title: Rac1 regulates bacterial toxin-induced thrombin generation.
abstract: OBJECTIVE
  Systemic inflammatory response syndrome is associated with severe coagulopathy. The purpose of this study was to examine thrombin generation in systemic inflammation triggered by the endotoxin lipopolysaccharide (LPS) and the exotoxin streptococcal M1 protein.
  
  
  METHODS
  Thrombin generation, lung histology and myeloperoxidase (MPO) activity were determined 6 and 24 h after induction of systemic inflammation. Male C57BL/6 mice received the Rac1 inhibitor NSC23766 prior to challenge with bacterial toxins.
  
  
  RESULTS
  LPS and M1 protein challenge increased neutrophil infiltration and caused damage in the lung. Time to peak thrombin formation was increased and peak and total generation of thrombin were decreased in plasma from LPS- and M1 protein-treated mice. Coincubation of samples from mice exposed to bacterial toxins with platelet poor plasma from healthy mice completely reversed the inhibitory effect of LPS and M1 protein on thrombin generation, suggesting that bacterial toxins decreased levels of plasma factors explaining the reduction of thrombin generating capacity of plasma from septic animals. NSC23766 treatment not only decreased LPS- and M1 protein-induced neutrophil accumulation as well as levels of interleukin-6 and CXCL2 in the lung, but also abolished bacterial toxin-induced changes in thrombin generation. For example, NSC23766 increased peak formation by 57% and total thrombin generation by 48% in LPS-treated animals at 6 h.
  
  
  CONCLUSIONS
  Taken together, our novel findings show that bacterial toxins increase thrombin generation via consumption of plasma factors and that Rac1 signaling plays an important role in thrombin generation in response to bacterial toxins. Thus, targeting Rac1 activity might be a useful way not only to ameliorate pulmonary inflammation, but also inhibit pathological changes in coagulation in bacterial infections.
authors.affiliation: Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Skåne University Hospital, 205 02, Malmö, Sweden.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Skåne University Hospital, 205 02, Malmö, Sweden.
authors.forename: Rundk
authors.initials: R
authors.lastname: Hwaiz
authors.affiliation: Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Skåne University Hospital, 205 02, Malmö, Sweden.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Clinical Sciences, Lund, Section of Cardiology, Lund University, Lund, Sweden.
authors.forename: Oscar Ö
authors.initials: OÖ
authors.lastname: Braun
authors.affiliation: Department of Laboratory Medicine, Malmö, Section of Clinical Chemistry, Lund University, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Norström
authors.affiliation: Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Skåne University Hospital, 205 02, Malmö, Sweden. henrik.thorlacius@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology*; D054426:Chemokine CXCL2 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D010976:Platelet Count; D011516:Prothrombin / Q000032:analysis; D011743:Pyrimidines / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; C487513:NSC 23766; D009479:Neuropeptides; D011743:Pyrimidines; C484602:Rac1 protein, mouse; C577686:interleukin-6, mouse; C014689:streptococcal M protein; D011516:Prothrombin; D009195:Peroxidase; D013917:Thrombin; D020830:rac1 GTP-Binding Protein
keywords: Coagulation; Inflammation; Sepsis; Thrombin