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)

Substantial attention has been paid to the role of the toll-like receptor (TLR) ligands of late and their role in regulating the innate immune response. They serve as exogenous danger signals important in informing and driving the distal adaptive immune response to pathogens. Less clear has been the role of the nominal endogenous danger signals released and recognized in stressed cells following genotoxic or metabolic stress as occurs in progressively growing tumors. HMGB1 (high-mobility group B1) is a nuclear protein well characterized for its ability to modify DNA access to transcriptional proteins that is released from necrotic cells as well as secreted through the endosomal route from hematopoietic cells, serving as a late mediator of sepsis. It interacts with high-affinity RAGE (receptor for advanced glycation end products) and TLR2 receptors. Here we show that HMGB1 enhances interferon gamma release from macrophage (but not dendritic cell)-stimulated NK cells. This is effective only when coupled with other pro-inflammatory cytokines particularly with IL-2 in combination with IL-1 or IL-12. We have used this information to suggest that HMGB1, which also promotes epithelial migration and proliferation, drives repair in the absence or inhibition of other factors but enhances inflammation in their presence. The implications for tumorigenesis and tumor progression are quite important as they may be for other states of chronic inflammation.
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PMID:Monocytes promote natural killer cell interferon gamma production in response to the endogenous danger signal HMGB1. 1560 95

Despite recent advances in antibiotic therapy and intensive care, sepsis remains widespread problems in critically ill patients. The high mortality of sepsis is in part mediated by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., HMGB1) pro-inflammatory cytokines. In light of our recent discovery of HMGB1 as a late mediator of lethal systemic inflammation, and the observation that green tea (Camellia sinensis) dose-dependently attenuated bacterial endotoxin-induced HMGB1 release, we propose that regular tea intake might decrease the incidence of and mortality rates from lethal endotoxemia and sepsis.
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PMID:More tea for septic patients?--Green tea may reduce endotoxin-induced release of high mobility group box 1 and other pro-inflammatory cytokines. 1626 89

HMGB1 was originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be "passively released" into the extracellular milieu by necrotic and damaged somatic cells. Extracellular HMGB1 represents an optimal "necrotic marker" selected by the innate immune system to recognize tissue damage and initiate reparative responses. HMGB1 in the extracellular milieu promotes maturation of myeloid and plasmacytoid dendritic cells, and induces myocardial regeneration after infarction. However, extracellular HMGB1 also acts as a potent pro-inflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. A growing number of studies indicate that HMGB1 is a successful therapeutic target in experimental models of ischemia/reperfusion, acute respiratory distress syndrome, rheumatoid arthritis, sepsis, and cancer. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses while preventing its pathological potential. This article focus on the immuno-regulatory role of HMGB1 and its contribution to infectious and inflammatory disorders.
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PMID:High-mobility group box 1 (HMGB1) protein: friend and foe. 1651 9

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

Sepsis and systemic inflammatory response syndrome (SIRS) are associated with an exacerbated production of both pro- and anti-inflammatory mediators that are mainly produced within tissues. Although a systemic process, the pathophysiological events differ from organ to organ, and from organ to peripheral blood, leading to the concept of compartmentalization. The nature of the insult (e.g. burn, hemorrhage, trauma, peritonitis), the cellular composition of each compartment (e.g. nature of phagocytes, nature of endothelial cells), and its micro-environment (e.g. local presence of granulocyte-macrophage colony stimulating factor [GM-CSF] in the lungs, low levels of arginine in the liver, release of endotoxin from the gut), and leukocyte recruitment, have a great influence on local inflammation and on tissue injury. High levels of pro-inflammatory mediators (e.g. interleukin-1 [IL-1], tumor necrosis factor [TNF], gamma interferon [IFN-gamma], high mobility group protein-1 [HMGB1], macrophage migration inhibitory factor [MIF]) produced locally and released into the blood stream initiate remote organ injury as a consequence of an organ cross-talk. The inflammatory response within the tissues is greatly influenced by the local delivery of neuromediators by the cholinergic and sympathetic neurons. Acetylcholine and epinephrine contribute with IL-10 and other mediators to the anti-inflammatory compensatory response initiated to dampen the inflammatory process. Unfortunately, this regulatory response leads to an altered immune status of leukocytes that can increase the susceptibility to further infection. Again, the nature of the insult, the nature of the leukocytes, the presence of circulating microbial components, and the nature of the triggering agent employed to trigger cells, greatly influence the immune status of the leukocytes that may differ from one compartment to another. While anti-inflammatory mediators predominate within the blood stream to avoid igniting new inflammatory foci, their presence within tissues may not always be sufficient to prevent the initiation of a deleterious inflammatory response in the different compartments.
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PMID:Compartmentalization of the inflammatory response in sepsis and SIRS. 1671 87

