title: Activated protein C ameliorates Bacillus anthracis lethal toxin-induced lethal pathogenesis in rats.
abstract: BACKGROUND
  Lethal toxin (LT) is a major virulence factor of Bacillus anthracis. Sprague Dawley rats manifest pronounced lung edema and shock after LT treatments, resulting in high mortality. The heart failure that is induced by LT has been suggested to be a principal mechanism of lung edema and mortality in rodents. Since LT-induced death occurs more rapidly in rats than in mice, suggesting that other mechanisms in addition to the heart dysfunction may be contributed to the fast progression of LT-induced pathogenesis in rats. Coagulopathy may contribute to circulatory failure and lung injury. However, the effect of LT on coagulation-induced lung dysfunction is unclear.
  
  
  METHODS
  To investigate the involvement of coagulopathy in LT-mediated pathogenesis, the mortality, lung histology and coagulant levels of LT-treated rats were examined. The effects of activated protein C (aPC) on LT-mediated pathogenesis were also evaluated.
  
  
  RESULTS
  Fibrin depositions were detected in the lungs of LT-treated rats, indicating that coagulation was activated. Increased levels of plasma D-dimer and thrombomodulin, and the ameliorative effect of aPC further suggested that the activation of coagulation-fibrinolysis pathways plays a role in LT-mediated pathogenesis in rats. Reduced mortality was associated with decreased plasma levels of D-dimer and thrombomodulin following aPC treatments in rats with LT-mediated pathogenesis.
  
  
  CONCLUSIONS
  These findings suggest that the activation of coagulation in lung tissue contributes to mortality in LT-mediated pathogenesis in rats. In addition, anticoagulant aPC may help to develop a feasible therapeutic strategy.
authors.affiliation: Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Jyh-Hwa
authors.initials: JH
authors.lastname: Kau
authors.forename: Yung-Luen
authors.initials: YL
authors.lastname: Shih
authors.forename: Te-Sheng
authors.initials: TS
authors.lastname: Lien
authors.forename: Chin-Cheng
authors.initials: CC
authors.lastname: Lee
authors.forename: Hsin-Hsien
authors.initials: HH
authors.lastname: Huang
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Lin
authors.forename: Der-Shan
authors.initials: DS
authors.lastname: Sun
authors.forename: Hsin-Hou
authors.initials: HH
authors.lastname: Chang
mesh_terms: D000818:Animals; D000881:Anthrax / Q000188:drug therapy / Q000382:microbiology / Q000503:physiopathology; D000942:Antigens, Bacterial / Q000187:drug effects / Q000633:toxicity; D001408:Bacillus anthracis / Q000187:drug effects / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D001777:Blood Coagulation / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007276:Injections, Intraventricular; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011486:Protein C / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011486:Protein C; C030325:anthrax toxin