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Thrombin generation in abdominal sepsis is Rho-kinase-dependent.

Author:
  • Yongzhi Wang
  • Oscar Braun
  • Su Zhang
  • Eva Norström
  • Henrik Thorlacius
Publishing year: 2015
Language: English
Pages: 691-696
Publication/Series: Biochemical and Biophysical Research Communications
Volume: 460
Issue: 3
Document type: Journal article
Publisher: Elsevier

Abstract english

Sepsis causes severe derangements of the coagulation system. However, the signaling mechanisms regulating sepsis-induced thrombin generation remain elusive. Herein, we hypothesized that Rho-kinase might be an important regulator of thrombin generation in abdominal sepsis. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57Bl/6 mice. Thrombin generation, coagulation factors, lung histology and myeloperoxidase (MPO) activity were determined 6 h and 24 h after induction of CLP. Induction of CLP triggered a systemic inflammatory response characterized by neutrophil accumulation and tissue injury in the lung as well as thrombocytopenia and leukocytopenia. Administration of Y-27632, a Rho-kinase inhibitor, attenuated these markers of systemic inflammation in CLP animals. Moreover, peak thrombin formation was decreased by 77% and 81% in plasma from mice 6 h and 24 h after induction of CLP. Total thrombin generation was reduced by 64% and 67% 6 h and 24 h after CLP induction, respectively. Notably, administration of Y-27632 increased peak formation by 99% and total thrombin generation by 66% in plasma from septic animals. In addition, CLP markedly decreased plasma levels of prothrombin, factor V and factor X at 6 h and 24 h. Interestingly, Rho-kinase inhibition significantly enhanced levels of prothrombin, factor V and factor X in plasma from septic mice. In addition, inhibition of Rho-kinase decreased CLP-induced elevations of CXCL2 by 36%and interleukin-6 by 38%. These novel findings suggest that sepsis-induced thrombin generation is regulated by Rho-kinase. Moreover, inhibition of Rho-kinase reverses sepsis-evoked consumption of coagulation factors. Thus, our results show that targeting Rho-kinase signaling might protect against coagulation dysfunction in abdominal sepsis.

Keywords

  • Biological Sciences

Other

Published
  • Surgery Research
  • Clinical Chemistry, Malmö
  • ISSN: 1090-2104
E-mail: oscar [dot] braun [at] med [dot] lu [dot] se

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