This Article Full Text Full Text (PDF) All Versions of this Article: 200411-1483OCv1 171/10/1125    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van der Poll, T. Articles by Abraham, E. Search for Related Content PubMed PubMed Citation Articles by van der Poll, T. Articles by Abraham, E.

Activated Protein C Inhibits Local Coagulation after Intrapulmonary Delivery of Endotoxin in Humans

Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; and Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Tom van der Poll, M.D., Academic Medical Center, Room G2-130, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands. 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 (APC) has systemic anticoagulant effects in patients with sepsis. Objective: To determine the effect of systemic administration of recombinant human APC on endotoxin-induced hemostatic alterations in the bronchoalveolar space in humans. Methods: Healthy humans received intravenous APC (24 µg/kg/hour; 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 APC (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. APC 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 APC. Protein C did not influence the endotoxin-induced rise in local soluble thrombomodulin levels. Conclusion: APC exerts an anticoagulant effect in the human lung challenged with endotoxin.

Key Words: fibrinolysis • lipopolysaccharide • lung

This article has been cited by other articles:

				M. A. Richardson, A. Gupta, L. A. O'Brien, D. T. Berg, B. Gerlitz, S. Syed, G. R. Sharma, M. S. Cramer, J. G. Heuer, E. J. Galbreath, et al. Treatment of Sepsis-Induced Acquired Protein C Deficiency Reverses Angiotensin-Converting Enzyme-2 Inhibition and Decreases Pulmonary Inflammatory Response J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 17 - 26. [Abstract] [Full Text] [PDF]

				G. Choi, A. P. J. Vlaar, M. Schouten, C. van't Veer, T. van der Poll, M. Levi, and M. J. Schultz Natural anticoagulants limit lipopolysaccharide-induced pulmonary coagulation but not inflammation Eur. Respir. J., September 1, 2007; 30(3): 423 - 428. [Abstract] [Full Text] [PDF]

				M. J Schultz and M. Levi Pulmonary coagulopathy: a potential therapeutic target in different forms of lung injury Thorax, July 1, 2007; 62(7): 563 - 564. [Full Text] [PDF]

				L. O. Mosnier, B. V. Zlokovic, and J. H. Griffin The cytoprotective protein C pathway Blood, April 15, 2007; 109(8): 3161 - 3172. [Abstract] [Full Text] [PDF]

				L. Wang, J. A. Bastarache, N. Wickersham, X. Fang, M. A. Matthay, and L. B. Ware Novel Role of the Human Alveolar Epithelium in Regulating Intra-Alveolar Coagulation Am. J. Respir. Cell Mol. Biol., April 1, 2007; 36(4): 497 - 503. [Abstract] [Full Text] [PDF]

				C. S. Calfee and M. A. Matthay Nonventilatory Treatments for Acute Lung Injury and ARDS Chest, March 1, 2007; 131(3): 913 - 920. [Abstract] [Full Text] [PDF]

				X.-Q. Wang, K. Bdeir, S. Yarovoi, D. B. Cines, W. Fang, and E. Abraham Involvement of the Urokinase Kringle Domain in Lipopolysaccharide-Induced Acute Lung Injury J. Immunol., October 15, 2006; 177(8): 5550 - 5557. [Abstract] [Full Text] [PDF]

				L. B. Ware, E. Camerer, K. Welty-Wolf, M. J. Schultz, and M. A. Matthay Bench to bedside: targeting coagulation and fibrinolysis in acute lung injury Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L307 - L311. [Abstract] [Full Text] [PDF]

				M. Cepkova and M. A. Matthay Pharmacotherapy of acute lung injury and the acute respiratory distress syndrome. J Intensive Care Med, May 1, 2006; 21(3): 119 - 143. [Abstract] [PDF]

				E. B. Milbrandt, A. Ishizaka, and D. C. Angus Update in critical care 2005. Am. J. Respir. Crit. Care Med., April 15, 2006; 173(8): 833 - 841. [Full Text] [PDF]

				M. A. Matthay and E. Abraham beta-Adrenergic Agonist Therapy as a Potential Treatment for Acute Lung Injury Am. J. Respir. Crit. Care Med., February 1, 2006; 173(3): 254 - 255. [Full Text] [PDF]