title: Thrombin generation in abdominal sepsis is Rho-kinase-dependent.
abstract: 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.
authors: Department of Clinical Sciences, Malmö, Section for Surgery, Malmö, Sweden.
authors: Yongzhi
authors: Y
authors: Wang
authors: Department of Clinical Sciences, Lund, Section for Cardiology, Lund, Sweden.
authors: Oscar Ö
authors: OÖ
authors: Braun
authors: Department of Clinical Sciences, Malmö, Section for Surgery, Malmö, Sweden.
authors: Su
authors: S
authors: Zhang
authors: Department of Translational Medicine, Malmö, Section of Clinical Chemistry, Malmö, Sweden.
authors: Eva
authors: E
authors: Norström
authors: Department of Clinical Sciences, Malmö, Section for Surgery, Malmö, Sweden. Electronic address: henrik.thorlacius@med.lu.se.
authors: Henrik
authors: H
authors: Thorlacius
mesh_terms: D000005:Abdomen / Q000473:pathology*; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D018805:Sepsis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D013917:Thrombin / Q000096:biosynthesis*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D009195:Peroxidase; D054460:rho-Associated Kinases; D013917:Thrombin
keywords: Coagulation; Inflammation; Sepsis; Thrombin