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)

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

Acute, acalculous cholecystitis is seen among patients suffering with bacterial sepsis, burns, trauma, or cancer; clinical conditions that could lead to activation of factor XII-dependent pathways and result in inflammation of the gall bladder. To test this hypothesis, dogs were injected intravenously with ellagic acid or rutin, known polyphenol activators of factor XII, or with Escherichia coli endotoxin, also known to activate factor XII, and monkeys were injected intravenously with ellagic acid. In both species, in vivo activation of factor XII-dependent pathways with polyphenol activator resulted in rapid and selective development of acute vasculitis in the serosa and muscularis of the gallbladder and margination of polymorphonuclear neutrophils in pulmonary blood vessels. Intravenous injection of E. coli endotoxin in dogs resulted in necrosis and thrombosis of vessels that were especially severe in the serosa and muscularis of the gallbladder but also present in vessels of many other organs. These observations indicate that blood vessels of the gall bladder and, to a lesser degree, the lung are especially sensitive to injury consequent to in vivo activation of factor XII-dependent pathways and, in view of the common ingestion of plant polyphenols, may provide important insight into the pathogenesis of cholecystitis in man.
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PMID:Induction of acute cholecystitis by activation of factor XII. 676 72

Acute acalculous cholecystitis was observed to increase in frequency between 1950 and 1979, an increase that was statistically significant. The greatest part of this increase occurred between 1965 and 1979. Acute acalculous cholecystitis was also found to be associated with a higher mortality rate, more than twice that of acute calculous cholecystitis. Acute acalculous cholecystitis occurred in a variety of clinical settings including bacterial sepsis, severe trauma including surgical trauma and burns, multiple transfusions, and severe debilitation. The lesion in the gallbladder consists of intense injury of blood vessels in the muscularis and serosa similar to those induced experimentally by in vivo activation of factor XII dependent pathways. Possibly because of the intensity of vascular injury, acute acalculous cholecystitis with minimal clinical manifestations may rapidly progress to gangrene with perforation. Undelayed surgical treatment, which has become more widely accepted over the past 50 years, is essential. It may have also contributed to the increased recognition of this clinical entity.
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PMID:Acute acalculous cholecystitis. An increasing entity. 705 88

Although routine cardiac surgical procedures are now performed with low rates of mortality and relatively low rates of morbidity, certain categories of patients continue to present a major challenge. Patients who have reoperations and those with active infective endocarditis represent high-risk categories. The pathophysiologic mechanisms involved in such patients include impaired left ventricular function and low cardiac output, sepsis, endotoxemia, and gut permeability, and impaired hemostasis. Although these mechanisms are distinct, they do interrelate. Low cardiac output and imperfect systemic perfusion during and after cardiopulmonary bypass are known to induce splanchnic ischemia with altered permeability of the gut mucosal barrier to gut contents, including endotoxin. The systemic inflammatory response, triggered by contact activation of factor XII, produces functional disturbance in vital organs, notably the brain and lung. In addition, factor XII activation induces disordered hemostasis, which is related to increased fibrinolysis and a possible disturbance in platelet function. Measures to modify these mechanisms and improve outcome in high-risk patients include pulsatile perfusion during cardiopulmonary bypass and aprotinin therapy to modify the inflammatory response and prevent the disorder in hemostasis. Clinical experience with high-dose aprotinin therapy in patients who have reoperations and active endocarditis has demonstrated a very high level of efficacy in reducing blood loss and blood/blood product transfusion requirements. The potential role of aprotinin in stabilizing the microcirculation and modifying the systemic inflammatory response requires further study and may prove to be a major contribution to improved outcome in high-risk patients.
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PMID:Improved outcome for seriously ill open heart surgery patients: focus on reoperation and endocarditis. 768 Feb 32

