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)

C1 inhibitor therapy improves outcome in several animal models of inflammatory disease. These include sepsis and Gram negative endotoxin shock, vascular leak syndromes, hyperacute transplant rejection, and ischemia-reperfusion injury. Furthermore, some data suggest a beneficial effect in human inflammatory disease. In many inflammatory conditions, complement system activation plays a role in pathogenesis. The contact system also very likely is involved in mediation of damage in inflammatory disease. Therefore, the beneficial effect of C1 inhibitor has been assumed to result from inhibition of one or both of these systems. Over the past several years, several other potential anti-inflammatory effects of C1 inhibitor have been described. These effects do not appear to require protease inhibition and depend on non-covalent interactions with other proteins, cell surfaces or lipids. In the first, C1 inhibitor binds to a variety of extracellular matrix components including type IV collagen, laminin, entactin and fibrinogen. The biologic role of these reactions is unclear, but they may serve to concentrate C1 inhibitor at extravascular inflammatory sites. The second is a non-covalent interaction with C3b that results in inhibition of formation of the alternative pathway C3 convertase, a function analogous to that of factor H. The third is an interaction with E and P selectins on endothelial cells that is mediated by the Lewis(x) tetrasaccharides that are expressed on C1 inhibitor. These interactions result in suppression of leukocyte rolling and transmigration. The fourth interaction is the binding of C1 inhibitor to Gram negative bacterial endotoxin that results in suppression of endotoxin shock by interference with the interaction of endotoxin with its receptor complex on macrophages. Lastly, C1 inhibitor binds directly to Gram negative bacteria, which leads to suppression of the development of sepsis, as demonstrated in the cecal ligation and puncture model. These observations suggest that C1 inhibitor is a multi-faceted anti-inflammatory protein that exerts its effects through a variety of mechanisms including both protease inhibition and several different non-covalent interactions that are unrelated to protease inhibition.
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PMID:C1 inhibitor: biologic activities that are independent of protease inhibition. 1754 16

The administration of insulin is recommended to patients with severe sepsis and hyperglycemia. Previously, we demonstrated that insulin may have direct anti-inflammatory properties and counteracted fluid losses from the circulation by normalizing the interstitial fluid pressure (P(IF)). P(IF) is one of the Starling forces determining fluid flux over the capillary wall, and a lowered P(IF) is one of the driving forces in early edema formation in inflammatory reactions. Here we demonstrate that insulin restores a lipopolysaccharide (LPS)-lowered P(IF) via a mechanism involving integrin alpha(v)beta(3). In C57 black mice (n = 6), LPS lowered P(IF) from -0.2 +/- 0.2 to -1.6 +/- 0.3 (P < 0.05) and after insulin averaged -0.8 +/- 0.2 mmHg (P = 0.098 compared with after LPS). Corresponding values in wild-type BALB/c mice (n = 5) were -0.8 +/- 0.1, -2.1 +/- 0.3 (P < 0.05), and -0.8 +/- 0.3 mmHg (P < 0.05 compared with LPS) after insulin administration. In BALB/c integrin beta(3)-deficient (beta(3)(-/-)) mice (n = 6), LPS lowered P(IF) from -0.1 +/- 0.2 to -1.5 +/- 0.3 mmHg (P < 0.05). Insulin did not, however, restore P(IF) in these mice (averaged -1.7 +/- 0.3 mmHg after insulin administration). Cell-mediated collagen gel contraction can serve as an in vitro model for in vivo measurements of P(IF). Insulin induced alpha(v)beta(3)-integrin-dependent collagen gel contraction mediated by C2C12 cells. Our findings suggest a beneficiary effect of insulin for patients with sepsis with regard to the fluid balance, and this effect may in part be due to a normalization of P(IF) by a mechanism involving the integrin alpha(v)beta(3).
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PMID:Integrin alphavbeta3 acts downstream of insulin in normalization of interstitial fluid pressure in sepsis and in cell-mediated collagen gel contraction. 1855 65

Group B Streptococcus (GBS) is a major etiologic agent of neonatal bacterial infections and is the most common cause of sepsis and pneumonia in newborns. Surface and secreted molecules of GBS are often essential virulence factors which are involved in the adherence of the bacteria to host cells or are required to suppress the defense mechanisms of hosts. We analyzed the peptidase profiles of GBS by detection of proteolytic activities on SDS-PAGE containing copolymerized gelatin as substrate. Based on the inhibition by o-phenathroline and EGTA, three distinct peptidases of 220, 200 and 180 kDa were identified in the culture medium, besides one major cell-associated proteolytic activity, a 200-kDa metallopeptidase, suggesting that all were zinc-metallopeptidases. GBS culture supernatants, rich in metallotype peptidases, also cleaved fibronectin, laminin, type IV collagen, fibrinogen and albumin. Cleavage of the host extracellular matrix by GBS may be a relevant factor in the process of bacterial dissemination and/or invasion. Notably, metallopeptidase inhibitors strongly blocked GBS growth as well as its interaction with human cell lineages. Understanding the contribution of peptidases to the pathogenesis of GBS disease may broaden our perception of how this significant pathogen causes severe infections in newborn infants.
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PMID:Metallopeptidases produced by group B Streptococcus: influence of proteolytic inhibitors on growth and on interaction with human cell lineages. 1857 84

