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)

During sepsis the complement system, the contact activation system and the coagulation cascade are activated. Activation of these plasmatic cascades contributes to the development of multiple organ failure and the high mortality rate of severe sepsis and septic shock. C1-inhibitor is the main inhibitor of the classical pathway of the complement system (C1s and C1r), of the contact activation system (factor XIIa and kallikrein) and of the intrinsic pathway of coagulation (factor XIa). During sepsis, C1-inhibitor is proteolytically inactivated. The increase of inactivated C1-inhibitor in plasma correlates positively with mortality in septic patients. C1-inhibitor substitution has been shown to reduce the mortality in experimental animals with severe sepsis or septic shock. Only a few cases of C1-inhibitor substitution in patients with severe sepsis or septic shock have been reported. C1-inhibitor has been shown to attenuate the activation of the complement system and the contact activation system and to improve hypotension. Based on this convincing pathophysiological concept and the results of the animal studies, we initiated the "Bernese C1-inhibitor study", a randomised double-blind and placebo-controlled pilot study involving administration of C1-inhibitor to patients with severe sepsis or septic shock. If the results of this pilot study confirm the results of the reports mentioned above, they will serve as a base for larger multicentre studies.
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PMID:[Activation of plasma cascade systems in sepsis: role of C1 inhibitors]. 1054 99

The complement system is a multifactorial protein cascade system which is essentially involved in the early unspecific immune response. Its major function is the activation of cellular defense mechanisms, opsonisation of foreign particles and the destruction of target cells. While the impact of the different complement components for bacterial elimination still remains controversial, overwhelming activation of the complement cascade, however, can induce life threatening tissue damage due to the effective cytotoxic properties. In the last years a variety of studies demonstrated beneficial, organ protective effects of complement modulation in models of severe inflammation. Attempts to control the complement system include the application of endogenous complement inhibitors e.g. C1-inhibitor (C1-INH) or the administration of recombinant complement receptors such as the soluble complement receptor 1 (rsCR1). Moreover antibodies against key proteins (C3, C5), against their activation products (C5a) or against complement receptor 3 (CR3, CD18/11b) mediated adhesion of leukocytes to the vascular endothelium, represent effective options of complement modulation. Besides this, insertion of membrane bound human complement regulators (DAF- CD55, MCP- CD46 or CD59) into xenogenic donor organs has proven effectiveness to prevent xenograft rejection. The described interventions protected from severe organ damage in various animal models of sepsis, myocardial and intestinal ischaemia-reperfusion injury, ARDS, nephritis, and xenograft rejection. With respect to recent clinical data, complement inhibition could represent a useful therapeutic strategy to control overwhelming inflammation. Own experiments demonstrated protective effects of complement modulation with C1 INH and rsCR1 in a model of complement induced pulmonary injury. With respect to sufficient host defense, however, the use of complement inhibitors must be considered carefully.
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PMID:[The complement system: an old story or target of new therapeutic approaches?]. 1083 72

A prospective cohort study was performed in 50 patients with dengue haemorrhagic fever (DHF) to determine the potential role of the contact activation system and factor XI activation (intrinsic pathway) in the coagulation disorders in DHF. To establish whether TAFI (thrombin-activatable fibrinolysis inhibitor) was involved in the severity of the coagulation disorders, the TAFI antigen and activity levels were also determined. Markers of contact activation (kallikrein--C1-inhibitor complexes), the intrinsic pathway of coagulation (factor XIa--C1-inhibitor complexes) and TAFI were measured and correlated to thrombin generation markers (thrombin--anti-thrombin complexes (TAT), prothrombin fragment 1+2 (F1+2)) and a marker for fibrinolysis [plasmin--alpha 2--anti-plasmin complexes (PAP)]. Activation of the intrinsic pathway of coagulation was clearly demonstrated by elevated levels of factor XIa--C1-inhibitor complexes, without evidence of contact activation, reflected by undetectable kallikrein--C1-inhibitor complexes. Both TAFI antigen and activity levels were decreased in all patients, which may contribute to the severity of bleeding complications in DHF because of the impaired capacity of the coagulation system to protect the fibrin clot from fibrinolysis. These findings in a human viral infection model are in accordance with earlier findings in bacterial sepsis.
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PMID:Activation of coagulation factor XI, without detectable contact activation in dengue haemorrhagic fever. 1132 87

