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)

Traumatology deals with two different types of shock - the early hypovolemic-traumatic, and the late, so called septic shock, which is often associated with multi-organ failure. Both types of shock are triggered by several mediator systems of humoral and cellular origin, with numerous interactions between each other. In hypovolemic-traumatic shock central events are a perfusion deficit (ischemia with reperfusion injury via the xanthine-xanthine oxidase system) and activation of the humoral axis - of coagulation, of fibrinolysis, of the complement and kallikrein-kinin system by injured tissue. Coagulation and complement are responsible for the activation of platelets and granulocytes respectively. These cells further interact with each other e.g. via platelet activation factor, which finally causes tissue damage. Granulocytes play a central role because of their ability to release oxygen radicals and neutral proteinases, which can be monitored (elastase) and probably used to predict organ failure. The gut area is less resistant to the events of shock and therefore is a "locus minoris resistentiae" for further development of endotoxemia, bacteremia, septic shock and multi-organ failure without a typical septic focus. By this "septic challenge" further mediator systems get involved, especially those of macrophages like interleukin-1 or cachectin. Similar to the activation marker of PMN-elastase, we could demonstrate that it was possible to use neopterin for monitoring macrophage activation in sepsis and organ failure. By the action of these cellular elements in microcirculation at the endothelial and interstitial level tissue damage occurs, which finally leads to individual and multi-organ failure.
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PMID:[Current findings in the pathogenesis of the shock process in traumatology]. 328 34

Alterations of the kallikrein-kinin system consistent with activation and increased consumption have been reported in septic patients and it has been suggested that this activation could contribute to the development of septic shock. The aim of this work was to confirm these alterations in septic patients and to investigate the possible existence of similar changes in subjects developing cardiogenic shock secondary to myocardial infarction as a model of non septic shock. Patients with septic shock, especially in fatal cases, showed a highly significant decrease in levels of factor XII, prekallikrein, high molecular weight kininogen (HMW-kininogen), alpha 2-macroglobulin (alpha 2-M) and antithrombin III (AT-III). C1-esterase inhibitor (C1-INH) activity was increased in uncomplicated sepsis but came back to normal or was slightly decreased in septic shock. Components and inhibitors of the kallikrein-kinin system were within normal limits in patients with cardiogenic shock. Our findings support the idea of a contribution of the kallikrein-kinin system to the development of septic shock though this system does not seem to play a significant role in the pathogenesis of cardiogenic shock or seem to be altered as a consequence of it.
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PMID:Plasma kallikrein-kinin system in patients with uncomplicated sepsis and septic shock--comparison with cardiogenic shock. 367 21

A major nonrespiratory function of the mammalian lung is that of a polymorphonuclear leukocyte reservoir. Within this reservoir, granulocytes are distributed between marginating and circulating pools. Under normal conditions these cells release little, if any, toxic metabolites. Situations which facilitate chemotactic release, activation of complement, or prolonged lowering of pulmonary blood flow lead to sequestration of large numbers of polymorphonuclear leukocytes in the lungs. If these polymorphonuclear leukocytes are then stimulated to release toxic oxygen species, proteases or other metabolites, existing defense mechanisms are overwhelmed and lung injury results. Anaphylatoxins generated by complement activation, humoral factors released from platelets or macrophages, and activation of the kallikrein-kinin and coagulation systems, may exacerbate damage to the alveolar-capillary membrane. Permeability of this membrane increases, there is interstitial and then alveolar edema, with subsequent pulmonary dysfunction. While there is little doubt that this scenario holds true for some experimental models of acute lung injury, its applicability to adult respiratory distress syndrome is still controversial. Nevertheless, adult respiratory distress syndrome does arise under conditions facilitating chemotactic factor release from macrophages (e.g. hyperoxia), in situations where widespread activation of complement occurs (e.g. sepsis, trauma, microemboli), and in shock conditions where pulmonary blood flow is often lowered. Correlations exist between adult respiratory distress syndrome and activation of complement, acute neutropenia, sequestration of polymorphonuclear leukocytes and enhanced functional and metabolic activity of granulocytes. Although these findings suggest that polymorphonuclear leukocytes are an important factor in the pathogenesis of adult respiratory distress syndrome, its precise role remains to be determined.
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PMID:The role of the polymorphonuclear leukocyte in the pathogenesis of the adult respiratory distress syndrome. 383 38

In a controlled study of fibronectin supplementation in sepsis, 11 ICU patients in septic shock were scheduled to receive either cryoprecipitate from 20-40 donors (n = 6) or 250-300 ml of stored plasma (n = 5) (two infusions over 24 h). We wanted to: compare some "conventional" DIC variables in the ICU (platelet count, prothrombin complex = NT, FDP) to additional variables: Fibronectin (Fn), fibrinogen (Fg), F V, FVIII R:Ag, F VIII:C activity, F XII, plasminogen (Plg), antiplasmin (AP), antithrombin (AT), kallikrein inhibiting activity (KI) and spontaneous proteolytic activity (SPA): study the effects of cryoprecipitate or plasma infusion on three variables. Samples were taken before the first infusion, and 24 and 48 h after. At onset, high levels (p less than .001 when compared to blood donors) of Fg, VIIIR:Ag and VIII:C were seen. KI levels were within the normal range. F V was low (p less than .05). Fn, NT, XII, Plg, AP and AT were markedly low (p less than .001). SPA showed great variation. When compared to 28 patients with severe infections, but not in septic shock, the ICU group had higher VIIIR:Ag (p less than .05) and VIII:C (p less than .01), and lower XII, Plg, AP and AT (p less than .001). FDP was elevated in all ICU patients. Five patients were thrombocytopenic, and in these a pattern with low levels of Plg and AT was observed. Fn did not correlate well to the other variables measured. These results indicate a marked activation of coagulation and fibrinolysis in these severely ill patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fibronectin and other DIC-related variables in septic ICU patients receiving cryoprecipitate. 393 20

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

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

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


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