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)

TLR are primary triggers of the innate immune system by recognizing various microorganisms through conserved pathogen-associated molecular patterns. TLR2 is the receptor for a functional recognition of bacterial lipopeptides (LP) and is up-regulated during various disorders such as chronic obstructive pulmonary disease and sepsis. This receptor is unique in its ability to form heteromers with TLR1 or TLR6 to mediate intracellular signaling. According to the fatty acid pattern as well as the assembling of the polypeptide tail, LP can signal through TLR2 in a TLR1- or TLR6-dependent manner. There are also di- and triacylated LP, which stimulate TLR1-deficient cells and TLR6-deficient cells. In this study, we investigated whether heterodimerization evolutionarily developed to broaden the ligand spectrum or to induce different immune responses. We analyzed the signal transduction pathways activated through the different TLR2 dimers using the three LP, palmitic acid (Pam)octanoic acid (Oct)(2)C-(VPGVG)(4)VPGKG, fibroblast-stimulating LP-1, and Pam(2)C-SK(4). Dominant-negative forms of signaling molecules, immunoblotting of MAPK, as well as microarray analysis indicate that all dimers use the same signaling cascade, leading to an identical pattern of gene activation. We conclude that heterodimerization of TLR2 with TLR1 or TLR6 evolutionarily developed to expand the ligand spectrum to enable the innate immune system to recognize the numerous, different structures of LP present in various pathogens. Thus, although mycoplasma and Gram-positive and Gram-negative bacteria may activate different TLR2 dimers, the development of different signal pathways in response to different LP does not seem to be of vital significance for the innate defense system.
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PMID:Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling. 1805 80

PCT is a 116-amino acid polypeptide glycoprotein that is ubiquitously expressed from various extrathyroid neuroendocrine tissues during bacterial infection. PCT was shown to closely correlate with the severity of sepsis. PCT synthesis is probably induced by tumor necrosis factor-alpha (TNFalpha) or interleukin-6 (IL-6), the primary cytokines in the inflammatory cascade, as they always peak before PCT. In healthy and septic animals, PCT injection did not initiate or enhance the production of TNFalpha, while TNFalpha injection induced a 25-fold massive and sustained PCT increase. This indicates that PCT release is not a ''proximal'' but rather an ''intermediary'' event in the sepsis cascade that requires a ''primed'' inflammatory background to exert its effect. PCT, a prohormone that follows a cytokine-like expression pathway, was coined a ''hormokine'' to signify its cytokine-like host-response. In our center, over a period of 2 years, we investigated subsets of postoperative ICU patients with sepsis. The area under the Receiver Operating Characteristic curve for PCT's prediction of survival outcome demonstrated a very high discriminative power of 0.90 from day 6, with a cut-off value of 3.2 ng mL(-1) PCT concentration. Interestingly, in our study, PCT declined a few days before a lethal outcome. This ominous sign clearly demonstrates that patients with poor prognosis would manifest, at a certain stage, a decrease in their ability to mount an effective response to sepsis.
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PMID:Procalcitonin's role in the sepsis cascade. Is procalcitonin a sepsis marker or mediator? 1898 69

The genetic expression and secretion of the cardiac polypeptide hormones atrial natriuretic factor (ANF or ANP) and brain natriuretic peptide (BNP) have been studied mainly in the context of cardiac diseases associated with neuroendocrine and hemodynamic changes arising from cardiac dysfunction such as in chronic congestive heart failure. In this type of pathology, both ANF and BNP plasma levels change in an approximate coordinated fashion so that the use of these hormones as biomarkers of cardiac disease is, in principle, indistinctive. However, we reported that during an acute cardiac allograft rejection episode, BNP plasma levels can significantly increase in the absence of a similar increase in ANF plasma levels. We tested the hypothesis that these changes were related to cytokines and found that some pro-inflammatory cytokines, including TNFalpha and IL-1beta, selectively promote BNP synthesis and secretion in cultures of neonatal rat ventricular cardiocytes. This effect was found related to increased BNP promoter activity and sensitive to p38 mitogen-activated protein kinase inhibition.In order to determine in vivo if the selective up-regulation of BNP would be observed in inflammatory processes other than acute cardiac allograft rejection, we carried out investigation using the experimental autoimmune myocarditis rat model, which histologically resembles human giant cell myocarditis. It was found that this model is also accompanied by a specific increase in BNP-circulating levels although the cytokines involved seem to differ from those characterized earlier through in vitro studies.Recent studies in humans have found that in sepsis, plasma BNP levels increase in the absence of hemodynamic changes.In conclusion, BNP appears to be regulated uniquely in the setting of an inflammatory process. This sets it apart from ANF in terms of potential roles in the pathogenesis of disease and in its use as a biomarker of cardiac disease.
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PMID:Cardiac natriuretic peptides gene expression and secretion in inflammation. 1915 4

Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. After entering the body, the spores germinate into bacteria and secrete a toxin that causes local edema and, in systemic infections, cardiovascular collapse and death. The toxin is a tripartite polypeptide, consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF), which have key roles in the bacterial pathogenesis and disease progression. PA facilitates transfer of LF and EF to the cytosol. Lethal toxin is a zinc metalloproteinase, which has the capacity to inactivate mitogen-activated protein (MAP) kinase kinase (MEK) and stimulates the release of sepsis-related cytokines tumor necrosis factor-alpha and interleukin-1beta. Edema factor is a calmodulin (CaM)-dependent adenylate cyclase, which increases levels of cyclic AMP, causing impaired neutrophil function and disruption of water balance that ultimately results in massive tissue edema. Together, the toxins effectively inhibit host innate and adaptive immune responses, allowing the bacteria to grow unrestrained and overwhelming any resistance. Clinically, inhalational anthrax presents in a biphasic pattern with initial nonspecific "flu-like" symptoms nausea and vomiting 1 to 4 days after exposure, followed by severe illness with dyspnea, high fever and circulatory shock. The latter symptoms represent a terminal stage and treatment is often ineffective when started at that time. Key indicators of early anthrax cardiovascular-related pathogenesis include mediastinal widening in association with pleural effusion and edema. In this review, we describe the current understanding of anthrax toxins on cellular function in the context of cardiovascular function and discuss potential therapeutic strategies.
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PMID:Anthrax toxin: pathologic effects on the cardiovascular system. 1927 4

Congestive heart failure (CHF) is the main cause of acute dyspnea in patients presented to an emergency department (ED), and it is associated with high morbidity and mortality. B-type natriuretic peptide (BNP) is a polypeptide, released by ventricular myocytes directly proportional to wall tension, for lowering renin-angiotensin-aldosterone activation. For diagnosing CHF, both BNP and the biologically inactive NT-proBNP have similar accuracy. Threshold values are higher in elderly population, and in patients with renal dysfunction. They might have also a prognostic value. Studies demonstrated that the use of BNP or NT-proBNP in dyspneic patients early in the ED reduced the time to discharge, total treatment cost. BNP and NT-proBNP should be available in every ED 24 hours a day, because literature strongly suggests the beneficial impact of an early appropriate diagnosis and treatment in dyspneic patients.Etiologic diagnosis of febrile patients who present to an ED is complex and sometimes difficult. However, new evidence showed that there are interventions (including early appropriate antibiotics), which could reduce mortality rate in patients with sepsis. For diagnosing sepsis, procalcitonin (PCT) is more accurate than C-reactive protein. Thus, because of its excellent specificity and positive predictive value, an elevated PCT concentration (higher than 0.5 ng/mL) indicates ongoing and potentially severe systemic infection, which needs early antibiotics (e.g. meningitis). In lower respiratory tract infections, CAP or COPD exacerbation, PCT guidance reduced total antibiotic exposure and/or antibiotic treatment duration.
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PMID:Useulness of B Natriuretic Peptides and Procalcitonin in Emergency Medicine. 1957 5

Transcriptional profiling data accumulated in recent years for the clinically relevant pathogen Staphylococcus aureus have established a cell wall stress stimulon, which comprises a coordinately regulated set of genes that are upregulated in response to blockage of cell wall biogenesis. In particular, the expression of cwrA (SA2343, N315 notation), which encodes a putative 63 amino acid polypeptide of unknown biological function, increases over 100-fold in response to cell wall inhibition. Herein, we seek to understand the biological role that this gene plays in S. aureus. cwrA was found to be robustly induced by all cell wall-targeting antibiotics tested - vancomycin, oxacillin, penicillin G, phosphomycin, imipenem, hymeglusin and bacitracin - but not by antibiotics with other mechanisms of action, including ciprofloxacin, erythromycin, chloramphenicol, triclosan, rifampicin, novobiocin and carbonyl cyanide 3-chlorophenylhydrazone. Although a DeltacwrA S. aureus strain had no appreciable shift in MICs for cell wall-targeting antibiotics, the knockout was shown to have reduced cell wall integrity in a variety of other assays. Additionally, the gene was shown to be important for virulence in a mouse sepsis model of infection.
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PMID:cwrA, a gene that specifically responds to cell wall damage in Staphylococcus aureus. 2016 23

Sepsis is often associated with cholestatic liver dysfunction caused by changes in the expression profile of hepatic bile salt transporters. However, in rodent endotoxin models, the role of ischemic hepatitis caused by liver hypoperfusion cannot be delineated. We hypothesized that hepatocytes change their expression pattern of bile salt transporters during early severe sepsis despite adequate resuscitation. Fifteen anesthetized and instrumented pigs were randomized to either fecal peritonitis (n = 8) or control (n = 7). Resuscitation was performed by hydroxyethyl starch and norepinephrine infusion. Hemodynamic parameters and markers of cholestatic and ischemic hepatic dysfunction were recorded. At baseline and after 21 h, messenger RNA (mRNA) and protein expression of bile salt transporters was determined by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, on in vivo liver biopsies. All resuscitated septic pigs developed a normotensive hyperdynamic circulation with increased portal flow. After 21 h of peritonitis, no signs of biochemical or histological cholestasis were present. Na-taurocholate cotransporting polypeptide and bile salt export pump mRNA were downregulated by 83% (P = 0.001) and 67% (P = 0.001), respectively, in comparison with controls, whereas multidrug resistance-associated protein 4 (MRP4) mRNA was upregulated by 85% (P = 0.02). Bile salt export pump and MRP2 staining were downregulated in septic pigs. During early porcine fluid-resuscitated sepsis, hepatic basolateral influx (Na-taurocholate cotransporting polypeptide) and canalicular efflux (bile salt export pump) of bile salts were downregulated without hemodynamic signs of hepatic hypoperfusion or biochemical signs of cholestasis. In parallel, the basolateral escape transport (MRP4) was markedly upregulated, possibly as an early adaptive response to counteract hepatocellular accumulation of toxic bile acids.
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PMID:The impact of resuscitated fecal peritonitis on the expression of the hepatic bile salt transporters in a porcine model. 2035 97

