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)

HMGB1 (high mobility group box chromosomal protein 1), historically known as an abundant, nonhistone architectural chromosomal protein, is extremely conserved across species. As a nuclear protein, HMGB1 stabilizes nucleosomes and allows bending of DNA that facilitates gene transcription. Unexpectedly, recent studies identified extracellular HMGB1 as a potent macrophage-activating factor, signaling via the receptor for advanced glycation end-products to induce inflammatory responses. It is released as a late mediator during inflammation and participates in the pathogenesis of systemic inflammation after the early mediator response has resolved. HMGB1 occupies a critical role as a proinflammatory mediator passively released by necrotic but not apoptotic cells. Necrotic Hmgb1(-/-) cells mediate minimal inflammatory responses. Stimulated macrophages actively secrete HMGB1 to promote inflammation and in turn, stimulate production of multiple, proinflammatory cytokines. HMGB1 mediates endotoxin lethality, acute lung injury, arthritis induction, activation of macrophages, smooth muscle cell chemotaxis, and epithelial cell barrier dysfunction. HMGB1 is structurally composed of three different domains: two homologous DNA-binding sequences entitled box A and box B and a highly, negatively charged C terminus. The B box domain contains the proinflammatory cytokine functionality of the molecule, whereas the A box region has an antagonistic, anti-inflammatory effect with therapeutic potential. Administration of highly purified, recombinant A box protein or neutralizing antibodies against HMGB1 rescued mice from lethal sepsis, even when initial treatment was delayed for 24 h after the onset of infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known cytokines.
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PMID:HMGB1 as a DNA-binding cytokine. 1248 89

The discovery of tumor necrosis factor (TNF) as a necessary and sufficient mediator of systemic inflammation started a new field of research to rationally modulate cytokine responses to therapeutic advantage. However, the early kinetics of the TNF response during infection defined an extremely narrow window of opportunity during which anti-TNF therapeutics are efficacious, hampering clinical development for severe sepsis. Because death from severe sepsis often occurs as a late phenomenon, we began a search began for putative "late" mediators that could be targeted after the onset of infection. We have now identified high mobility group box-1 (HMGB1) as a late mediator of endotoxemia and sepsis. HMGB1 is released by activated macrophages, induces the release of other proinflammatory mediators, and mediates lethality when overexpressed. Administration of anti-HMGB1 antibodies inhibit systemic inflammation, even in established cases, because HMGB1 activity is elevated at significantly later time points than TNF or interleukin-1. It will now be important to determine whether this wider window of activity can be translated into therapeutic advantage for human inflammatory disease.
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PMID:High mobility group box-1 as a therapeutic target downstream of tumor necrosis factor. 1279 56

Therapeutic intervention against exaggerated cytokine activity has been proved to be clinically successful in several serious, inflammatory disorders [reviewed in 1, 2] in the last decade. Half a million patients with chronic arthritis have shown tremendous improvement with tumour necrosis factor (TNF)- or interleukin (IL)-1-blocking treatment. Similarly anti-TNF therapy is beneficial for chronic inflammatory bowel disorders such as Crohn's disease. The success of this novel strategy has generated a search for additional endogenous mediators suitable for therapeutic targeting. The high mobility group box protein 1 (HMGB1) is a lately discovered candidate molecule identified as an important extracellular mediator in local and systemic inflammation in both human and experimental diseases such as, e.g., arthritis and sepsis [3]. Therapeutic neutralization of HMGB1 has shown encouraging results in experimental disease models, but has not yet reached clinical trials. This volume of the Journal of Internal Medicine contains a collection of four reviews addressing novel aspects of HMGB1 biology of potentially clinical interest. The manuscripts are the product of a recent meeting entitled the 'First HMGB1 Cytokine World Congress' sponsored by the Journal of Internal Medicine.
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PMID:HMGB1, a pro-inflammatory cytokine of clinical interest: introduction. 1487 55

