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)

In this paper, we show that plasma from patients with severe sepsis and septic shock but not normal plasma supports lipopolysaccharide (LPS) activation of epithelial cells expressing Toll-like receptor 4 (TLR4). Recombinant soluble myeloid differentiation protein-2 (MD-2) complemented normal plasma and allowed LPS activation of epithelial cells to levels measured with "septic" plasma, whereas soluble MD-2-depleted plasma lost its effects. The same "MD-2 activity" was found in urine from a patient with septic shock and in lung edema fluids from patients with adult respiratory distress syndrome (ARDS). Recombinant soluble MD-2 enabled LPS-dependent activation of epithelial cells bearing TLR4. LPS-binding protein (LBP) and soluble CD14 increased the sensitivity of TLR4-expressing epithelial cells to LPS but were not able to mediate LPS activation of these cells in the absence of soluble MD-2. An anti-MD-2 monoclonal antibody blocked LPS activation of TLR4-expressing cells only in the presence of septic plasma or septic urine. These results suggest that septic plasma containing soluble MD-2 leaking into the extravascular space supports LPS activation of TLR4-expressing epithelial cells. We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis.
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PMID:Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock. 1532 61

The protein-bound polysaccharide isolated from basidiomycetes (PSK) is a biological response modifier capable of exhibiting various biological activities, such as antitumor and antimicrobial effects. In the present study, we found that PSK suppressed interleukin (IL)-6 production in murine peritoneal macrophages stimulated with endotoxic lipopolysaccharide (LPS) and its synthetic lipid A (compound 506). Nitric oxide production and p38 mitogen-associated protein kinase phosphorylation induced in a murine macrophage cell line, J774-A1, by LPS and compound 506 were also inhibited by PSK. Further, PSK distinctly suppressed nuclear factor-kappaB activation in Ba/F3 cells expressing mouse Toll-like receptor 4 and MD-2, following stimulation with LPS and compound 506, however, not with Taxol. These PSK-induced inhibitory activities were caused by inhibition of the physical associations of LPS with LPS-binding protein (LBP) and CD14. PSK also protected mice from LPS-induced lethality, presumably by down-regulating IL-6 and tumor necrosis factor-alpha concentrations in serum. These findings indicate that PSK, which also has an ability to regulate LBP/CD14 functions, may be useful for clinical control of endotoxic sepsis.
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PMID:Protein-bound polysaccharide isolated from basidiomycetes inhibits endotoxin-induced activation by blocking lipopolysaccharide-binding protein and CD14 functions. 1560 41

Antimicrobial peptides are important components of host defenses against microbial invasions. Bactericidal permeability-increasing protein (BPI) is an antimicrobial peptide belonging to the lipid transfer/LPS-binding protein family. It serves important roles in defending against Gram-negative bacteria in the innate immune system. Here we report cloning of complete BPI cDNA from channel catfish (Ictalurus punctatus) by 5' RACE after obtaining the partial BPI cDNA sequence from EST analysis. The channel catfish BPI cDNA is 1640 bp in length with a 1428-bp open reading frame that encodes a protein of 475 amino acids. Catfish BPI gene shows high similarity with the BPI/LBP gene isolated from other teleost fish. As part of ongoing efforts in comparative genome analysis, we have assigned the catfish BPI gene to bacterial artificial chromosome (BAC) clones. Southern blot analysis on multiple BPI BAC clones indicated the presence of a single copy of the BPI gene in the catfish genome. Reverse transcription-polymerase chain reaction (RT-PCR) analysis on healthy tissues showed that BPI was expressed in a wide range of tissues including head kidney, gill, skin, trunk kidney, brain, intestine, liver, muscle, ovary, spleen and stomach. The BPI gene was not developmentally expressed until 48 h after fertilization. Quantitative real time PCR (QRT-PCR) analysis indicated that the BPI gene expression was induced after challenge with Edwardsiella ictaluri, the causative agent of enteric septicemia of catfish (ESC). BPI upregulation peaked 3 days after challenge, mirroring the expression pattern of inflammatory chemokines in catfish, suggesting that it plays a role in the innate defense response.
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PMID:Characterization and expression analysis of bactericidal permeability-increasing protein (BPI) antimicrobial peptide gene from channel catfish Ictalurus punctatus. 1589 43

