There is strong evidence that the extravascular activation of coagulation proteinases contributes to both inflammation and fibrosis in response to tissue injury in a number of organs, including the lung. Extravascular intra-alveolar accumulation of fibrin, often evident as hyaline membranes, is commonly observed in the lungs of patients with pulmonary fibrosis, in acute lung injury (ALI) and in the acute respiratory distress syndrome (ARDS), in which rapid fibroproliferation and matrix synthesis can lead to the development of extensive fibrotic lesions. Excessive procoagulant activity and intra-alveolar fibrin deposition observed in these conditions is thought to arise from an imbalance between locally produced pro- and anti-coagulant factors, in combination with leakage of plasma proteins (including fibrinogen) into the alveolar space. We and others have shown that modulation of procoagulant activity within the alveolar compartment attenuates lung inflammation and fibrosis in response to bleomycin-induced lung injury in experimental animals. In addition to their critical role in blood coagulation, it is now well recognised that coagulation proteinases exert potent pro-inflammatory and pro-fibrotic effects via proteolytic activation of proteinase-activated receptors (PARs). The PARs currently comprise four members, PAR1 to PAR4, which are activated by a unique mechanism involving the unmasking of a tethered ligand by limited proteolysis. Collectively, the proteinases of the coagulation cascade can target all four family members. Thrombin is considered to be a major activator of PAR1, PAR3 and PAR4; whereas factor Xa, on its own or as part of the tissue factor-factorVIIa-factor Xa ternary complex, activates either PAR1 or PAR2 depending on cell-type. Current in vitro evidence suggests that PAR1 is one of the major receptors by which coagulation proteinases exert a range of potent pro-inflammatory and pro-fibrotic effects. In vivo evidence for the potential importance of this receptor was obtained in studies performed in our laboratory demonstrating that PAR1 deficiency affords protection from microvascular leak, inflammatory cell recruitment and lung fibrosis in response to bleomycin injury. This protection was accompanied by significant reductions in pulmonary levels of the potent PAR1-inducible mediators, MCP-1 (CCL2), TGF-beta1 and CTGF/FISP12. We have further shown that PAR1 is highly expressed in inflammatory and fibroproliferative lesions in lung sections obtained from patients with fibrotic lung disease. Recent unpublished work using microarray analysis to generate a transcriptional profile of bleomycin injury in mice revealed a large number of chemokines and their receptors which are regulated during the fibrotic phase of lung injury. To our surprise, expression of the gene for coagulation FX was dramatically upregulated, suggesting that part of the procoagulant activity in lung fibrosis may be due to locally produced coagulation zymogens. Immunohistochemistry and real-time RT-PCR analysis of laser-capture microdissected lung biopsies from patients with pulmonary fibrosis confirmed that FX mRNA and protein are significantly upregulated in this condition. Subsequent in vitro studies further demonstrated that FXa was a potent inducer of fibroblast to myofibroblast differentiation via activation of PAR1 but not PAR2. Myofibroblasts are the major effector cells in pulmonary fibrosis and are responsible for the elaboration of excessive extracellular matrix proteins within the lung parenchyma. In conclusion, these data place PAR1 as one of the critical receptors involved in orchestrating the interplay between coagulation, inflammation and remodelling in response to lung injury. We propose that strategies aimed at blocking this receptor may prove useful for a number of respiratory conditions associated with excessive activation of the coagulation proteinases within both intra- and extra-vascular compartments.