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)

In late sepsis, it has been established that the liver plays a major role in the initiation of multiorgan failure, which is the most lethal complication in hospitals. The molecular mechanism underlying liver failure that results from sepsis remains elusive. This study was undertaken to identify the bona fide differentially expressed genes in the 18-h septic liver by suppression subtractive hybridization, and the data were corroborated by Northern blot analysis. The differential gene expression profile renders a clue as to the genes involved in septic liver failure. The cecal ligation and puncture (CLP) model of a polymicrobial septic rat was used, with the late sepsis referring to animals sacrificed at 18 h after CLP. We have identified three upregulated genes (TII-kininogen, serine protease inhibitor 2.2 [Spi2.2], and alpha 2 macroglobulin [alpha M]) and six down-regulated genes (hydroxysteroid dehydrogenase [3 alpha HSD], EST189895/mouse RNase4, bile acid-CoA-amino acid N-acyltransferase [kan-1/rBAT], IF1, albumin, and alpha 2u-globulins [alpha 2u-G PGCL1]). Among these genes, the 3 alpha HSD and kan-1/rBAT are involved in bile acid metabolism. The IF1 plays a crucial role in any disease that involves ATP hydrolysis by F1F0-ATPase. The alpha 2M, TII-kininogen, and Spi2.2 are protease inhibitors. The functions of the alpha 2u-G PGCL1 and EST189895/mouse RNase4 genes are unknown. The present results suggest that the roles of disturbance of bile acid metabolism/synthesis and the abolishment of ATP production may contribute to liver failure during late sepsis.
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PMID:Isolation of bona fide differentially expressed genes in the 18-hour sepsis liver by suppression subtractive hybridization. 1516 84

The kinin B1 receptor (B1R) has attracted interest as a potential therapeutic target because this inducible G protein-coupled receptor is involved in sustained inflammation and inflammatory pain production. Compound 11 (2-[(2R)-1-[(3,4-dichlorophenyl) sulfonyl]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl]acetamide) is a high-affinity nonpeptide antagonist for the human B1R, but it is potent at the rabbit B1R as well: its Ki value for the inhibition of [3H]Lys-des-Arg9-BK (bradykinin) binding to a novel myc-labeled rabbit B1R expressed in COS-1 is 22 pM. In contractility tests (organ bath pharmacology), we found that compound 11 is an apparently surmountable antagonist of des-Arg9-BK- or Lys-des-Arg9-BK-induced contraction of the rabbit isolated aorta (pA2 values of 10.6+/-0.14 and 10.4+/-0.12, respectively). It did not influence contractions induced by angiotensin II in the rabbit aorta or by BK or histamine in the jugular vein, but it suppressed the prostaglandin-mediated relaxant effect of des-Arg9-BK on the rabbit isolated mesenteric artery. Compound 11 (1 nM) inhibited both the phosphorylation of the extracellular signal-regulated kinase1/2 mitogen-activated protein kinases induced by Lys-des-Arg9-BK in serum-starved rabbit aortic smooth muscle cells and the agonist-induced translocation of the fusion protein B1R-yellow fluorescent protein expressed in human embryonic kidney (HEK) 293 cells. Compound 11 does not importantly modify the expression of myc-B1R over 24 h in HEK 293 cells (no detectable action as "pharmacological chaperone"). The present results support that compound 11 is a potent and highly selective antagonist suitable for further investigations of the role of the kinin B1R in models of inflammation, pain, and sepsis based on the rabbit.
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PMID:A novel nonpeptide antagonist of the kinin B1 receptor: effects at the rabbit receptor. 1527 82

