A critical pathophysiological feature of the acute respiratory distress syndrome (ARDS) is local activation of extrinsic coagulation and inhibition of fibrinolysis. These events promote deposition of fibrin in the lung as the injury evolves. Components of the extrinsic coagulation pathway, e.g. tissue factor, thrombin and fibrin, signal alterations in inflammatory cell traffic and increases in vascular permeability. Procoagulants and fibrin also promote other key events in the injury including complement activation, production of pro-inflammatory cytokines, inhibition of fibrinolysis and remodeling of the injured lung. To test the hypotheses that activation of extrinsic coagulation and disordered fibrin turnover in the lung are central to the pathogenesis of lung injury and impaired gas exchange in ARDS, it is proposed that specific blockade of the initiating steps of extrinsic coagulation with site- inactivated factor VIIa (FFR-FVIIa) or tissue factor pathway inhibitor (TFPI) will prevent acute lung injury and gas exchange impairment in experimental ARDS. It is also proposed that the two agents will have equivalent effects on blockade of extrinsic coagulation but FFR-FVIIa will have superior anti-inflammatory properties by inhibiting signaling by tissue factor-FVIIa complex. The hypotheses will be tested in non-human primates with acute lung injury from either sepsis or hyperoxia.
The Specific Aims are: 1) To determine the key inflammatory mechanisms and the extent of protection from acute lung injury (ALI) effected by blockade of the extrinsic coagulation pathway in sepsis; 2) To determine the key inflammatory mechanisms and the extent of protection from ALI effected by blockade of the extrinsic coagulation pathway in hyperoxia; and 3) To determine the efficacy of inhibition of the extrinsic coagulation pathway when this treatment strategy is implemented after ARDS is established in baboons.
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