Cerebral and myocardial ischemia, two of the leading causes of morbidity and mortality worldwide, are associated with inflammation that can lead to multiple organ failure and death. High-mobility group box 1(HMGB1), a recently described mediator of lethal systemic inflammation, has been detected in individuals with severe sepsis and hemorrhagic shock, but its role during ischemic injury in humans is unknown. To determine whether systemic HMGB1 levels are elevated after ischemic injury, a prospective observational study was performed in subjects with a diagnosis of either Acute Coronary Syndrome (ACS) or cerebral vascular ischemia (transient ischemic attack or cerebral vascular accident). Subjects (n, 16; age [mean], 67+/-16.3 years) were enrolled in the North Shore-LIJ emergency department within 24 h of symptom onset. Blood samples were collected, and HMGB1 levels analyzed by Western blot analysis using previously described methods (Wang et al. Science. 1999). Control samples were obtained from healthy age- and sex-matched volunteers (n, 16; age [mean], 68+/-15.8 years). Here, we report that serum HMGB1 levels were significantly elevated in both myocardial ischemia subjects (myocardial control serum HMGB1, 1.94+/-2.05 ng/mL, vs. myocardial ischemia serum HMGB1, 159+/-54.3 ng/mL; P<0.001); and in cerebral ischemia subjects (cerebral control serum HMGB1, 16.8+/-10.9 ng/mL, vs. cerebral ischemia serum HMGB1, 218+/-18.8 ng/mL; P<0.001). These results suggest that systemic HMGB1 levels are elevated in human ischemic disease.
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PMID:Elevated high-mobility group box 1 levels in patients with cerebral and myocardial ischemia. 1672 Dec 63

In response to bacterial endotoxin (e.g., LPS) or endogenous proinflammatory cytokines (e.g., TNF and IL-1beta), innate immune cells release HMGB1, a late cytokine mediator of lethal endotoxemia and sepsis. The delayed kinetics of HMGB1 release makes it an attractive therapeutic target with a wider window of opportunity for the treatment of lethal systemic inflammation. However, the receptor(s) responsible for HMGB1-mediated production of proinflammatory cytokines has not been well characterized. Here we demonstrate that in human whole blood, neutralizing antibodies against Toll-like receptor 4 (TLR4, but not TLR2 or receptor for advanced glycation end product) dose-dependently attenuate HMGB1-induced IL-8 release. Similarly, in primary human macrophages, HMGB1-induced TNF release is dose-dependently inhibited by anti-TLR4 antibodies. In primary macrophages from knockout mice, HMGB1 activates significantly less TNF release in cells obtained from MyD88 and TLR4 knockout mice as compared with cells from TLR2 knockout and wild-type controls. However, in human embryonic kidney 293 cells transfected with TLR2 or TLR4, HMGB1 effectively induces IL-8 release only from TLR2 overexpressing cells. Consistently, anti-TLR2 antibodies dose-dependently attenuate HMGB1-induced IL-8 release in human embryonic kidney/TLR2-expressing cells and markedly reduce HMGB1 cell surface binding on murine macrophage-like RAW 264.7 cells. Taken together, our data suggest that there is a differential usage of TLR2 and TLR4 in HMGB1 signaling in primary cells and in established cell lines, adding complexity to studies of HMGB1 signaling which was not previously expected.
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PMID:HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. 1687 26