The sodium-taurocholate (TC) cotransporting polypeptide (NTCP) facilitates bile formation by mediating sinusoidal Na(+)-TC cotransport. During sepsis-induced cholestasis, there is a decrease in NTCP-dependent uptake of bile acids and an increase in nitric oxide (NO) levels in hepatocytes. In rat hepatocytes NO inhibits Na(+)-dependent uptake of taurocholate. The aim of this study was to extend these findings to human NTCP and to further investigate the mechanism by which NO inhibits TC uptake. Using a human hepatoma cell line stably expressing NTCP (HuH-NTCP), we performed experiments with the NO donors sodium nitroprusside and S-nitrosocysteine and demonstrated that NO inhibits TC uptake in these cells. Kinetic analyses revealed that NO significantly decreased the V(max) but not the K(m) of TC uptake by NTCP, indicating noncompetitive inhibition. NO decreased the amount of NTCP in the plasma membrane, providing a molecular mechanism for the noncompetitive inhibition of TC uptake. One way that NO can modify protein function is through a posttranslational modification known as S-nitrosylation: the binding of NO to cysteine thiols. Using a biotin switch technique we observed that NTCP is S-nitrosylated under conditions in which NO inhibits TC uptake. Moreover, dithiothreitol reversed NO-mediated inhibition of TC uptake and S-nitrosylation of NTCP, indicating that NO inhibits TC uptake via modification of cysteine thiols. In addition, NO treatment led to a decrease in Ntcp phosphorylation. Taken together these results indicate that the inhibition of TC uptake by NO involves S-nitrosylation of NTCP.
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PMID:Nitric oxide-mediated inhibition of taurocholate uptake involves S-nitrosylation of NTCP. 2110 90

A substantial body of experimental and clinical evidence suggests that neutralising or removing lipopolysaccharide endotoxin would be an effective adjunctive approach to the management of Gram-negative sepsis. Polymyxins are a group of cyclic cationic polypeptide antibiotics. Although they have useful antimicrobial activity against Gram-negative bacteria, their clinical use has been limited because of toxicity. However, in addition to their antimicrobial property, polymyxins can bind to and neutralise endotoxin. Thus, investigators have explored the possibility of using polymyxin bound to a solid-phase carrier for specific haem-adsorption in patients with sepsis, thereby retaining the lipopolysaccharide-binding properties but minimising systemic toxic effects. This system has been widely used in Japan for many years, but convincing clinical evidence of efficacy is lacking. A recent Italian study has some promising data. Although polymyxin has been the principal agent used to explore this approach, other molecules have the ability to bind endotoxin, and some of these have very recently been proposed as the basis for other endotoxin-removal devices. The available evidence is reviewed to assess the potential use of such devices in clinical practice.
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PMID:Endotoxin removal devices for the treatment of sepsis and septic shock. 2161 54

Tregs are involved in immune disorder during sepsis; they can lead to a Th2 immune reaction. Their inhibitory effects can help alleviate inflammatory injury, but may also cause secondary immune inhibition. Thymosin-alpha1 is a polypeptide with powerful immunomodulatory activities. Current reports have shown that Thymosin-alpha1 conferred beneficial effects to septic patients. To explore the relationship between Thymosin-alpha1 and Tregs, in this study, we investigated the changing trend in CD4(+)CD25(+)Foxp3(+) T lymphocytes in a CLP septic mouse model. We also investigated the variation of apoptotic rate of CD4(+)CD25(+) T lymphocytes, cytokine variation, and change of model survival rate when Thymosin-alpha1 intervening or not. We observed that the 72-h survival rate was improved, the percentage of CD4(+)CD25(+)Foxp3(+) T lymphocytes decreased and the apoptosis rate of CD4(+)CD25(+) T lymphocytes increased after intervention of Thymosin-alpha1. At same time the expression of pro-inflammation cytokines IL-2, TNF-alpha and anti-inflammatory cytokines IL-10 and TGF-beta were regulated. In conclusion, Thymosin-alpha1 can effectively control the inflammatory response intensity and improve the 72-h survival rate of septic mice. Regulating Tregs may be another important role of Thymosin-alpha1 conditioning the immune reaction in sepsis.
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PMID:Thymosin-alpha1 promotes the apoptosis of regulatory T cells and survival rate in septic mice. 2162 17


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