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The role of coagulation pathways and treatment with activated protein C in hyperoxic lung injury in mice
  1. Mark R Looney (mark.looney{at}
  1. University of California, San Francisco, United States
    1. Charles T Esmon (charles-esmon{at}
    1. University of Oklahoma, United States
      1. Michael A Matthay (michael.matthay{at}
      1. University of California, San Francisco, United States


        Background: Activated protein C significantly decreases mortality in severe sepsis but its role in acute lung injury from non-infectious etiologies is unclear. We tested the role of activated protein C in hyperoxic acute lung injury by studying the physiology of lung injury development, measurement of key coagulation proteins, and treatment with murine activated protein C.

        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 the plasma. Recombinant, murine activated protein C was administered in preventive and treatment strategies.

        Results: Hyperoxia produces dramatic increases in lung vascular permeability and extravascular lung water between 72 and 96 hours. Lung fluid balance is also adversely affected by progressive decreases in basal and cAMP-stimulated alveolar fluid clearance. Plasma activated protein C levels decrease beginning at 72 hours and are 90% depleted at 96 hours. There were no significant changes in plasma protein C, thrombomodulin, endothelial protein C receptor, plasminogen activator inhibitor-1, or thrombin-antithrombin complexes at later time points of hyperoxia. Lung thrombomodulin expression was severely decreased during late hyperoxia and activated protein C plasma levels were not restored by excess thrombin administration. Finally, administration of recombinant, murine activated protein C failed to improve indices of lung injury.

        Conclusions: Endogenous activated protein C plasma levels decrease with hyperoxic lung injury due to significant endothelial dysfunction, but replacement of murine activated protein C fails to improve lung injury.

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