In an isolated perfused lung model, bradykinin induced pulmonary vasoconstriction in rats made septic by the injection of lipopolysaccharide (LPS). To mimic the pathophysiology of sepsis in humans more closely, we investigated pulmonary endothelial injury in a peritonitis model (cecal ligation and perforation; CLP). Male Sprague-Dawley rats were randomly divided into nine groups (n = 6-8). LPS and CLP rats were compared after 6 h with and without treatment with a selective inhibitor of inducible nitric oxide synthase (iNOS), L-N(6)-(1-iminoethyl)-lysine. Time dependency was investigated in CLP-treated rats at 24 h. The pulmonary circulation was isolated and perfused with a constant flow after the rats' tracheas were intubated and ventilated. Bradykinin (1, 3, and 6 microg) was injected, and changes in perfusion pressure were measured. Lungs were harvested for Western blot analysis to determine the role of iNOS in pulmonary endothelial dysfunction. In contrast to CLP 24 h rats, dose-dependent bradykinin-induced pulmonary vasoconstriction was observed in LPS and CLP 6 h rats. Concomitant administration of L-N(6)-(1-iminoethyl)-lysine significantly attenuated this vasoconstriction in both groups. The iNOS protein was expressed in lung homogenates from LPS 6 h and CLP 6 h but not from CLP 24 h rats. Both sepsis models caused bradykinin-induced pulmonary vasoconstriction, with the CLP groups demonstrating a time dependency of this effect. In conjunction with the time-dependent decrease in iNOS protein, the attenuated bradykinin-induced vasoconstriction due to selective iNOS inhibition suggests an important role for iNOS in pulmonary endothelial injury for both sepsis models.
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PMID:Bradykinin-induced pulmonary vasoconstriction is time and inducible nitric oxide synthase dependent in a peritonitis sepsis model. 1533 23

Vibrio vulnificus is an opportunistic human pathogen causing septicemia, and the infection is characterized by formation of the edematous skin lesions on limbs. This pathogenic species secretes a thermolysin-like metalloprotease as a virulence determinant. The metalloprotease was confirmed to activate human factor XII-plasma kallikrein-kinin cascade that results in liberation of bradykinin, a chemical mediator enhancing the vascular permeability, from high-molecular weight kininogen. Namely, the metalloprotease showed to generate active fragments by cleavage of Arg-Ile, Arg-Val or Gly-Leu peptide bond in human zymogens (plasma prekallikrein and factor XII). In spite of induction of the sufficient vascular permeability-enhancing and edema-forming reaction in the guinea pig model, a serine protease from V. parahaemolyticus, a human pathogen causing primarily watery diarrhea, showed far less ability to activate and to cleave the human zymogens. These results in part may explain why only V. vulnificus often causes serious edematous skin damages in humans.
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PMID:Generation of active fragments from human zymogens in the bradykinin-generating cascade by extracellular proteases from Vibrio vulnificus and V. parahaemolyticus. 1553 Sep 71

The transcription factor nuclear factor-kappaB (NF-kappaB) plays a key role in expression of many inflammatory genes responsible for the pathophysiology of sepsis-induced acute lung injury. We investigated whether the introduction of synthetic double-stranded oligodeoxynucleotides (ODNs) with consensus NF-kappaB sequence as transcription factor decoy can prevent acute lung injury with suppression of pulmonary expression of multiple genes involved in its pathological process in a cecal ligation and puncture septic mouse model. NF-kappaB decoy ODNs were introduced with the aid of the hemagglutinating virus of Japan-envelope vector method. Northern blot analysis indicated that transfection of NF-kappaB decoy ODN, but not of its scrambled form, resulted in a significant inhibition of sepsis-induced gene overexpression of inducible nitric-oxide synthase (iNOS), cyclooxygenase-2, histamine H(1)-receptor, platelet-activating factor receptor, and bradykinin B(1) and B(2) receptors in lung Histological damage in lungs tissues. (wall thickening, inflammatory infiltrate, and hemorrhage), increased pulmonary vascular permeability, and blood gas exchange impairment were clearly documented in mice after cecal ligation and puncture. These changes were strongly eliminated by the introduction of NF-kappaB decoy but not of scrambled ODN. The effects of the iNOS inhibitor FR260330 on these histological and functional derangements compared unfavorably with those of NF-kappaB decoy ODN transfection. Our results suggest that ODN decoy, acting as in vivo competitor for the transcription factor's ability to bind to cognate recognition sequence, may represent an effective strategy in the treatment of septic acute lung injury.
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PMID:Nuclear factor-kappaB decoy oligodeoxynucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis. 1557 32

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.
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PMID:International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. 1573 27

