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)

Macrophage dysfunction occurs late in sepsis and is implicated in increased mortality. Interferon gamma (IFN-gamma) stimulates transmigration of high mobility group box 1 (HMGB-1) from the nucleus into cytoplasm of macrophages and subsequent release. Because HMGB-1 release also occurs late, and because one of the actions of HMGB-1 in the nucleus is to enhance transcription factors, we investigated if HMGB-1 transmigration is involved in macrophage suppression in sepsis. Alveolar macrophages were isolated 12 and 24 h from sham controls, cecal ligation and puncture (CLP), and CLP rats given IFN-gamma antibody (1.2 mg/kg, i.v.). All injections were given immediately after surgery. At 12 h, 60% of cells from sham controls had HMGB-1 located primarily in the nucleus, whereas 35% of cells had diffuse staining in both cytoplasm and nucleus. In CLP rats, HMGB-1 was located predominantly in the cytoplasm of 37% of cells, and 48% had diffuse staining, whereas in IFN-gamma antibody (Ab)-treated rats, HMGB-1 was located predominantly in the nucleus of 56% of cells, whereas 32% had diffuse staining. At 24 h, most cells from CLP rats (82%) had HMGB-1 located in the cytoplasm, whereas in contrast, HMGB-1 was located in the nucleus of 80% and 82% of cells from sham control and IFN-gamma Ab-treated rats, respectively. Gene expression of TNF-alpha was not significantly changed 12 h after surgery, but at 24 h, alveolar macrophages from CLP rats had reduced gene expression of TNF-alpha. Interferon gamma Ab treatment prevented the reduction in TNF-alpha gene expression. TNF-alpha release was not altered at 12 h. At 24 h, LPS-stimulated release of TNF-alpha was decreased in macrophages from CLP rats compared with sham controls. Interferon gamma Ab treatment prevented the decrease in LPS-stimulated TNF-alpha release. The results suggest that alveolar macrophage suppression after CLP is associated with HMGB-1 transmigration out of the cell nucleus and provides evidence that intranuclear HMGB-1 may play an integral role in macrophage activation in sepsis.
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PMID:Alveolar macrophage suppression in sepsis is associated with high mobility group box 1 transmigration. 1800 27

The systemic inflammatory response observed in the setting of overwhelming infection bears striking similarities to that observed in the setting of severe traumatic injury from a clinical and physiologic standpoint. Recent observations have demonstrated that these disparate clinical entities share common mediators on a molecular level. TLRs, specifically TLR4, and the endogenous molecule high-mobility group box 1 are among the mediators that are known to play a role in inflammation in the setting of sepsis. Evidence is accumulating that demonstrates that these mediators also play a role in the host response to tissue injury. Here, we highlight findings from the 7th World Conference on Trauma, Shock, Inflammation and Sepsis in Munich, Germany, in the context of this growing body of literature.
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PMID:Early events in the recognition of danger signals after tissue injury. 1803 91

Sepsis, a systemic inflammatory response to infection, is a leading cause of death in intensive care units. Recent investigations into the pathogenesis of sepsis reveal a biphasic inflammatory process. An early phase is characterized by pro-inflammatory cytokines (e.g. tumour necrosis factor-alpha), whereas a late phase is mediated by an inflammatory high-mobility group box 1 and an anti-inflammatory interleukin-10. Inflammation aberrantly activates coagulation cascades as sepsis progresses. This dual inflammatory response concomitant with dysregulated coagulation partially accounts for unsuccessful anti-cytokine therapies that have solely targeted early pro-inflammatory mediators (e.g. tumour necrosis factor-alpha). In contrast, activated protein C, which modifies both inflammatory and coagulatory pathways, has improved survival in patients in severe sepsis. Inhibition of the late mediator high-mobility group box 1 improves survival in established sepsis in pre-clinical studies. In addition, recent advances in molecular medicine have shed light on two novel experimental interventions against sepsis. Accelerated apoptosis of lymphocytes has been shown to play an important role in organ dysfunction in sepsis and techniques to suppress apoptosis have improved survival rate in sepsis models. The vagus nerve system has also been shown to suppress innate immune response through endogenous release and exogenous administration of cholinergic agonists, ameliorating inflammation and lethality in sepsis models.
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PMID:Advances in understanding sepsis. 1828 33

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

The alpha7 subunit-containing nicotinic acetylcholine receptor (alpha7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural alpha7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis, and the role of the alpha7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1-50 mM) dose-dependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-kappaB activation. Choline (50 mg/kg, intraperitoneally [i.p.]) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels. In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in alpha7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from alpha7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires alpha7nAChR-mediated signaling.
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PMID:Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. 1858 48