The intranuclear architectural protein that is termed high mobility group box chromosomal protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator when present extracellularly. HMGB1 has been demonstrated to be a long-searched-for nuclear danger signal passively released by necrotic, as opposed to apoptotic, cells that will induce inflammation. Furthermore, HMGB1 can also be actively secreted by stimulated macrophages or monocytes in a process requiring acetylation of the molecule, which enables translocation from the nucleus to secretory lysosomes. Subsequent transport out of the cells depends on a secretion signal mediated by either extracellular lysophophatidyl-choline or ATP. HMGB1 passively released from necrotic cells and HMGB1 actively secreted by inflammatory cells are thus molecularly different. Extracellular HMGB1 acts as a cytokine by signaling via the receptor for advanced glycated end-products and via members of the Toll-like receptor family. The initiated inflammatory responses include the production of multiple cytokines, chemoattraction of certain stem cells, induction of vascular adhesion molecules and impaired function of intestinal epithelial cells. Therapeutic administration of HMGB1 antagonists rescues mice from lethal sepsis, even when initial treatment is delayed for 24 h after the onset of infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known cytokines.
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PMID:Mini-review: The nuclear protein HMGB1 as a proinflammatory mediator. 1516 19

Sepsis or its synonymously termed "SIRS (systemic inflammatory response syndrome)" is a common cause of individual morbidity and mortality in various clinical situations. In such conditions, high mobility group box-1 DNA binding protein (HMGB1), widely known as a nuclear structural protein, has been identified to act as a late mediator of delayed endotoxin lethality. Once released from necrotic damaged cells or secreted by activated monocytes/macrophage, it participates in the development of lethality and it activates downstream cytokine release. In this review, we describe herein the general features of sepsis focusing on the role of HMGB1 in the mechanism of development of systemic inflammation, and also introduce newly established therapeutic concept "Functional HMGB1 inhibition with thrombomodulin" against sepsis/SIRS/DIC.
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PMID:[Inflammation and its regulatory system]. 1559 89

Interferon (IFN)-gamma is an important immunomodulatory agent that is stimulated during infection to aid in host defense. However, increased IFN-gamma levels have been implicated as a mediator in various models of tissue injury and endotoxemia. We have previously shown that inhibition of IFN-gamma decreased bacterial load by accelerating peritoneal fibrin deposition in the cecal ligation and puncture (CLP) model of peritonitis. In addition, circulating inflammatory mediators such as interleukin (IL)-6 were reduced by IFN-gamma inhibition. In the present study, we show that administration of IFN-gamma antibody (1.2 mg/kg, i.v.) attenuated mortality after CLP. Administration of this antibody was able to reduce mortality when given immediately after CLP or 24 h after CLP surgery. Mortality in sepsis has been closely associated with increased release of high mobility group box-1 (HMGB1). Furthermore, it has been reported that IFN-gamma stimulates the release of HMGB1 from macrophages. Our studies showed that inhibition of IFN-gamma activity in vivo reduced the levels of HMGB1 in peritoneal fluid and serum of CLP rats 24 h after surgery. In addition, the decrease in HMGB1 was associated with an increase in tissue repair as evidenced by histological analyses. These results suggest that the attenuation of mortality in IFN-gamma antibody-treated rats was associated with a decrease in HMGB1 release.
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PMID:Interferon-gamma inhibition attenuates lethality after cecal ligation and puncture in rats: implication of high mobility group box-1. 1620 27

Because of the many difficult aspects in the treatment of septic shock and poor outcome of this condition, establishing the most appropriate therapeutic strategy is problematic. Recently, high mobility group box-1 (HMGB-1) has been shown to activate inflammatory responses and to be a late mediator in endotoxemia and sepsis. Therefore, we considered that it might be worthwhile to investigate the therapeutic potential of HMGB-1 blockade in cases of septic shock.Herein, we describe the case of a patient with septic shock with hepatic portal venous gas caused by intestinal obstruction. Hepatic portal venous gas is a rare condition associated with significant radiographic findings and a fatal outcome. Our patient, however, recovered from severe septic shock and was saved by the use of direct hemoperfusion with a polymyxin B immobilized fiber column (DHP-PMX). This treatment resulted in a decrease in the serum levels of endotoxin, interleukin-6 (IL-6), and HMGB-1.
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PMID:Effect of direct hemoperfusion with a polymyxin B immobilized fiber column on high mobility group box-1 (HMGB-1) in severe septic shock: report of a case. 1711 45