Complement activation is closely associated with plasma endotoxin levels in patients with meningococcal infections. This study assessed complement activation induced by purified Neisseria meningitidis lipopolysaccharide (Nm-LPS), native outer membrane vesicles (nOMVs), LPS-depleted outer membrane vesicles (dOMVs), wild-type meningococci, and an LPS-free mutant (lpxA(-)) from the same strain (44/76) in whole blood anticoagulated with the recombinant hirudin analogue. Complement activation products (C1rs-C1 inhibitor complexes, C4d, C3bBbP, and terminal SC5b-9 complex) were measured by double-antibody EIAs. Nm-LPS was a weak complement activator. Complement activation increased with preparations containing nOMVs, dOMVs, and wild-type bacteria at constant LPS concentrations. With the same protein concentration, complement activation induced by nOMVs, dOMVs, and the LPS-free mutant was equal. The massive complement activation observed in patients with fulminant meningococcal septicemia is, presumably, an indirect effect of the massive endotoxemia. Outer membrane proteins may be more potent complement activators than meningococcal LPSs.
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PMID:Complement activation induced by purified Neisseria meningitidis lipopolysaccharide (LPS), outer membrane vesicles, whole bacteria, and an LPS-free mutant. 1180 96

Coagulation and complement proteinases are activated in sepsis, and one approach to therapy is to develop proteinase inhibitors that will specifically inhibit these proteinases without inhibiting activated protein C, a proteinase that is beneficial to survival. In this study, we made mutants of the serpin alpha(1)-PI, designed to mimic the specificity of C1-inhibitor. The P3-P2-P1 residues of alpha1-PI were changed from IPM to LGR and PFR, sequences preferred by C1s and kallikrein, respectively. Inhibition of C1s, kallikrein, factor XIIa, and activated protein C was assessed by SDS-PAGE, and by determination of the k(app) and SI. alpha(1)-PI-LGR inhibited C1s with a rate of 7790 M(-1)s(-1), but only minimal inhibition of C1 in a hemolytic assay was observed. Kallikrein, factor XIIa, and activated protein C were inhibited with rates of 382,180 M(-1)s(-1), 10,400 M(-1)s(-1), and 3500 M(-1)s(-1), respectively. alpha(1)-PI-PFR was a poor inhibitor of C1s, factor XIIa, and activated protein C, but had enhanced reactivity with kallikrein. Changing the P4' residue of alpha(1)-PI-LGR Pro to Glu reduced the activity with C1s, consistent with the idea that C1s requires hydrophobic residues in this region of the serpin for optimal interaction. The data provide insight into the requirements for kallikrein and C1s inhibition necessary for designing inhibitors with appropriate properties for further investigation as therapeutic agents.
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PMID:alpha(1)-Proteinase inhibitor mutants with specificity for plasma kallikrein and C1s but not C1. 1219 78

C1 inhibitor (C1-Inh) is a protease inhibitor of the serpin family. It interacts and forms complexes with several serine proteases although not all these interactions were proved to be relevant in vivo. Based on studies in deficient patients, C1-Inh appears pivotal in regulating the activation of complement classical pathway and of contact system. The best recognized consequence of defective C1-Inh function is predisposition to episodes of self-limited, increased vascular permeability (angioedema) that is restricted to three specific sites, which include the subcutaneous space, the gut and the upper airway. Candidate mediator of angioedema is bradykinin, a potent vasoactive peptide, released upon contact system activation. Mutations in C1-Inh structural gene are the most common cause of C1-Inh deficiency and lead to hereditary angioedema. Recurrent angioedema are also seen in the acquired defect of C1-Inh that is due to autoantibodies against this protein or to an associated disease causing accelerated catabolism of C1-Inh. Apart from the profound deficiency of C1-Inh characteristic of angioedema, it has been suggested that, in specific pathologic settings, C1-Inh levels in the low normal range could still represent a significant functional deficiency. Such conditions, as extensively investigated in sepsis, are of great relevance because they open the possibility of using C1-Inh as therapeutic agent in several different diseases.
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PMID:Mechanisms of C1-inhibitor deficiency. 1239 14