Multiple trauma patients have an impaired immune system and thus frequently develop life-threatening septic complications. Because there is an ongoing debate on which are the most predictive immunologic parameters of clinical outcome, we prospectively studied 19 multiple trauma patients with sepsis (mean age, 38.7 +/- 15.8 years; mean Injury Severity Score, 40.6 +/- 11.6) over a period of 14 days. The following parameters were measured daily after admission to the intensive care unit: ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production, monocyte human leukocyte antigen (HLA)-DR expression, constitutive interleukin (IL) 6 secretion, white blood cell count, and C-reactive protein. In addition, procalcitonin, neopterin, LPS-binding protein, and constitutive TNF-alpha secretion were measured every third day. Immediately after trauma, all patients had significantly lower levels of HLA-DR and ex vivo LPS-stimulated TNF-alpha secretion than healthy controls (n = 7; P < 0.001). On the day after clinical diagnosis of sepsis, before any other parameter differed between survivors (n = 13) and nonsurvivors (n = 6), ex vivo LPS-induced TNF-alpha secretion was significantly lower (P < 0.05) in nonsurvivors than in survivors. We conclude that ex vivo LPS-induced TNF-alpha production is an earlier predictor of clinical outcome in multiple trauma patients with sepsis than monocyte HLA-DR expression, constitutive IL-6 secretion, or any other parameter assessed.
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PMID:Lipopolysaccharide-induced tumor necrosis factor alpha production and not monocyte human leukocyte antigen-DR expression is correlated with survival in septic trauma patients. 1652 50

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

High-density lipoprotein (HDL) is an abundant plasma lipoprotein that is generally thought to be anti-inflammatory in both health and infectious disease. It binds and neutralizes the bioactivity of the potent bacterial lipids, LPS and lipoteichoic acid, that stimulate host innate immune responses. LPS-binding protein (LBP) plays an important role in augmenting leukocyte responses to LPS, whereas high concentrations of LBP, in the range of those found in plasma, can be inhibitory. We found that native HDL (nHDL) augmented human monocyte responses to LPS in the presence of inhibitory concentrations of LBP as measured by production of TNF and other cytokines. HDL did not stimulate cells in the absence of LPS, and it did not augment responses that were stimulated by IL-1beta or lipoteichoic acid. This activity of HDL was inhibited by trypsin treatment, suggesting that one or more protein constituents of HDL are required. In contrast to nHDL, low-density lipoprotein, and reconstituted HDL did not possess this activity. The total lipoprotein fraction of normal plasma had activity that was similar to that of nHDL, whereas lipoproteins from septic patients with reduced HDL levels had a reduced ability to augment responses to LPS; this activity was restored by adding normal HDL to the patient lipoproteins. Our results demonstrate a novel proinflammatory activity of HDL that may help maintain sensitive host responses to LPS by suppressing the inhibitory activity of LBP. Our findings also raise the possibility that the decline of HDL during sepsis may help control the response to LPS.
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PMID:Native high-density lipoprotein augments monocyte responses to lipopolysaccharide (LPS) by suppressing the inhibitory activity of LPS-binding protein. 1698 30

Lipopolysaccharide (LPS) is an exdotoxin found in the outer membrane of gram-negative bacteria. In circulation, LPS is bound by LPS-binding protein (LBP), which participates in cell activation by transferring LPS to CD14 and Toll-like receptor 4. A high LPS concentration may give rise to an exaggerated immune response, which may lead to septic shock during septicemia. However, LBP also neutralizes and removes LPS by transferring it to plasma lipoproteins. Recently, the presence of an amino acid-changing polymorphism in the LBP gene was reported, which, in men, was associated with sepsis and its severity and with myocardial infarction. Here, we describe a new LightCycler real-time PCR method for genotyping this LBP C(1341)-->T (Leu(436)-->Phe) polymorphism. In our study population of 393 Finnish blood donors, the genotype frequencies were: 86% TT, 13% CT and 1% CC.
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PMID:Rapid genotyping of lipopolysaccharide-binding protein (LBP) C(1341)-->T (Leu(436)-->Phe) polymorphism by LightCycler real-time PCR. 1710 Nov 45