Sepsis is due to its lethality, which varies round 25%, one of the major problems of contemporary clinical medicine. Classical therapeutic approaches, i.e. chemotherapy, surgical elimination of foci and intensive therapy focused on maintenance of vital functions have obviously reached the limit of effectiveness beyond which they are unable to advance any further. Therefore great efforts are devoted to research into pathogenetic mechanisms involved in sepsis with the aim to use their effect to improve therapeutic results. In the submitted paper the authors analyze the definition of sepsis, explain the concept of the syndrome of systemic inflammatory response and summarize the contemporary state of knowledge of the pathogenesis. A review of structures and mechanisms involved in the genesis and development of sepsis (complement, factor XII, macrophage, endothelial cell, polymorphonuclear leucocyte, thrombocyte etc.) is supplemented by a list of substances which act as mediators of inflammations. The conclusions for practice summarize contemporary therapeutic possibilities, i.e. classical means as well as more recent approaches (colony stimulating factors, haemodiafiltration, antithrombin III, monoclonal antibody against endotoxin). The authors review briefly therapeutic means which are developed at present and which should make it possible to interfere actively with the pathogenesis of the disease.
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PMID:[Contemporary views on the problem of sepsis]. 816 68

In previous studies, we have shown that administration of monoclonal antibody (MoAb) C6B7 against human factor XII to baboons challenged with a lethal dose of Escherichia coli abrogates activation of the contact system and modulates secondary hypotension. To evaluate the contribution of activated contact proteases to the appearance of other inflammatory mediators in this experimental model of sepsis, we studied the effect of administration of MoAb C6B7 on activation of complement and fibrinolytic cascades, stimulation of neutrophil degranulation, and release of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Activation of the complement system, as reflected by circulating C3b/c and C4b/c levels, was significantly reduced in five animals that had received MoAb C6B7 before a lethal dose of E coli as compared with five control animals that had been given a lethal challenge only. Inhibition of contact activation also modulated the fibrinolytic response, since the release of tissue-type plasminogen activator (t-PA) and the appearance of plasmin-alpha2-antiplasmin (PAP) complexes into the circulation was significantly attenuated upon pretreatment with anti-factor XII MoAb. In contrast, plasma levels of plasminogen activator inhibitor (PAI) were modestly enhanced in the treatment group. Degranulation of neutrophils, as assessed by circulating elastase-alpha1-protease inhibitor complexes, and release of IL-6 but not of TNF-alpha was decreased in anti-factor XII-treated animals. Observed differences in the inflammatory response between treatment and control groups were not likely due to different challenges, since the number of E coli that had been infused, as well as circulating levels of endotoxin after the challenge, were similar for both groups. These data suggest that activation of the contact system modulates directly or indirectly various mediator systems involved in the inflammatory response during severe sepsis in nonhuman primates.
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PMID:Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase. 863 Mar 96

Previous work has demonstrated that most strains of the human pathogen Streptococcus pyogenes bind kininogens through M protein, a fibrous surface protein and virulence determinant. Here we find that strains of several other pathogenic bacterial species, both Gram-positive and Gram-negative, isolated from patients with sepsis, also bind kininogens, especially kininogen (HK). The most pronounced interaction was seen between HK and Escherichia coli. Among clinical isolates of E. coli, the majority of the enterohaemorrhagic, enterotoxigenic, and sepsis strains, but none of the enteroinvasive and enteropathogenic strains, bound HK. Binding of HK to E. coli correlated with the expression of curli, another fibrous bacterial surface protein, and the binding of HK to purified curli was specific, saturable, and of high affinity; Ka = 9 x 10(7) M-1. Other contact phase proteins such as factor XI, factor XII, and prekallikrein bound to curliated E. coli, but not to an isogenic curli-deficient mutant strain, suggesting that contact phase activation may occur at the surface of curliated bacteria. Kininogens are also precursor molecules of the vasoactive kinins. When incubated with human plasma, curli-expressing bacteria absorbed HK. Addition of purified plasma kallikrein to the HK-loaded bacteria resulted in a rapid and efficient release of bradykinin from surface-bound HK. The assembly of contact phase factors at the surface of pathogenic bacteria and the release of the potent proinflammatory and vasoactive peptide bradykinin, should have a major impact on the host-microbe relationship and may contribute to bacterial pathogenicity and virulence.
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PMID:Assembly of human contact phase proteins and release of bradykinin at the surface of curli-expressing Escherichia coli. 880 46