Acute respiratory distress syndrome and acute lung injury for a part of a devastating syndrome characterized by acute onset, hypoxemia and bilateral infiltrates in the chest x-ray with absence of heart failure signs. Acute lung injury is the response of the lung to a local or systemic aggression, resulting in local inflammation and coagulation disorders, this leading to increased inflammatory pulmonary edema. Acute lung injury/acute respiratory distress syndrome are associated with increased procoagulant and reduced fibrinolytic activities mainly in alveoli and interstitial spaces in the lung. Fibrin deposits, which are the hallmark of early phase acute lung injury, stimulate fibroblast aggregation and collagen secretion, participating to the constitution of pulmonary fibrosis. The only clinical intervention found to have a significant impact on mortality in acute respiratory distress syndrome, despite the significant pro - gress in the understanding of the disease made over the past 10 years, is the use of low tidal volume ventilation. In severe sepsis, only recombinant human activated protein C administration has demonstrated a mortality reduction, together with faster improvement in respiratory dysfunction and shorter duration of mechanical ventilation. Future clinical trials should consider the potential benefit of anticoagulants administrated systemically or locally in the lungs to determine the role of anticoagulants in the treatment of acute pulmonary injury/acute respiratory distress syndrome.
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PMID:[Role of coagulation in acute pulmonary lesion physiopathology. Parallelism with sepsis]. 1860 38

Subcapsular hematoma and/or rupture of the graft is uncommon but serious complication of liver transplantation. It may develop spontaneously or following parenchymal injuries or percutaneous transhepatic invasive procedures. This report describes three cases of subcapsular hematoma and/or rupture of the graft with different courses among 350 liver transplantations. In the first case, the patient died due to graft rupture caused by a pseudoaneurysm after biopsy. In the second case, a small injury of the donor liver resulted in a deep rupture, which required partial resection of the graft. The patient died in sepsis later. The third patient presented with a large subcapsular haematoma during transplantation, which was successfully treated. The authors' strategies developed intraoperatively for the management of hematomas. These involve opening and removing of the haematoma, haemostasis with Argon coagulation, which resulted in an adherent Glisson's capsule to the parenchyma and covering with collagen fleece coated with fibrinogen and thrombin.
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PMID:[Subcapsular hematoma and rupture of the liver graft]. 1879 7

The intestinal epithelium is repetitively deformed by shear, peristalsis, and villous motility. Such repetitive deformation stimulates the proliferation of intestinal epithelial cells on collagen or laminin substrates via ERK, but the upstream mediators of this effect are poorly understood. We hypothesized that the phosphatidylinositol 3-kinase (PI3K)/AKT cascade mediates this mitogenic effect. PI3K, AKT, and glycogen synthase kinase-3beta (GSK-3beta) were phosphorylated by 10 cycles/min strain at an average 10% deformation, and pharmacologic blockade of these molecules or reduction by small interfering RNA (siRNA) prevented the mitogenic effect of strain in Caco-2 or IEC-6 intestinal epithelial cells. Strain MAPK activation required PI3K but not AKT. AKT isoform-specific siRNA transfection demonstrated that AKT2 but not AKT1 is required for GSK-3beta phosphorylation and the strain mitogenic effect. Furthermore, overexpression of AKT1 or an AKT chimera including the PH domain and hinge region of AKT2 and the catalytic domain and C-tail of AKT1 prevented strain activation of GSK-3beta, but overexpression of AKT2 or a chimera including the PH domain and hinge region of AKT1 and the catalytic domain and C-tail of AKT2 did not. These data delineate a role for PI3K, AKT2, and GSK-3beta in the mitogenic effect of strain. PI3K is required for both ERK and AKT2 activation, whereas AKT2 is sequentially required for GSK-3beta. Furthermore, AKT2 specificity requires its catalytic domain and tail region. Manipulating this pathway may prevent mucosal atrophy and maintain the mucosal barrier in conditions such as ileus, sepsis, and prolonged fasting when peristalsis and villous motility are decreased and the mucosal barrier fails.
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PMID:Strain-induced proliferation requires the phosphatidylinositol 3-kinase/AKT/glycogen synthase kinase pathway. 1904 55