Oxidized phospholipids that are generated during inflammation exert anti-inflammatory properties and prevent death during murine endotoxemia. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) inhibits the interaction of LPS with LPS-binding protein and CD14. In this study, we determined the functional properties of OxPAPC and potential interference with CD14 during abdominal sepsis caused by Escherichia coli. Administration of OxPAPC rendered mice highly susceptible to E. coli peritonitis, as indicated by an accelerated mortality and enhanced bacterial outgrowth and dissemination. CD14(-/-) mice also displayed increased mortality and bacterial outgrowth and OxPAPC did not further impair host defense in these animals. The mechanisms by which OxPAPC and CD14 deficiency impaired the immune response differed: whereas CD14(-/-) mice demonstrated a strongly reduced recruitment of phagocytes to the site of the infection, OxPAPC did not influence the influx of inflammatory cells but strongly diminished the phagocytosing capacity of neutrophils and macrophages by a CD14-independent mechanism. Furthermore, OxPAPC potently inhibited uptake of fluorospheres as well as receptor-mediated endocytosis and fluid-phase pinocytosis. These data suggest that oxidized phospholipids such as produced during inflammatory reactions may contribute to mortality during Gram-negative sepsis in vivo via impairment of the phagocytic properties of professional phagocytes.
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PMID:Oxidized phospholipids inhibit phagocytosis and impair outcome in gram-negative sepsis in vivo. 1720 62

The term sepsis describes a potentially lethal clinical condition that develops as a result of a dysregulated host response to bacterial infection. The most common bacterial component implicated in initiating the septic syndrome is a cell wall molecule derived from Gram-negative bacteria, known as lipopolysaccharide (LPS) or endotoxin. Like all mammals, humans are equipped with an LPS-sensing machinery consisting, primarily, of LPS-binding protein (LBP), CD14, a glycosylphosphatidylinositol (GPI)-anchored monocyte differentiation antigen, and toll-like receptor 4 (TLR4), a signal-transducing integral membrane protein. Modest stimulation of TLR4 facilitates the elimination of invading microorganisms. Potent TLR4 stimulation, however, produces severe reactions in the host, often leading to multiple organ failure and death. The search for pharmaceuticals that reduce mortality in septic patients has been a painstaking process. Thus far, only a few compounds have been found to significantly reduce mortality rates. Perhaps one of the more promising therapeutic strategies currently pursued is based on the identification of synthetic or naturally occurring substances that neutralize LPS or inhibit LPS-mediated activation of host immune cells, such as monocytes and macrophages. Here, we describe a number of diverse molecular structures with a capacity to either enhance or blunt LPS-induced monocyte activation. The underlying molecular mechanisms are discussed.
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PMID:Targeting bacterial endotoxin: two sides of a coin. 1740 10

Recent research has yielded many interesting and potentially important therapeutic targets in sepsis. Specifically, the effects of antagonistic anti-cytokine therapies (tumor necrosis factor-alpha [TNF-alpha], interleukin-1 [IL-1]) and anti-endotoxin strategies utilizing antibodies against endotoxin or endotoxin receptor/carrier molecules (anti-CD14 or anti-LPS-binding protein) have been studied. Unfortunately, these approaches often failed clinically, and in many cases, the efficacy of these treatments was dependent on the severity of sepsis. Recently, clinical trials using insulin to lock blood glucose levels and activated protein C treatment have showed that while they provided some survival benefit, their efficacy does not appear to be predicated solely upon anti-inflammatory effects. Here, we will review work done in animal models of polymicrobial sepsis and clinical findings that support the hypothesis that apoptosis in the immune system is a pathologic event in sepsis that can be a therapeutic target. In this respect, experimental studies looking at the septic animal suggest that loss of lymphocytes during sepsis may be due to dysregulated apoptosis and that this appears to be brought on by a variety of mediators effecting 'intrinsic' as well as 'extrinsic' cell death pathways. From a therapeutic perspective this has provided a number of novel targets for clinically successful current, as well as future therapies, such as caspases (caspase inhibition/protease inhibition), pro-apoptotic protein-expression (via administration and/or over-expression of Bcl-2) and the death receptor family Fas-FasL (via. FasFP [fas fusion protein] and the application of siRNA against a number pro-apoptotic factors).
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PMID:The apoptotic pathway as a therapeutic target in sepsis. 1743 Jan 19


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