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)

Components of the plasma proteolytic enzyme systems were studied in 15 multiple trauma patients. There were 9 survivors and 6 fatal cases. All fatal cases had sepsis and/or post traumatic adult respiratory distress syndrome. Within the first day after trauma significantly reduced values were found for plasma prekallikrein (PKK), Hageman factor (HF) and Antithrombin III (AT III). In the survivors these parameters were normalized within the first five days after the injury. In the fatal cases, however, the same parameters remained reduced or declined during the observation period. The fatal cases also revealed a high frequency of positive ethanol gelation tests (EGT), elevated serum fibrin - fibrinogen degradation products (FDP) values and persisting low platelet counts. Analyses of plasma samples from both survivors and fatal cases, fractions by Sephadex G-150 gel filtration, demonstrated alpha 2-macroglobulin - plasma kallikrein complexes. These findings demonstrate activation of the kallikrein-kinin system as a part of pathological plasma proteolysis in multiple trauma patients. Persistent reductions of PKK, HF and AT III combined with positive EGT, elevated FDP values and reduced platelet counts indicate a poor prognosis.
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PMID:Determination of components of the plasma proteolytic enzyme systems gives information of prognostic value in patients with multiple trauma. 634 78

Components of the plasma protease systems were determined by means of chromogenic peptide substrate assays during the early stage of septicemia in 21 patients of whom 11 died. The proenzyme functional inhibition index, calculated from the measured values for plasma prekallikrein, functional kallikrein inhibition, plasminogen and functional antiplasmin and antithrombin III activities, were markedly reduced in both groups, but significantly lower in the fatal cases than in the survivors from the first day of septicemia and throughout the observation period. Fatal septicemia thus appear to be associated with a more extensive proteolytic activity in plasma than nonfatal septicemia and can be readily disclosed by calculation of the proenzyme functional inhibition index.
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PMID:Evaluation of severity and prognosis in early stages of septicemia by means of chromogenic peptide substrate assays. 637 97

Plasma prekallikrein and functional kallikrein inhibition were studied in 18 surgical patients with complicating septicemia using chromogenic peptide substrate assays. Nine patients died and nine survived. In all 18 patients plasma prekallikrein values were reduced markedly when septicemia was diagnosed. During treatment gradually increasing values were found in the survivors, whereas values remained low in the fatal cases. Significantly reduced functional plasma kallikrein inhibition was associated with the development of fatal septic shock. The findings show that determination of these components of the plasma kallikrein-kinin system gives valuable information of prognostic value in patients with septicemia. Furthermore, the chromogenic peptide substrate assays used are fast and easy to perform and therefore suitable for intensive care medicine.
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PMID:Plasma kallikrein-kinin system in septicemia. 654 98

These studies have indicated some quantitative aspects of the kallikrein kinin system in sepsis. While other investigators have noted the fall in plasma kininogen in patients with sepsis, e.g. Erdos and colleagues (23), this study has indicated that it is the fall in the LMWK that is significant in these patients. LMWK comprises of three-quarters of the total plasma kininogen and its consumption can lead to the production of 2.24 million picograms bradykinin/ml plasma. In health bradykinin concentration is of the order of 100-400 picograms/ml. It is not unreasonable to suggest therefore, that bradykinin levels are increased in acute disease and other investigators have shown this by direct assay of the peptide in such patients. The present study has shown that once bradykinin is generated in the circulation in terms of ng/ml, even with passage through the lung, systemic effects occur, namely reduction in TPR and a fall in CO and BP. Thus, bradykinin could be the humoral factor responsible for the hyperdynamic state and systemic hypotension in severe sepsis. It is apparent that metabolism of bradykinin involves more than simply clearance of the peptide. It appears that bradykinin can stimulate the production of other vasoactive mediators by the lung. The consumption of LMWK in sepsis indicates that it is not plasma kallikrein activity but rather non-specific kininogenase activity that is critical. This may be important not only from the viewpoint of kinin generation, but also because of the consumption of plasma protease inhibitors. A mechanism to control or inhibit such protease activity offers a possible therapeutic approach to circulatory failure in these patients.
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PMID:The kallikrein-kinin system in the acutely-ill: (A) changes in plasma kininogen in acutely-ill patients. (B) the efficacy of pulmonary clearance of bradykinin. 655 53

Functional kallikrein inhibition and prekallikrein levels have been studied during septic shock and septicemia in 13 patients using chromogenic peptide substrate assays. Eleven septic shock episodes were studied of which 5 were fatal. Marked reductions in functional kallikrein inhibition and prekallikrein values occurred during fatal septic shock. In patients who could be resuscitated from septic shock, functional kallikrein inhibition was in the normal range, but significantly lower than in patients with septicemia only. Also in these two groups of patients decreased prekallikrein values were found. During treatment a gradual increase in prekallikrein was observed in the survivors and functional kallikrein inhibition values remained in the normal range during the whole course. Our results indicate that the functional inhibition of plasma kallikrein plays a major role in determining the outcome of septic shock.
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PMID:The functional inhibition of plasma kallikrein. A critical factor in septic shock. 655 54

