Published ahead of print on March 4, 2005, doi:10.1164/rccm.200411-1483OC
Am. J. Respir. Crit. Care Med., Volume 171, Number 10, May 2005, 1125-1128
A more recent version of this article appeared on May 15, 2005
Submitted on November 6, 2004
Accepted on February 22, 2005
Activated Protein C Inhibits Local Coagulation after Intrapulmonary Delivery of Endotoxin in Humans
Tom van der Poll1*, Marcel Levi1, Jerry A Nick2, and Edward Abraham3
1 Department of Medicine, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands,
2 Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA,
3 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
* To whom correspondence should be addressed. E-mail: t.vanderpoll{at}AMC.UVA.NL.
Rationale: Acute lung injury and pneumonia are associated with pulmonary activation of coagulation and suppression of fibrinolysis resulting in fibrin deposition in the lung. Activated Protein C has systemic anticoagulant effects in patients with sepsis. Objective: To determine the effect of systemic administration of recombinant human Activated Protein C on endotoxin-induced hemostatic alterations in the bronchoalveolar space in man. Methods: Healthy humans received intravenous Activated Protein C (24 µg/kg/hr; N = 8) or vehicle (N = 7); all subjects were administered saline in one lung subsegment and endotoxin (4 ng/kg) into the contralateral lung. Bronchoalveolar lavage was performed 16 hours after saline and endotoxin administration. Measurements and Main Results: Endotoxin induced local activation of coagulation, as reflected by elevated levels of thrombin-antithrombin complexes (1.9±0.1 ng/mL) and soluble tissue factor (15.0±0.6 pg/mL) in bronchoalveolar lavage fluid, which was inhibited by Activated Protein C (1.4±0.1 ng/mL and 12.3±0.4 pg/mL respectively, both P < 0.01). Concurrently, endotoxin suppressed fibrinolysis, as indicated by reduced bronchoalveolar levels of plasminogen activator activity accompanied by elevated levels of plasminogen activator inhibitor type I activity. Activated Protein C diminished the rise in plasminogen activator inhibitor type I activity (from 3.9±0.1 to 3.0±0.2 ng/mL, P=0.002), while not significantly influencing plasminogen activator activity levels. Endotoxin reduced bronchoalveolar Protein C concentrations, which was prevented by Activated Protein C. Protein C did not influence the endotoxin-induced rise in local soluble thrombomodulin levels. Conclusion: Activated Protein C exerts an anticoagulant effect in the human lung challenged with endotoxin.
Key words: fibrinolysis, lung, lipopolysaccharide
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