The pathogenesis of sepsis is mediated in part by bacterial endotoxin (lipopolysaccharide; LPS), which stimulates macrophages/monocytes to sequentially release early (e.g., TNF-alpha, IL-1beta) and late [e.g., high mobility group box 1 (HMGB1) protein] pro-inflammatory cytokines. Specifically targeting early mediators has not been effective clinically, in part, because peak mediator activity often has passed before therapy can be initiated. Recent discovery of HMGB1 as a late mediator of lethal sepsis has provided a new target for the treatment of septic shock. Here, we demonstrate that pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide, significantly attenuated circulating HMGB1 levels and increased survival in animals with established endotoxemia, even if treatment began after acute cytokine response has occurred. In vitro, PACAP suppressed LPS-induced HMGB1 release from macrophages/monocytes, even when given 2-4 h after LPS stimulation. PACAP also suppressed HMGB1 release induced by TNF-alpha or IFN-gamma. Moreover, PACAP inhibits HMGB1-induced cytokine release in vitro and in vivo. These results indicate that PACAP inhibits the release and pro-inflammatory activity of HMGB1 and improves survival during lethal endotoxemia, which confirms this peptide as a candidate for therapy of septic shock.
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PMID:PACAP inhibit the release and cytokine activity of HMGB1 and improve the survival during lethal endotoxemia. 1871 53

Systemic inflammatory mediators, including the protein high-mobility group box 1 (HMGB1), play an important role in the development of acute pancreatitis. Anticoagulants such as danaparoid sodium (DA) may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesized that DA would act as an inhibitor of inflammation and prevent cerulein-induced acute pancreatitis. Male Wistar rats were used as subjects in this study. Each received a bolus of 50 U/kg of DA or saline-injected into the tail vein, followed by 4 injections of 50 mg/kg cerulean (i.p.) at 1-h intervals. Cytokine (IL-6), NO, and HMGB1 levels in serum and pancreatic tissue were measured after the cerulein injection. Pancreas histopathology and wet-dry ratio significantly improved in the DA-injected (50 U/kg) animals compared with saline-injected rats. Serum and pancreatic HMGB1 levels decreased over time in DA-treated animals. Danaparoid sodium also decreased cytokine, NO, and HMGB1 levels during cerulein-induced inflammation. As a result, DA ameliorated pancreas pathology in the rat model of cerulein-induced acute pancreatitis. This study demonstrates that DA treatment prevents cerulein-induced acute pancreatitis in a rat model. This effect may be mediated through inhibition of cytokines, NO, and HMGB1.
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PMID:Danaparoid sodium prevents cerulein-induced acute pancreatitis in rats. 1894 46

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. The inflammatory response is partly mediated by innate immune cells (such as macrophages, monocytes and neutrophils), which not only ingest and eliminate invading pathogens but also initiate an inflammatory response upon recognition of pathogen-associated molecular patterns (PAMPs). The prevailing theories of sepsis as a dysregulated inflammatory response, as manifested by excessive release of inflammatory mediators such as tumour necrosis factor and high-mobility group box 1 protein (HMGB1), are supported by extensive studies employing animal models of sepsis. Here we review emerging evidence that support extracellular HMGB1 as a late mediator of experimental sepsis, and discuss the therapeutic potential of several HMGB1-targeting agents (including neutralising antibodies and steroid-like tanshinones) in experimental sepsis.
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PMID:Therapeutic potential of HMGB1-targeting agents in sepsis. 1898 Jul 7

Sepsis is a devastating condition characterized by a systemic inflammatory response. Recently, high mobility group box 1 (HMGB1) was identified as a necessary and sufficient mediator of the lethal systemic inflammation caused by sepsis. However, despite its clinical importance, the mechanism of HMGB1 release has remained to be elusive. In this study, we demonstrate that the IFN-beta-mediated JAK/STAT pathway is essential for LPS or Escherichia coli-induced HMGB1 release, which is dependent on Toll/IL-1R domain-containing adapter-inducing IFN-beta adaptor. Additionally, we show that NO acts as a downstream molecule of the IFN-beta signaling. Furthermore, the JAK inhibitor treatment as well as the STAT-1 or IFN-beta receptor deficiency reduced HMGB1 release in a murine model of endotoxemia. Our results suggest that HMGB1 release in sepsis is dependent on the IFN-beta signaling axis; thus, therapeutic agents that selectively inhibit IFN-beta signaling could be beneficial in the treatment of sepsis.
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PMID:Bacterial endotoxin induces the release of high mobility group box 1 via the IFN-beta signaling pathway. 1920 1

The present study was to investigate the effects of rosmarinic acid (RA) in cultured RAW264.7 cells and experimental model of sepsis induced by cecal ligation and puncture in rats and the potential mechanism. Results showed that RA concentration dependently down-regulated the levels of TNF-alpha, IL-6, and high-mobility group box 1 protein in LPS-induced RAW264.7 cells, inhibited the IkappaB kinase pathway, and modulated nuclear factor-kappaB. Intravenous injection of RA alone or in combination with imipenem reduced cecal ligation and puncture-induced lethality in rats. In addition, serum levels of TNF-alpha, IL-6, high-mobility group box 1 protein, triggering receptor expressed on myeloid cells, and endotoxin were down-regulated; in contrast, serum level of IL-10 was up-regulated. Amelioration of hemodynamics and decrease in serum enzyme activities and myeloperoxidase in lung, liver, and small intestine were also observed after RA injection. These data indicate that the antisepsis effect of RA was mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. This article provides the first evidence that RA has the capacity to inactivate inflammatory response in sepsis. The anti-inflammatory mechanism of RA may inhibit activation of the nuclear factor- kappaB pathway by inhibiting IkappaB kinase activity.
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PMID:Rosmarinic acid protects against experimental sepsis by inhibiting proinflammatory factor release and ameliorating hemodynamics. 1929 75


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