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)

Objective- Activation of coagulation FXI (factor XI) by FXIIa (activated factor XII) is a prothrombotic process. The endothelium is known to play an antithrombotic role by limiting thrombin generation and platelet activation. It is unknown whether the antithrombotic role of the endothelium includes sequestration of FXIa (activated factor XI) activity. This study aims to determine the role of endothelial cells (ECs) in the regulation of the intrinsic pathway of coagulation. Approach and Results- Using a chromogenic assay, we observed that human umbilical veins ECs selectively blocked FXIa yet supported kallikrein and FXIIa activity. Western blotting and mass spectrometry analyses revealed that FXIa formed a complex with endothelial PAI-1 (plasminogen activator inhibitor-1). Blocking endothelial PAI-1 increased the cleavage of a chromogenic substrate by FXIa and the capacity of FXIa to promote fibrin formation in plasma. Western blot and immunofluorescence analyses showed that FXIa-PAI-1 complexes were either released into the media or trafficked to the early and late endosomes and lysosomes of ECs. When baboons were challenged with Staphylococcus aureus to induce a prothrombotic phenotype, an increase in circulating FXIa-PAI-1 complex levels was detected by ELISA within 2 to 8 hours postchallenge. Conclusions- PAI-1 forms a complex with FXIa on ECs, blocking its activity and inducing the clearance and degradation of FXIa. Circulating FXIa-PAI-1 complexes were detected in a baboon model of S. aureus sepsis. Although ECs support kallikrein and FXIIa activity, inhibition of FXIa by ECs may promote the clearance of intravascular FXIa. Visual Overview- An online visual overview is available for this article.
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PMID:Endothelial PAI-1 (Plasminogen Activator Inhibitor-1) Blocks the Intrinsic Pathway of Coagulation, Inducing the Clearance and Degradation of FXIa (Activated Factor XI). 3124 30

Sepsis causes an activation of the human contact system, an inflammatory response mechanism against foreign surfaces, proteins and pathogens. The serine proteases of the contact system, factor XII and plasma kallikrein, are decreased in plasma of septic patients, which was previously associated with an unfavorable outcome. However, the precise mechanisms and roles of contact system factors in bacterial sepsis are poorly understood. We, therefore, studied the physiological relevance of factor XII and plasma kallikrein in a mouse model of experimental sepsis. We show that decreased plasma kallikrein concentration in septic mice is a result of reduced mRNA expression plasma prekallikrein gene, indicating that plasma kallikrein belong to negative acute phase proteins. Investigations regarding the pathophysiological function of contact system proteases during sepsis revealed different roles for factor XII and plasma kallikrein. In vitro, factor XII decelerated bacteria induced fibrinolysis, whereas plasma kallikrein supported it. Remarkably, depletion of plasma kallikrein (but not factor XII) by treatment with antisense-oligonucleotides, dampens bacterial dissemination and growth in multiple organs in the mouse sepsis model. These findings identify plasma kallikrein as a novel host pathogenicity factor in Streptococcus pyogenes sepsis.
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PMID:The contact system proteases play disparate roles in streptococcal sepsis. 3132 May 52

Canine pyometra is a common inflammatory disease of uterus in sexually mature bitches caused by secondary bacterial infection, leading to change in plasma proteins associated with the innate immune system. Proteomic investigation is increasingly being applied to canine diseases in order to identify and quantify significant changes in the plasma proteome. The aim of the study was to assess and quantify changes in plasma proteome profiles of healthy dogs and pyometra affected bitches using a TMT-based high-resolution quantitative proteomic approach. As a result, 22 proteins were significantly down-regulated including transthyretin, antithrombin, retinol-binding protein, vitamin D binding protein, paraoxonase 1, and kallikrein, while 16 were significantly up-regulated including haptoglobin light chain, alpha-1-acid glycoprotein, C-reactive protein precursor, and lipopolysaccharide-binding protein in dogs with pyometra. Pathway analysis indicated that acute inflammatory response, regulation of body fluid levels, protein activation cascade, the humoral immune response, and phagocytosis were affected in pyometra. Validation of biological relevance of the proteomic study was evident with significant increases in the concentrations of haptoglobin, C-reactive protein, alpha-1-acid glycoprotein, and ceruloplasmin by immunoassay. Pyometra in bitches was shown to stimulate an increase in host defence system proteins in response to inflammatory disease including the acute phase proteins. SIGNIFICANCE: The label-based high-resolution quantitative proteomics analysis and bioinformatic approach used in this study provide insight into the complex pathophysiology of inflammation associated with pyometra revealing proteins with biomarker potential. Early diagnosis and therapeutic intervention may prevent severe complications associated with advancing sepsis in dogs with pyometra. Therefore the identification of diagnostic biomarkers that, after clinical validation may be used in veterinary practice and protein relevant to pathways responding to disease are important findings of the study. Data are available via ProteomeXchange with identifier PXD015951.
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PMID:The plasma proteome and the acute phase protein response in canine pyometra. 3241 15

The newly identified coronavirus SARS-CoV-2 that spread from China is causing the pandemic COVID-19 with a fatality rate from 5-15%. It causes fever, cough, myalgia, fatigue up to dyspnoea, responsible for hospitalization and artificial oxygenation. SARS-CoV-2 infects human cells using ACE2, the transmembrane protease serine 2 (TMPRSS2) and the SARS-CoV-2 main protease (Mpro ). Once bound to ACE2 and the other two proteases in concert they allow the virus replication and spread throughout the body. Our attention has been focused on the role of ACE2 as its binding to by the virus increases bradykinin and its metabolites, which facilitate inflammation in the lung (causing cough and fever), coagulation and the complement system. These three systems are involved in angioedema, cardiovascular dysfunction and sepsis, pathologies which occur in COVID-19 patients. Thus, we propose that blocking the kallikrein-kinin system with lanadelumab, approved for hereditary angioedema, will prevent facilitation of these 3 systems. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.
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PMID:A lesson from a saboteur: High-MW kininogen impact in coronavirus-induced disease 2019. 3249 57


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