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)

The host's inflammatory response to sepsis can be divided into two phases, the initial detection and response to the pathogen initiated by the innate immune response, and the persistent inflammatory state characterized by multiple organ dysfunction syndrome (MODS). New therapies aimed at pathogen recognition receptors (PRRs) particularly the TLRs and the NOD-like receptors offer hope to suppress the initial inflammatory response in early sepsis and to bolster this response in late sepsis. The persistence of MODS after the initial inflammatory surge can also be a determining factor to host survival. MODS is due to the cellular damage and death induced by sepsis. The mechanism of this cell death depends in part upon mitochondrial dysfunction. Damaged mitochondria have increased membrane permeability prompting their autophagic removal if few mitochondria are involved but apoptotic cell death may occur if the mitochondrial losses are more extensive. In addition. severe loss of mitochondria results in low cell energy stores, necrotic cell death, and increased inflammation driven by the release of cell components such as HMGB1. Therapies, which aim at improving cellular energy reserves such as the promotion of mitochondrial biogenesis by insulin, may have a role in future sepsis therapies. Finally, both the inflammatory responses and the susceptibility to organ failure may be modulated by nutritional status and micronutrients, such as zinc, Therapies aimed at micronutrient repletion may further augment approaches targeting PRR function and mitochondrial viability.
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PMID:Sepsis: links between pathogen sensing and organ damage. 1869 Oct 95

Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and critical to resolution of inflammation. Impaired efferocytosis is associated with an unfavorable outcome from inflammatory diseases, including acute lung injury and pulmonary manifestations of cystic fibrosis. High mobility group protein-1 (HMGB1), a nuclear nonhistone DNA-binding protein, has recently been found to be secreted by immune cells upon stimulation with LPS and cytokines. Plasma and tissue levels of HMGB1 are elevated for prolonged periods in chronic and acute inflammatory conditions, including sepsis, rheumatoid arthritis, acute lung injury, burns, and hemorrhage. In this study, we found that HMGB1 inhibits phagocytosis of apoptotic neutrophils by macrophages in vivo and in vitro. Phosphatidylserine (PS) is directly involved in the inhibition of phagocytosis by HMGB1, as blockade of HMGB1 by PS eliminates the effects of HMGB1 on efferocytosis. Confocal and fluorescence resonance energy transfer demonstrate that HMGB1 interacts with PS on the neutrophil surface. However, HMGB1 does not inhibit PS-independent phagocytosis of viable neutrophils. Bronchoalveolar lavage fluid from Scnn(+) mice, a murine model of cystic fibrosis lung disease which contains elevated concentrations of HMGB1, inhibits neutrophil efferocytosis. Anti-HMGB1 Abs reverse the inhibitory effect of Scnn(+) bronchoalveolar lavage on efferocytosis, showing that this effect is due to HMGB1. These findings demonstrate that HMGB1 can modulate phagocytosis of apoptotic neutrophils and suggest an alternative mechanism by which HMGB1 is involved in enhancing inflammatory responses.
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PMID:High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine. 1876 81

Severe sepsis is the leading cause of mortality in intensive care units. The limited ability of current therapies to reduce sepsis mortality rates has fueled research efforts for the development of novel treatment strategies. Through the close collaboration between clinicians and scientists, progress can be seen in the struggle to develop effective therapeutic approaches for the treatment of sepsis and other immune and inflammatory disorders. Indeed, significant advances in intensive care, such as lung protective mechanical ventilation, improved antibiotics, and superior monitoring of systemic perfusion, are improving patient survival. Nonetheless, specific strategies that target the pathophysiological disorders in sepsis patients are essential to further improve clinical outcomes. This article reviews current clinical management approaches and experimental interventions that target pleiotropic or late-acting inflammatory mediators like caspases, C5a, MIF, and HMGB1, or the body's endogenous inflammatory control mechanisms such as the cholinergic anti-inflammatory pathway. These inflammatory mediators and anti-inflammatory mechanisms, respectively, show significant potential for the development of new experimental therapies for the treatment of severe sepsis and other infectious and inflammatory disorders.
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PMID:Experimental therapeutic strategies for severe sepsis: mediators and mechanisms. 1907 79