High-mobility group protein 1 (HMGB1) is a nonhistone nuclear protein whose function depends on cellular location. Inside the cell, HMGB1 modulates a variety of important cellular processes, including transcription, whereas outside the cell, HMGB1 acts as a cytokine that can promote inflammation and mediate sepsis and arthritis in animal models. In in vitro studies, proinflammatory molecules such as LPS, lipoteichoic acid, polyinosinic-polycytidylic acid (poly(I:C)), TNF-alpha, and type I and II IFNs can induce HMGB1 release from macrophages. Although these agents can activate cells, they can also induce apoptosis under certain circumstances. Therefore, because of evidence that apoptotic as well as necrotic cells can contribute to HMGB1-mediated events in sepsis, we have investigated the relationship between apoptosis and HMGB1 release in macrophages and other cells. In these experiments, using RAW 264.7 cells as a model, LPS and poly(I:C) caused HMGB1 release into the medium whereas CpG ODN failed to induce this response. With both LPS and poly(I:C), the extent of HMGB1 release correlated with the occurrence of apoptosis as measured by caspase 3 activation, lactate dehydrogenase release, and TUNEL staining. Similar results were obtained with primary murine macrophages as well as human Jurkat T cells. For Jurkat cells, poly(I:C) and NO donors induced apoptosis as well as HMGB1 release. Together, these results indicate that HMGB1 release from macrophages is correlated with the occurrence of apoptosis and suggest that these processes reflect common mechanisms and can occur concomitantly.
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PMID:The relationship between apoptosis and high-mobility group protein 1 release from murine macrophages stimulated with lipopolysaccharide or polyinosinic-polycytidylic acid. 1747 79

HMGB1/Amphoterin is a ubiquitous, highly conserved DNA-binding protein that can be also released to the extracellular space by various cell types. Extracellular HMGB1 regulates migratory responses of several cell types through binding to RAGE that communicates with the cytoskeleton to regulate cell motility. HMGB1-induced cell signalling has been associated with mechanisms of several diseases, including cancer, sepsis, rheumatoid arthritis, stroke and atherosclerosis. This article reviews the evidence linking the functional roles of HMGB1 to RAGE signalling. Furthermore, we discuss the molecular and cellular mechanisms that may explain the roles of HMGB1/RAGE in diverse disease processes.
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PMID:RAGE as a receptor of HMGB1 (Amphoterin): roles in health and disease. 1833 Dec 30

Sepsis, a life-threatening complication of infections and the most common cause of death in intensive care units, is characterized by a hyperactive and out-of-balance network of endogenous proinflammatory cytokines. None of the current therapies are entirely effective, illustrating the need for novel therapeutic approaches. Ghrelin (GHR) is an orexigenic peptide that has emerged as a potential endogenous anti-inflammatory factor. In this study, we show that the delayed administration of GHR protects against the mortality in various models of established endotoxemia and sepsis. The therapeutic effect of GHR is mainly mediated by decreasing the secretion of the high mobility box 1 (HMGB1), a DNA-binding factor that acts as a late inflammatory factor critical for sepsis progression. Macrophages seem to be the major cell targets in the inhibition of HMGB1 secretion, in which GHR blocked its cytoplasmic translocation. Interestingly, we also report that GHR shows a potent antibacterial activity in septic mice and in vitro. Remarkably, GHR also reduces the severity of experimental arthritis and the release of HMGB1 to serum. Therefore, by regulating crucial processes of sepsis, such as the production of early and late inflammatory mediators by macrophages and the microbial load, GHR represents a feasible therapeutic agent for this disease and other inflammatory disorders.
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PMID:Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria. 1852 4


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