Role of coagulation pathways and treatment with activated protein C in hyperoxic lung injury
- 1Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA
- 2Howard Hughes Medical Institute, Oklahoma Medical Research Foundation, and Departments of Pathology and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
- Dr M R Looney, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0130, USA; mark.looney{at}ucsf.edu
- Received 25 March 2008
- Accepted 14 September 2008
- Published Online First 13 November 2008
Abstract
Background: Activated protein C (APC) significantly decreases mortality in severe sepsis, but its role in acute lung injury from non-infectious aetiologies is unclear. The role of APC in hyperoxic acute lung injury was tested by studying the physiology of lung injury development, measurement of key coagulation proteins and treatment with murine APC (mAPC).
Methods: Mice were continuously exposed to >95% oxygen and lung injury was assessed by extravascular lung water, lung vascular protein permeability and alveolar fluid clearance. Coagulation proteins were measured in bronchoalveolar lavage (BAL) fluid and plasma. Recombinant mAPC was administered in preventive and treatment strategies.
Results: Hyperoxia produced dramatic increases in lung vascular permeability and extravascular lung water between 72 and 96 h. Lung fluid balance was also adversely affected by progressive decreases in basal and cAMP-stimulated alveolar fluid clearance. Plasma levels of APC decreased at 72 h and were 90% depleted at 96 h. There were significant increases in BAL fluid levels of thrombomodulin, thrombin-antithrombin complexes and plasminogen activator inhibitor-1 at later time points of hyperoxia. Lung thrombomodulin expression was severely decreased during late hyperoxia and plasma levels of APC were not restored by excess thrombin administration. Administration of recombinant mAPC failed to improve indices of lung injury.
Conclusions: Hyperoxic acute lung injury produces procoagulant changes in the lung with a decrease in plasma levels of APC due to significant endothelial dysfunction. Replacement of mAPC failed to improve lung injury.
Footnotes
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See Editorial, p 95
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‣ Additional data are published online only at http://thorax.bmj.com/content/vol64/issue2
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Funding: This work was supported in part by a GlaxoSmithKline Pulmonary Fellowship and HL82742 (MRL), HL51854 and HL74005 (MAM), and HL54502 (CTE) from the National Institutes of Health.
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Competing interests: MRL and MAM have no competing interests. CTE holds patents on production of protein C and on the use of activated protein C in sepsis. He also consults with several companies interested in sepsis and applications of anticoagulants to disease processes.
