Natural anticoagulants limit LPS-induced pulmonary coagulation but not inflammation

¹ Depts of Intensive Care Medicine; Internal Medicine; Center for Experimental and Molecular Medicine, Center for Infection and Immunity Amsterdam; and Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
² Depts of Intensive Care Medicine; and Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
³ Center for Experimental and Molecular Medicine, Center for Infection and Immunity Amsterdam
⁴ Internal Medicine; and Center for Experimental and Molecular Medicine, Center for Infection and Immunity Amsterdam
⁵ Internal Medicine

^* To whom correspondence should be addressed. E-mail: GodaChoi{at}mail.com.

	Abstract

Pulmonary coagulopathy and hyperinflammation may contribute to an adverse outcome in sepsis. We sought to determine the effects of natural inhibitors of coagulation on bronchoalveolar hemostasis and inflammation in a rat model of endotoxemia.

Male Sprague-Dawley rats were randomized to treatment with normal saline, recombinant human activated protein C (APC), plasma-derived antithrombin (AT), recombinant human tissue factor pathway inhibitor (TFPI), heparin, or recombinant tissue plasminogen activator (tPA). Rats were intravenously injected with lipopolysaccharide (LPS), inducing a systemic inflammatory response and pulmonary inflammation. At 4 and 16 h after LPS injection, blood and bronchoalveolar lavage were obtained and markers of coagulation and inflammation were measured. LPS injection caused an increase in levels of thrombin-antithrombin complexes, whereas plasminogen activator activity was attenuated, both systemically and within the bronchoalveolar compartment. Administration of APC, AT, and TFPI significantly limited LPS-induced generation of thrombin-antithrombin complexes in the lungs, and tPA stimulated pulmonary fibrinolytic activity. Yet, none of the agents had significant effects on the production of pulmonary cytokines, chemokines, neutrophil influx, and myeloperoxidase activity.

Natural inhibitors of coagulation prevent bronchoalveolar activation of coagulation, but do not induce major alterations of the pulmonary inflammatory response in rat endotoxemia.

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