Krupiczojc, M.A.; (2008) The role of coagulation factor Xa in pulmonary fibrosis. Doctoral thesis , University of London.

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Abstract

Pulmonary fibrosis is the end stage of a heterogeneous group of disorders, characterised by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium. Current evidence suggests that the differentiation of fibroblasts into highly synthetic and contractile myofibroblasts plays a central role in the pathogenesis of pulmonary fibrosis. Uncontrolled coagulation activity with extravascular expression of tissue factor (TF) leading to the activation of coagulation zymogens, including FVII, FX and prothrombin, has been documented in the lungs of patients with pulmonary fibrosis. In addition to their role in blood clotting, coagulation proteinases induce multiple pro inflammatory and pro-fibrotic cellular effects via the activation of their major signalling receptors the PARs, including PAR!. Until recently, coagulation zymogens were thought to be exclusively derived from the circulation and then locally activated in response to tissue injury. This thesis shows for the first time that FX is locally upregulated in human and murine fibrotic lung tissue and that the alveolar epithelium represents a prominent cellular source of this protein. This thesis further reports that FXa is a potent inducer of the myofibroblast differentiation programme via PAR! and the transcriptional upregulation of thrombospondin-1 leading to the activation of TGF-P!. The work presented here further demonstrates that PAR1f TSP-1 and a-SMA co-localize to fibrotic foci in idiopathic pulmonary fibrosis and a direct causal link between FXa and the development of fibrosis was demonstrated by showing that a direct FXa inhibitor attenuated bleomycin-induced lung fibrosis. This thesis therefore identifies a novel pathogenic mechanism by which FXa, a central proteinase of the coagulation cascade, is locally upregulated and drives the fibrotic response to lung injury. These findings herald a paradigm shift in the current understanding of the tissue origin of excessive procoagulant activity and further place PAR! central to the crosstalk between pro-coagulant signalling and tissue remodelling.

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