Activation of the kallikrein-kinin system in sepsis has long been recognized, but its role, beneficial or pathologic, has not been defined. Recently, however, specific bradykinin (BK) antagonists have become available and this study investigated the effects of a BK antagonist, NPC17731 (Scios-Nova) on systemic and pulmonary hemodynamics in a model of gram-negative sepsis. Anesthetized swine were studied for 5 h receiving a 1-h infusion of saline (controls, group 1, N = 8) or live Pseudomonas aeruginosa (septic, group 2, N = 8). Group 3 (treatment, N = 6) received NPC17731 (5 mg/kg initial bolus followed by 1 mg/kg hourly) just prior to the onset of sepsis. Group 2 animals showed a rapid decrease in systemic arterial pressure (SAP) from 30 min onward, and sustained significant hypotension from 2 h onward. In group 3, SAP fell similarly until 2 h then progressively rose, returning to baseline levels by 5 h. In contrast, cardiac index fell progressively from 3 h onward in groups 2 and 3. Systemic vascular resistance index (SVRI) fell significantly by 2 h in group 2 animals, recovering to baseline by 5 h. Group 3 showed a similar initial fall followed by a rebound increase in SVRI, which, at 5 h was significantly raised above the other groups. Group 2 developed significant, persistent pulmonary artery hypertension which was not reduced by NPC17731. The data imply a significant role for bradykinin in the pathogenesis of hypotension in septic shock in this model. Septic shock was reversed by a BK antagonist which increased peripheral resistance without affecting cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic effects of bradykinin antagonism in porcine gram-negative sepsis. 761 81

Ecotin, a serine protease inhibitor found in the periplasm of Escherichia coli, has been characterized as a potent reversible tight-binding inhibitor of the human contact activation proteases factor XIIa (FXIIa) and plasma kallikrein, having Ki values of 89 pM and 163 pM, respectively. Ecotin also inhibited human leukocyte elastase (HLE) with high affinity (Ki = 55 pM). The association rate constants kon for FXIIa and kallikrein were 5.3 x 10(5) M-1.s-1 and 2.9 x 10(5) M-1.s-1, respectively. The dissociation rate constant koff for kallikrein, measured in the presence of HLE to prevent reassociation, was 6.3 x 10(-5) s-1; the koff for ecotin with FXIIa was 4.7 x 10(-5) s-1. Both FXIIa and kallikrein cleaved ecotin slowly at pH 5.0, identifying Met-84 as the P1 residue. The potent anticoagulant effect by ecotin is explained by the coincident inhibition of FXIIa, kallikrein, and FXa and suggests that it may be useful in the study of inflammatory or thrombotic disorders such as sepsis or cardiopulmonary bypass.
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PMID:Ecotin is a potent inhibitor of the contact system proteases factor XIIa and plasma kallikrein. 778 71

C1-Inhibitor (Berinert, C1 INH), a 104 kDa protein, inhibits complement components (C1 esterase) as well as enzymes of the contact phase of coagulation (Factor XII, Factor XI) and kallikrein, thus regulating kinin generation. C1 INH is used for the treatment of the hereditary angioneurotic edema. This paper will give a survey about the evidence in recent literature concerning the potential efficacy of the compound on other diseases associated with shock, capillary leakage and inflammation as well. In our own experiments we evaluated whether the compound could influence acute inflammatory reactions or the severe systemic inflammatory response syndrome (SIRS) as a consequence of an experimental septic shock. To prevent the sepsis-induced DIC we co-infused the thrombin inhibitors AT III or rec. hirudin in combination with C1 INH. Coinfusion of C1-inhibitor (50-200 U/kg x h) with either rec. hirudin or AT III significantly improved survival rate compared to thrombin inhibitor alone.
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PMID:Influence of C1-inhibitor on inflammation, edema and shock. 817 80

Biochemical observations during clinical sepsis using functional and immunological measurements of enzymes, cofactors and inhibitors of the kallikrein-kinin system indicate that activation of these proteases occur during hypotensive gram-negative septicemia and adult respiratory distress syndrome. Using animal models of septicemia, we demonstrated that protease inhibitors or neutralizing monoclonal antibodies to proteins of the contact system inhibit or prevent the formation of kallikrein and the decrease in kininogen. In addition, the irreversible phase of hypotension can be prevented and survival prolonged. Thus, bradykinin is one of the important mediators of hypotension. In contrast, the contact system plays little role in the associated DIC. In cardiopulmonary bypass, the formation of kallikrein leads to neutrophil degranulation and release of elastase. Selective inhibitors of kallikrein not only block its activation but play a predominant role in inhibiting elastase release.
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PMID:Factor XII activation and inhibition in inflammation. 835 19

Trauma and sepsis activate different cascade systems. Activation of the coagulation and clotting systems, of the kinin-kallikrein system and of the complement system are important etiological mechanisms behind development of the adult respiratory distress syndrome (ARDS) and multisystem organ failure (MOF) after extensive trauma or severe septic situations. Activation of complement with the release of anaphylatoxins and terminal complement complexes is associated with increased mortality and development of ARDS and MOF after major surgery and in situations of septic shock. The anaphylatoxins have potent vascular properties and they activate leukocytes. Their effects on the leukocytes lead to the release of free oxygen radicals, different lysosomal enzymes and cytokines, leukotrienes and histamine. All these inflammatory mediators may, if released in extensive amounts, induce microvascular injury and interstitial edema. If this process takes place in the lung, ARDS may develop and if other organs, i.e the liver and the kidneys, are involved, MOF may be the result.
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PMID:Cascade system activation in shock. 848 Apr 99


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