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Open Access Research

Activated protein C ameliorates Bacillus anthracis lethal toxin-induced lethal pathogenesis in rats

Jyh-Hwa Kau1, Yung-Luen Shih23, Te-Sheng Lien4, Chin-Cheng Lee2, Hsin-Hsien Huang1, Hung-Chi Lin1, Der-Shan Sun4* and Hsin-Hou Chang4*

Author Affiliations

1 Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC

2 Department of Pathology and Laboratory Medicine, Shin-Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan, ROC

3 School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan, ROC

4 Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan, ROC

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Journal of Biomedical Science 2012, 19:98  doi:10.1186/1423-0127-19-98

Published: 21 November 2012

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.

Keywords:
Anthrax; Lethal toxin; Activated protein C; Coagulopathy