Bacterial LPS induces rapid thrombocytopenia, hypotension, and sepsis. Although growing evidence suggests that platelet activation plays a critical role in LPS-induced thrombocytopenia and tissue damage, the mechanism of LPS-mediated platelet activation is unclear. In this study, we show that LPS stimulates platelet secretion of dense and alpha granules as indicated by ATP release and P-selectin expression, and thus enhances platelet activation induced by low concentrations of platelet agonists. Platelets express components of the LPS receptor-signaling complex, including TLR (TLR4), CD14, MD2, and MyD88, and the effect of LPS on platelet activation was abolished by an anti-TLR4-blocking Ab or TLR4 knockout, suggesting that the effect of LPS on platelet aggregation requires the TLR4 pathway. Furthermore, LPS-potentiated thrombin- and collagen-induced platelet aggregation and FeCl(3)-induced thrombus formation were abolished in MyD88 knockout mice. LPS also induced cGMP elevation and the stimulatory effect of LPS on platelet aggregation was abolished by inhibitors of NO synthase and the cGMP-dependent protein kinase (PKG). LPS-induced cGMP elevation was inhibited by an anti-TLR4 Ab or by TLR4 deficiency, suggesting that activation of the cGMP/protein kinase G pathway by LPS involves the TLR4 pathway. Taken together, our data indicate that LPS stimulates platelet secretion and potentiates platelet aggregation through a TLR4/MyD88- and cGMP/PKG-dependent pathway.
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PMID:Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. 1949 25

Triggering receptor expressed on myeloid cells (TREM)-1 is inducible on monocyte/macrophages and neutrophils and accelerates tissue destruction by propagating inflammatory responses in diseases related to bacterial infection. Its blockade suppressed fatal immune responses in mice models of sepsis without impairing the host defense. However, the influence of TREM-1 on non-bacterial diseases was not elucidated. We describe here that TREM-1 expression was up-regulated by prostaglandin (PG) E(2) as well as lipopolysaccharide. Activation of TREM-1 expressed on PGE(2)-pretreated peripheral blood mononuclear cells by an agonistic TREM-1 mAb significantly enhanced the production of TNFalpha. Indeed, monosodium urate monohydrate (MSU) crystals induced TREM-1 expression in vitro and in vivo. MSU crystals and an anti-TREM-1 agonistic antibody synergistically increased the production of interleukin-1beta compared with stimulation with the crystals alone. Furthermore, TREM-1 was expressed on CD14+ cells in rheumatoid synovial tissue and synovial macrophages from mice with collagen-induced arthritis (CIA). Blockade of TREM-1 ameliorated CIA without affecting T cell and B cell immune responses to the inducing antigen. These results provide evidence that TREM-1 may contribute the development of non-microbial inflammatory diseases through the enhancement of inflammatory responses.
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PMID:[Triggering receptor expressed on myeloid cells-1 as an inflammation amplifier]. 1972 44

Injury to the common bile duct (CBD) during upper gastrointestinal surgery for peptic ulcer disease is a serious complication with an underestimated prevalence in light of the few cases reported in the surgical literature. Three cases of CBD injury were referred to a multidisciplinary specialized gastrointestinal unit for management over a 4-year period. Anomalous anatomy, adhesions, and potential duodenal shortening secondary to contracture all predispose the biliary ducts to intraoperative injury. The axial nature of the blood supply to the extrahepatic ducts and the tendency of bile itself to cause rapid collagen turnover and fibrosis, combined with the inflammation and subsequent fibrosis to the surrounding tissues caused by bile leakage, give the bile ducts a high propensity for stricture formation. Frequently presenting symptoms of CBD injury immediately after surgery include jaundice, elevated bilirubin values, elevated t-tube drainage, and symptoms of sepsis. The most common complaints noted in patients who present in a delayed manner are symptoms of cholangitis. Even when injuries are rapidly identified and corrected, the potential for lasting negative impact on quality of life is great in many cases. When CBD injury occurs, the pancreatic duodenal union can be concomitantly disrupted.
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PMID:Management of common bile duct injury during partial gastrectomy. 1972 97

Permacol mesh has shown promise when used in abdominal wall repair, especially in the presence of a contaminated surgical field. This biomaterial, derived from porcine dermis collagen, has proposed advantages over synthetic materials due to increased biocompatibility and reduced foreign body reaction within human tissues. However, we present a case report describing a patient who displayed rejection to a Permacol mesh when used in the repair of abdominal wound dehiscence following an emergency laparotomy. Review of the English language literature using PubMed and Medline, showed only two previously published cases of explantation of Permacol due to sepsis or wound breakdown. The authors believe this is the first case of severe foreign body reaction leading to rejection of Permacol. Both animal and human studies show conflicting evidence of biocompatibility. There are several reports of successful use of Permacol to repair complex incisional herniae or abdominal walls in the presence of significant contamination. It appears from the literature that Permacol is a promising material, but as we have demonstrated, it has the potential to evoke a foreign body reaction and rejection in certain subjects.
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PMID:Rejection of Permacol mesh used in abdominal wall repair: a case report. 2012 39


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