Coagulation cascade proteinases in lung injury and fibrosis

The primary function of the coagulation cascade is to promote hemostasis and limit blood loss in response to tissue injury. In addition, there is now considerable evidence that coagulation plays pivotal roles in orchestrating inflammatory and tissue repair responses via both the generation of fibrin and activation of the family of proteinase-activated receptors (PARs). Consequently, uncontrolled coagulation and PAR signaling responses have been shown to contribute to excessive inflammatory and fibroproliferative responses in the context of a broad range of conditions, including acute lung injury and fibrotic lung disease. In terms of the cellular origin of excessive coagulation activity in the context of lung injury, coagulation zymogens are principally thought to be derived from the circulation and locally activated via the extrinsic tissue factor-dependent coagulation pathway within the intraalveolar compartment. More recently, we have provided compelling evidence that several key coagulation zymogens are locally synthesized by the hyperplastic alveolar epithelium in pulmonary fibrosis. In terms of signaling receptors activated in response to the coagulation cascade, current evidence suggests a major role for PAR1 in influencing endothelial-epithelial barrier disruption, inflammatory cell recruitment, and collagen deposition in response to lung injury, whereas PAR2 signaling has been implicated mainly in mediating lung inflammatory responses. This article reviews current understanding of coagulation pathways in acute and fibrotic lung injury and expands on the scientific rationale for strategies that specifically target intraalveolar coagulation or PAR signaling responses.