Role of coagulation pathways and treatment with activated protein C in hyperoxic lung injury.
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.
Looney
M R
MR
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143-0130, USA. mark.looney@ucsf.edu
Esmon
C T
CT
Matthay
M A
MA
D055371:Acute Lung Injury / Q000097:blood / Q000209:etiology*; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001777:Blood Coagulation / Q000502:physiology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018496:Hyperoxia / Q000097:blood / Q000209:etiology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011486:Protein C / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D013917:Thrombin / Q000008:administration & dosage / Q000494:pharmacology; D014882:Water-Electrolyte Balance
D000925:Anticoagulants; D011486:Protein C; D013917:Thrombin