Therapeutic application of the serpin C1-inhibitor (C1-Inh) in inflammatory diseases like sepsis, acute myocardial infarction and vascular leakage syndrome seems promising, but large doses may be required. Therefore, a high-yield recombinant expression system for C1-Inh is very interesting. Earlier attempts to produce high levels of C1-Inh resulted in predominantly inactive C1-Inh. We describe the high yield expression of rhC1-Inh in Pichia pastoris, with 180 mg/l active C1-Inh at maximum. On average, 30 mg/l of 80-100% active C1-Inh was obtained. Progress curves were used to study the interaction with C1s, kallikrein, coagulation factor XIIa and XIa, and demonstrated that rhC1-Inh had the same inhibitory capacity as plasma C1-Inh. Structural integrity, as monitored via heat stability, was comparable despite differences in extent and nature of glycosylation. We conclude that the P. pastoris system is capable of high-level production of functionally and structurally intact human C1 inhibitor.
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PMID:Recombinant human C1-inhibitor produced in Pichia pastoris has the same inhibitory capacity as plasma C1-inhibitor. 1275 49

Forty patients with severe sepsis or septic shock recently received C1 inhibitor. In the present study we studied the effect of C1 inhibitor therapy on circulating elastase-alpha(1)-antitrypsin complex (EA) and lactoferrin (LF) levels in these patients to gain further insight about agonists involved in the activation of neutrophils in human sepsis. Elevated levels of EA and LF were found in 65 and 85% of the septic patients, respectively. Patients with elevated EA levels had higher organ dysfunction scores, higher levels of cytokines, and higher levels of complement activation products than patients with normal EA levels. C1 inhibitor therapy reduced EA as well as complement activation and IL-8 release in the patients with elevated EA on admission. We conclude that neutrophil activation in human sepsis correlates with the severity of organ dysfunction and involves complement and interleukin-8 as agonists. The effect of C1 inhibitor therapy on neutrophils may provide an explanation for the beneficial, although mild, effects of this treatment on organ dysfunction in sepsis.
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PMID:Administration of C1 inhibitor reduces neutrophil activation in patients with sepsis. 1285 81

C1 inhibitor (C1INH) is beneficial in animal models of endotoxemia and sepsis. However, the mechanism(s) of C1INH protection remain(s) ill-defined. In this study, we demonstrated that both active C1INH and reactive center-cleaved, inactive C1INH protected mice from lethal Gram-negative endotoxemia. Both forms of C1INH blocked the LPS-binding protein-dependent binding of Salmonella typhimurium LPS to the murine macrophage cell line, RAW 264.7, and suppressed LPS-induced TNF-alpha mRNA expression. Inhibition of LPS binding to RAW 264.7 cells was reversed with anti-C1INH Ab and was more efficient when C1INH was incubated first with LPS rather than with the cells. C1INH also suppressed LPS-induced up-regulation of TNF-alpha mRNA in whole human blood. The interaction of C1INH with LPS was directly demonstrated both by ELISA and by nondenaturing PAGE, but deletion of the amino-terminal 97-aa residues abrogated this binding. Therefore, C1INH, in addition to its function as a serine protease inhibitor, has a novel anti-inflammatory function mediated via its heavily glycosylated amino-terminal non-serpin domain.
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PMID:C1 inhibitor prevents endotoxin shock via a direct interaction with lipopolysaccharide. 1292 11

To evaluate the predictive value of protein C as a marker of severity in patients with diffuse peritonitis and abdominal sepsis, protein C levels were repeatedly determined and compared with serum levels of antithrombin III, plasminogen, alpha(2)-antiplasmin, Plasminogen activator inhibitor, D-dimer, C1-inhibitor, high molecular weight kininogen, and the C5a, C5b-9 fragments of the complement system. We carried out a prospective study from 44 patients with severe peritonitis confirmed by laparotomy and 15 patients undergoing elective ventral hernia repair who acted as controls. Analyzed biochemical parameters were determined before operations and on days 1, 2, 3, 5, 7, 10, and 14 after operations. For the study group, preoperative average protein C level was significantly lower in the patients who developed septic shock in the late course of the disease, with lethal outcome, than in the patients with severe peritonitis and sepsis who survived (p = 0.0001). In non-survivors, protein C activity remained decreased below 70%, whereas the course of survivors was characterized by increased values that were significantly higher (p < 0.03) at every time point than in those patients who died. Protein C was of excellent predictive value and achieved a sensitivity of 80% and a specificity of 87.5% in discriminating survivors from non-survivors within the first 48 hours of the study (AUC-0.917; p < 0.001), with a "cut-off" level of 66.0%. As for the control group, throughout the study period, protein C activity was permanently maintained within the range of normal, with significant differences with reference to the study group (p < 0.01). These results suggest that protein C represents a sensitive and early marker for the prediction of severe septic complications during diffuse peritonitis, and of outcome.
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PMID:Protein C as an early marker of severe septic complications in diffuse secondary peritonitis. 1588 Feb 75


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