(2) release. Taken together, we provided evidence demonstrating that thrombin can induce COX-2 mRNA and protein expression and PGE(2) production in macrophages through PAR1 activation and ERK1/2 and p38 MAPK-dependent pathway. The results presented here may explain, at least in part, the possible contribution of thrombin and macrophages in these pathological conditions.
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PMID:Thrombin induces cyclooxygenase-2 expression and prostaglandin E2 release via PAR1 activation and ERK1/2- and p38 MAPK-dependent pathway in murine macrophages. 1973 3

Hydrogen sulfide (H(2)S) has been shown to promote transient receptor potential vanilloid type 1 (TRPV1)-mediated neurogenic inflammation in sepsis and its associated multiple organ failure, including acute lung injury (ALI). Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)/PGE(2) pathway plays an important role in augmenting inflammatory immune response in sepsis and respiratory diseases. However, the interactions among H(2)S, COX-2, and PGE(2) in inciting sepsis-evoked ALI remain unknown. Therefore, the aim of this study was to investigate whether H(2)S would upregulate COX-2 and work in conjunction with it to instigate ALI in a murine model of polymicrobial sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in male Swiss mice. dl-propargylglycine, an inhibitor of H(2)S formation, was administrated 1 h before or 1 h after CLP, whereas sodium hydrosulfide, an H(2)S donor, was given during CLP. Mice were treated with TRPV1 antagonist capsazepine 30 min before CLP, followed by assessment of lung COX-2 and PGE(2) metabolite (PGEM) levels. Additionally, septic mice were administrated with parecoxib, a selective COX-2 inhibitor, 20 min post-CLP and subjected to ALI and survival analysis. H(2)S augmented COX-2 and PGEM production in sepsis-evoked ALI by a TRPV1 channel-dependent mechanism. COX-2 inhibition with parecoxib attenuated H(2)S-augmented lung PGEM production, neutrophil infiltration, edema, proinflammatory cytokines, chemokines, and adhesion molecules levels, restored lung histoarchitecture, and protected against CLP-induced lethality. The strong anti-inflammatory and antiseptic actions of selective COX-2 inhibitor may provide a potential therapeutic approach for the management of sepsis and sepsis-associated ALI.
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PMID:Hydrogen sulfide upregulates cyclooxygenase-2 and prostaglandin E metabolite in sepsis-evoked acute lung injury via transient receptor potential vanilloid type 1 channel activation. 2195 41


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