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection, which kills > 225,000 people annually in the U.S. alone. The high mortality of sepsis is partly mediated by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF) and late (e.g., HMGB1) pro-inflammatory cytokines. Although early proinflammatory cytokines may be protective against infection, excessive accumulation of late-acting proinflammatory mediators (such as HMGB1) may sustain a potentially injurious inflammatory response. Agents capable of inhibiting HMGB1 activities (e.g., neutralizing antibodies) or release [e.g., Chinese herbs, Danggui (Angelica sinensis), Danshen (Salvia miltiorrhiza) and Green tea (Camellia sinensis)] rescue mice from lethal sepsis even when given 24 hours after onset of the disease. Here we review emerging evidence that support a critical role for extracellular HMGB1 as a late mediator of lethal sepsis, and several commonly used Chinese herbs (Danggui, Danshen and Green tea) as potential HMGB1- targeting therapeutic agents in experimental sepsis.
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PMID:Caging a Beast in the Inflammation Arena: Use of Chinese Medicinal Herbs to Inhibit a Late Mediator of Lethal Sepsis, HMGB1. 1907 88

The pathogenesis of sepsis is mediated in part by the pathogen-associated molecular pattern molecule bacterial endotoxin, which stimulates macrophages to sequentially release early (e.g., TNF-alpha, IL-1beta) and late (e.g., high-mobility group box [HMGB] 1 protein) proinflammatory mediators. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation into development of several new experimental therapeutics that limit release, either blocking HMGB1 itself or its nominal receptors. Quercetin was recently identified as an experimental therapeutic that significantly protects against oxidative injury. Here, we report that quercetin attenuates lethal systemic inflammation caused by endotoxemia, even if treatment is started after the early TNF response. Quercetin treatment reduced circulating levels of HMGB1 in animals with established endotoxemia. In macrophage cultures, quercetin inhibited release as well as the cytokine activities of HMGB1, including limiting the activation of mitogen-activated protein kinase and NF-kappaB, two signaling pathways that are critical for HMGB1-induced subsequent cytokine release. Quercetin and autophagic inhibitor, wortmannin, inhibited LPS-induced type-II microtubule-associated protein 1A/1B-light chain 3 production and aggregation, as well as HMGB1 translocation and release, suggesting a potential association between autophagy and HMGB1 release. Quercetin delivery, a strategy to pharmacologically inhibit HMGB1 release that is effective at clinically achievable concentrations, now warrants further evaluation in sepsis and other systemic inflammatory disorders.
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PMID:Quercetin prevents LPS-induced high-mobility group box 1 release and proinflammatory function. 1926 75

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 by producing early (e.g., TNF and IFN-gamma) and late (e.g., high-mobility group box [HMGB1]) proinflammatory cytokines. Here, we briefly review emerging evidence that support extracellular HMGB1 as a late mediator of experimental sepsis and discuss therapeutic potential of several HMGB1-inhibiting agents (including neutralizing antibodies and steroid-like tanshinones) in experimental sepsis.
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PMID:Novel HMGB1-inhibiting therapeutic agents for experimental sepsis. 1933 43

Sepsis remains a major cause of morbidity and mortality worldwide. The systemic release of the nuclear protein HMGB1 is a late event in endotoxin-related lethality in mice. The platinating chemotherapeutic Cis induces DNA lesions that sequester HMGB1 within the nucleus of cells. We sought to determine if low, nontoxic doses of Cis could be an effective strategy in ameliorating sepsis-related mortality in a mouse model of CLP. In vitro studies with Cis prevented the LPS-induced release of HMGB1 from RAW264.7 cells, limited MAPK signaling, but had no effect on NF-kappaB activation or cytokine production. Low, nontoxic doses of Cis decreased mortality following CLP, whether delivered before or after puncture. Protection was associated with a decrease in the systemic release of HMGB1 and protection from end organ injury and in particular, less acute lung injury. Tissue-specific iNOS expression was markedly reduced. Low, nontoxic doses of Cis sequester HMGB1 effectively inside of the nucleus of LPS-stimulated immune cells and prevent its release in response to CLP. Platinating agents in general and Cis specifically may be a novel approach to the treatment of sepsis.
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PMID:Low-dose cisplatin administration in murine cecal ligation and puncture prevents the systemic release of HMGB1 and attenuates lethality. 1948 5

