Tissue factor-dependent coagulation protease signaling in acute lung injury

OBJECTIVESTo review the role of tissue factor-dependent coagulation in acute lung injury. To interpret preclinical and clinical data on therapeutic intervention of the coagulation cascade, focusing on the principles of proteolytic cell signaling of the coagulant and anticoagulant pathways. DATA EXTRACTION AND SYNTHESISThis review is based on published original research and relevant review articles on cell signaling by coagulation proteases and on experimental models that implicate the tissue factor-initiated coagulation cascade in acute lung injury and systemic inflammation. CONCLUSIONSThe coagulation cascade signals via protease activated receptors in the tissue factor-initiation phase and downstream via the effector protease, thrombin. Bleomycin-induced acute lung injury is an example of thrombin signaling-dependent pathology. Frequently, thrombin signaling is a major contributor to inflammation in the extravascular space but intravascular thrombin signaling is a threshold-regulated event. At low concentrations, intravascular thrombin activates the protein C pathway by converting protein C (bound to endothelial cell protein C receptor) to activated protein C and this generates antiinflammatory signals along the activated protein C–endothelial cell protein C receptor–protease activated receptor 1 pathway on endothelial cells. Direct thrombin signaling only occurs when intravascular thrombin concentrations exceed a coagulant threshold. In systemic bacterial toxin-mediated inflammation, inhibition of thrombin is not sufficient to limit inflammation, whereas tissue factor inhibition interrupts a self-sustaining inflammatory escalation in acute lung injury. Therefore, in the vasculature, inflammatory signaling by the tissue factor initiation complex is favored over thrombin signaling.