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Natural anticoagulants limit lipopolysaccharide-induced pulmonary coagulation but not inflammation

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

CORRESPONDENCE: G. Choi, Dept of Intensive Care Medicine, Academic Medical Centre, University of Amsterdam, C3-423, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands, Fax: 31 206972988. E-mail: godachoi{at}mail.com

Keywords: Acute lung injury, coagulation, fibrinolysis, protein C, sepsis

Received: December 20, 2006
Accepted May 14, 2007

Pulmonary coagulopathy and hyperinflammation may contribute to an adverse outcome in sepsis. The present study determines the effects of natural inhibitors of coagulation on bronchoalveolar haemostasis and inflammation in a rat model of endotoxaemia.

Male Sprague-Dawley rats were randomised 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), which induced a systemic inflammatory response and pulmonary inflammation. Blood and bronchoalveolar lavage were obtained at 4 and 16 h after LPS injection, and markers of coagulation and inflammation were measured.

LPS injection caused an increase in the levels of thrombin–AT 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–AT complexes in the lungs, and tPA stimulated pulmonary fibrinolytic activity. However, 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 endotoxaemia.

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