Signal transduction mechanism in the regulation of high mobility group box protein 1 (HMGB1) has not yet been well elucidated. Our data showed for the first time that Janus kinase-signal transduction and activator of transcription (JAK/STAT) pathway played a major role in the regulation of expression and inflammatory effect of HMGB1. The study was carried out in the following sequence. Firstly, the role of JAK/STAT pathway in the regulation of expression of HMGB1 was examined. After stimulation with 75 ng/mL LPS in vitro, significant increases in HMGB1 expression and prompt activation of JAK/STAT pathway were demonstrated in cultured macrophages. On the other hand, administration of AG490 (specific inhibitor for JAK2), fludarabine (specific inhibitor for STAT1) or rapamycin (specific inhibitor for STAT3) markedly suppressed HMGB1 expression. Secondly, the role of JAK/STAT pathway in the regulation of TNF-alpha expression induced by HMGB1 was examined. When macrophages were stimulated with 10 microg/mL HMGB1 in vitro, significant increases in TNF-alpha expression and prompt activation of JAK/STAT pathway were demonstrated, whereas inhibitors of JAK/STAT pathway significantly suppressed TNF-alpha expression. Taken together, our data strongly indicated that expression and inflammatory effect of HMGB1 could be mediated by JAK/STAT pathway and suggested a possible clinical strategy to control an inflammatory effect of HMGB1 in sepsis.
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PMID:Role of Janus kinase/signal transducer and activator of transcription pathway in regulation of expression and inflammation-promoting activity of high mobility group box protein 1 in rat peritoneal macrophages. 1717 81

Severely septic patients continue to experience excessive morbidity and mortality despite recent advances in critical care. Although significant resources have been invested in new treatments, almost all have failed to improve outcomes. An improved understanding of sepsis pathophysiology, including the complex interactions between inflammatory, coagulation, and fibrinolytic systems, has accelerated the development of novel treatments. Recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated) (DAA), is currently the only US Food and Drug Administration (FDA)-approved medicine for the treatment of severe sepsis, and only in patients with a high risk of death. This review will discuss the treatment of severe sepsis, focusing on recent discoveries and unresolved questions about DAA's optimal use. Increasing pharmacological experience has generated enthusiasm for investigating medicines already approved for other indications as treatments for severe sepsis. Replacement doses of hydrocortisone and vasopressin may reduce mortality and improve hypotension, respectively, in a subgroup of patients with catecholamine-refractory septic shock. In addition to discussing these new indications, this review will detail the provocative preliminary data from four promising treatments, including two novel modalities: antagonizing high mobility group box protein and inhibiting tissue factor (TF). Observational data from the uncontrolled administration of heparin or statins in septic patients will also be reviewed.
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PMID:Treatment of severe sepsis: where next? Current and future treatment approaches after the introduction of drotrecogin alfa. 1731 65

During sepsis, the anti-infectious response is closely linked to an overwhelming inflammatory process. The latter is illustrated by the presence in plasma of numerous inflammatory cytokines, markers of cellular stress (e.g. high mobility group box-1 protein), complement-derived compounds (e.g. anaphylatoxin C5a), lipid mediators, and activated coagulation factors. All mediators contribute in synergy to tissue injury, organ dysfunction, and possibly to lethality. To dampen this overzealous process, a counter-regulatory loop is initiated. The anti-inflammatory counterpart involves few anti-inflammatory cytokines (e.g. interleukin-10, transforming growth factor-beta), numerous neuromediators (e.g. adrenalin, acetylcholine), and some other factors (e.g. heat shock proteins, ligand of TREM-2, adenosine). These mediators modify the immune status of circulating leukocytes as illustrated by their decreased cell-surface expression of HLA-DR or their reduced ex vivo pro-inflammatory cytokine production in response to Toll-like receptor agonists (e.g. endotoxin, lipoproteins). However, circulating leukocytes remain responsive to whole bacteria and produce normal or even enhanced levels of anti-inflammatory cytokines. Thus, the immune dysregulation observed in sepsis corresponds to a reprogramming of circulating leukocytes.
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PMID:Determining the degree of immunodysregulation in sepsis. 1746 19


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