Increased release of BK by HK hydrolysis has been correlated with the severity of hypotension in septic patients and animals challenged with gram-negative bacteria or endotoxin (ETX). Since HK hydrolysis in vivo is attributed mainly to the catalytic reaction of kallikrein (KAL) formed by activation of plasma PK, I tested whether the known resistance to ETX-rhesus and baboon > man and chimp-correlated with PK levels. Immunoblots and amidolytic assays showed that PK levels did not correlate. They were in rhesus and man > baboon and chimp. Also, PK did not correlate with levels of other modulators of free KAL levels in plasma-factor XII, HK and KAL inhibitors. Nonetheless, the distribution of PK and its activation products in plasmas activated with kaolin at 37 degrees C is analogous in the 4 primates, suggesting a similar mechanism for KAL inhibition in vitro. The results suggest that factors not yet known must contribute to the differential resistance of primates to ETX. Knowledge of these factors will help in prophylaxis and therapy of septicemia.
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PMID:Does resistance to endotoxin in primates correlate with levels of plasma prekallikrein? 885 90

We investigated a new ELISA for measuring activated factor XII (FXIIa) in plasma. The intra-assay coefficient of variation was 3.5% and 5.1% for plasma containing 2.5 and 8.2 ng/ml FXIIa. The inter-assay coefficient of variation was 6.2% and 6.6%. FXIIa correlated with age in women older than 55 years (r = 0.55, P = 0.0003). Mean levels in the whole population of 160 healthy individuals included in this study were not different between men and women, but women younger than 55 years had lower levels than older women and men of the corresponding age. In a group of 25 healthy centenarians FXIIa was significantly higher (3.2 ng/ ml, 95% CI 2.3-3.6) than in controls (2.1 ng/ml, 95% CI 1.8-2.4). Increased levels were also found in pregnancy, with higher levels in the third trimester (4.7 ng/ml, 95% CI 3.9-5.5) than in the first trimester (2.9 ng/ml, 95% CI 2.2-3.9). FXIIa was unmeasurable in patients with FXII deficiency, but normal in patients with FXI deficiency and C1-inhibitor deficiency. FXIIa was significantly higher than in normal controls in patients with severe sepsis (3.9 ng/ml, 95% CI 2.8-5.4) and septic shock (5.4 ng/ml, 95% CI 3.7-7.7). After treatment with thrombolytic agents, a marked increase of FXIIa was found in patients with myocardial infarction. In conclusion, the immunoassay of FXIIa permits to study more directly the contact phase of blood coagulation in situations in which the involvement of this system may play a pathophysiological role.
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PMID:Measurement of activated factor XII in health and disease. 887 63

We evaluated the effect of C1 inhibitor (C1-inh), an inhibitor of the classical pathway of complement and the contact system, on the physiologic and inflammatory response in baboons suffering from lethal Escherichia coli sepsis. Five animals pretreated with 500 U/kg C1-inh (treatment group; n = 5), followed by a 9-h continuous infusion of 200 U/kg C1-inh subsequent to bacterial challenge, were compared with five controls receiving E. coli alone. Of the treatment group, one animal survived and another lived beyond 48 h, whereas all control animals died within 27 h. In four of five treated animals, less severe pathology was observed in various target organs. C1-inh administration did not prevent the hemodynamic or hematologic changes observed upon E. coli infusion. The activation of fibrinolysis and the development of disseminated intravascular coagulation were essentially unaffected by C1-inh. However, C1-inh supplementation significantly reduced decreases in plasma levels of factor XII and prekallikrein and abrogated the systemic appearance of C4b/c, indicating substantial inhibition of activation of the contact system and the classical complement pathway, respectively. Furthermore, treated animals displayed a reduced elaboration of various cytokines including TNF, IL-10, IL-6, and IL-8. Thus, the administration of C1-inh may have a beneficial but modest effect on the clinical course and outcome of severe sepsis in nonhuman primates. We suggest that activated complement and/or contact system proteases may, at least in part, contribute to the attendant manifestations of septic shock through an augmentation of the cytokine response.
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PMID:Effect of C1 inhibitor on inflammatory and physiologic response patterns in primates suffering from lethal septic shock. 955 6


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