The cholinergic antiinflammatory pathway modulates inflammatory cytokine production through a mechanism dependent on the vagus nerve and the alpha7 subunit of the nicotinic acetylcholine receptor. GTS-21 [3-(2,4-dimethoxybenzylidene) anabaseine], a selective alpha7 agonist, inhibits inflammatory cytokine production in murine and human macrophages and in several models of inflammatory disease in vivo, but to date its antiinflammatory efficacy in human monocytes has not been characterized. We report here our findings that GTS-21 attenuates tumor necrosis factor (TNF) and interleukin 1beta levels in human whole blood activated by exposure to endotoxin. GTS-21 inhibited TNF production in endotoxin-stimulated primary human monocytes in vitro at the transcriptional level. The suppressive effect of GTS-21 was more potent than nicotine in whole blood and monocytes. Furthermore, GTS-21 attenuated TNF production in monocytes stimulated with peptidoglycan, polyinosinic-polycytidylic acid, CpG, HMGB1 (high-mobility group box 1 protein), and advanced glycation end product-modified albumin. GTS-21 decreased TNF levels in endotoxin-stimulated whole blood obtained from patients with severe sepsis. These findings establish the immunoregulatory effect of GTS-21 on human monocytes, and indicate the potential benefits of further exploration of GTS-21's therapeutic uses in human inflammatory disease.
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PMID:The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. 1959 3

The pathogenesis of sepsis is partly attributable to dysregulated inflammatory response mediated by pathogen-associated molecular patterns (PAMPs) (for example, endotoxin) and damage-associated molecular patterns (DAMPs) (for example, high-mobility group box 1 [HMGB1]). An endogenous ubiquitous polyamine, spermine, inhibits endotoxin-induced cytokine release in vitro, but its capacities to attenuate sepsis- and HMGB1-induced inflammatory responses was previously unknown. We thus tested the hypothesis that spermine protects mice against lethal sepsis by attenuating sepsis-induced local and systemic inflammatory responses. Intraperitoneal (i.p.) administration of spermine (10 mg/kg, twice daily, for 3 d) conferred a significant protection against lethal sepsis. The protective effects were associated with a significant reduction in peritoneal and serum levels of several surrogate markers of sepsis (for example, Interleukin-6 [IL-6], keratinocyte-derived chemokine [KC], monocytes chemoattractant protein-1 [MCP-1], macrophage inflammatory protein-2 [MIP-2], tissue inhibitor of metalloproteinase-1 [TIMP-1], soluble tumor necrosis factor-alpha receptor I [sTNFRI], and soluble tumor necrosis factor-alpha receptor II [sTNFRII]) during a late stage of sepsis. In vitro, spermine effectively inhibited HMGB1-induced release of the above surrogate markers in peritoneal macrophages. Thus, spermine confers protection against lethal sepsis partly by attenuating sepsis- and HMGB1-induced inflammatory responses.
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PMID:Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory markers. 1959 12

Programmed necrosis is a mechanism of cell death that has been described for neuronal excitotoxicity and ischemia/reperfusion injury, but has not been extensively studied in the context of exposure to bacterial exotoxins. The alpha-toxin of Clostridium septicum is a beta-barrel pore-forming toxin and a potent cytotoxin; however, the mechanism by which it induces cell death has not been elucidated in detail. We report that alpha-toxin formed Ca(2+)-permeable pores in murine myoblast cells, leading to an increase in intracellular Ca(2+) levels. This Ca(2+) influx did not induce apoptosis, as has been described for other small pore-forming toxins, but a cascade of events consistent with programmed necrosis. Ca(2+) influx was associated with calpain activation and release of cathepsins from lysosomes. We also observed deregulation of mitochondrial activity, leading to increased ROS levels, and dramatically reduced levels of ATP. Finally, the immunostimulatory histone binding protein HMGB1 was found to be released from the nuclei of alpha-toxin-treated cells. Collectively, these data show that alpha-toxin initiates a multifaceted necrotic cell death response that is consistent with its essential role in C. septicum-mediated myonecrosis and sepsis. We postulate that cellular intoxication with pore-forming toxins may be a major mechanism by which programmed necrosis is induced.
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PMID:Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum. 1960 57


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