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

Sepsis, a systemic inflammatory syndrome, is a response to infection and when associated with multiple organ dysfunction is termed severe sepsis. It remains a leading cause of mortality in the critically ill. The response to the invading microorganisms may be considered as a balance between a pro-inflammatory and an anti-inflammatory reaction. While an inadequate pro-inflammatory reaction and a strong anti-inflammatory response could lead to overwhelming infection and the death of the patient, a strong and uncontrolled pro-inflammatory response, manifested by the release of pro-inflammatory mediators may lead to microvascular thrombosis and multiple organ failure. Endotoxin triggers sepsis via the release of various mediators such as tumour necrosis factor-alpha and interleukin-1 (IL-1). These cytokines activate the complement and coagulation systems, release adhesion molecules, prostaglandins, leukotrienes, reactive oxygen species and nitric oxide. Other mediators involved in the sepsis syndrome include IL-1, -6 and -8; arachidonic acid metabolites; platelet activating factor; histamine; bradykinin; angiotensin; complement components and vasoactive intestinal peptide. These pro-inflammatory responses are counteracted by IL-10. Most of the trials targeting the different mediators of the pro-inflammatory response have failed due to a lack of correct definition of sepsis. Understanding the exact pathophysiology of the disease will enable more advanced treatment options. Targeting the coagulation system with various anticoagulant agents including, activated protein C, and tissue factor pathway inhibitor (TFPI) is a rational approach. Many clinical trials have been conducted to evaluate these agents in severe sepsis. While trials on antithrombin and TFPI were not so successful, the double-blind, placebo-controlled, Phase III trial of recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) was successful, creating a significant decrease in mortality when compared to the placebo group. A better understanding of the pathophysiologic mechanism of severe sepsis will provide better treatment options, and combination antithrombotic treatment may provide a multipronged approach for the treatment of severe sepsis.
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PMID:Antithrombotic agents in the treatment of severe sepsis. 1598 40

Ion transport is essential for maintenance of transmembranous and transcellular electric potential, fluid transport and cellular volume. Disturbance of ion transport has been associated with cellular dysfunction, intra and extracellular edema and abnormalities of epithelial surface liquid volume. There is increasing evidence that conditions characterized by an intense local or systemic inflammatory response are associated with abnormal ion transport. This abnormal ion transport has been involved in the pathogenesis of conditions like hypovolemia due to fluid losses, hyponatremia and hypokalemia in diarrhoeal diseases, electrolyte abnormalities in pyelonephritis of early infancy, septicemia induced pulmonary edema, and in hypersecretion and edema induced by inflammatory reactions of the mucosa of the upper respiratory tract. Components of membranous ion transport systems, which have been shown to undergo a change in function during an inflammatory response include the sodium potassium ATPase, the epithelial sodium channel, the Cystic Fibrosis Transmembrane Conductance Regulator and calcium activated chloride channels and the sodium potassium chloride co-transporter. Inflammatory mediators, which influence ion transport are tumor necrosis factor, gamma interferon, interleukins, transforming growth factor, leukotrienes and bradykinin. They trigger the release of specific messengers like prostaglandins, nitric oxide and histamine which alter ion transport system function through specific receptors, intracellular second messengers and protein kinases. This review summarizes data on in vivo measurements of changes in ion transport in acute inflammatory conditions and in vitro studies, which have explored the underlying mechanisms. Potential interventions directed at a correction of the observed abnormalities are discussed.
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PMID:Changes in ion transport in inflammatory disease. 1657 Nov 16

The plasma kallikrein-kinin system (KKS) participates in the pathogenesis of inflammatory reactions involved in cellular injury, coagulation, fibrinolysis, kinin formation, complement activation, cytokine secretion and release of proteases. It has been shown that KKS activation in the systemic inflammatory response syndrome results in decrease of its component plasma proteins. Similar changes have been documented in diabetes, sepsis, children with vasculitis, allograft rejection, disseminated intravascular coagulation, patients with recurrent pregnancy losses, hereditary angioedema, adult respiratory distress syndrome and coronary artery disease. Direct involvement of the KKS in the pathogenesis of experimental acute arthritis and acute and chronic enterocolitis has been documented by previous studies from our laboratory using experimental animal models. It has been found that in HK deficient Lewis rats, experimental IBD was much less severe. We showed a genetic difference in kininogen structure between resistant Buffalo and susceptible Lewis rats, which results in accelerated cleavage of HK and it is responsible for the susceptibility to the inflammatory process in the Lewis rats. It has been demostrated that therapy with a specific plasma kallikrein inhibitor (P8720) modulated the experimental enterocolitis, arthritis and systemic inflammation. Furthermore, it has been shown that a bradykinin 2 receptor (B2R) antagonist attenuates the inflammatory changes in the same animal model. We have showed that a monoclonal antibody targeting HK decreases angiogenesis and arrests tumor growth in a syngeneic animal model. In summary, these results indicate that the plasma KKS plays a central role in the pathogenesis of chronic intestinal inflammation, arthritis and angiogenesis.
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PMID:[High molecular weight kininogen in inflammation and angiogenesis: a review of its properties and therapeutic applications]. 1670 6


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