Alexander, RE; (2016) The regulation of extra-hepatic coagulation factor X production in alveolar and bronchiolar epithelium. Doctoral thesis , UCL (University College London).

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating condition with poor survival (median five years) and few effective therapeutic options. IPF results from the misdirected deposition of extra-cellular matrix proteins (ECM) by activated myofibroblasts, which results in occlusion of airspaces, organ dysfunction, and eventual respiratory failure. Current hypotheses posit that chronic injury to the pulmonary epithelium leads to the activation of wound healing programs and that these processes, through abnormal crosstalk between mesenchymal and epithelial cells, remain progressively activated rather than being resolved. Two important factors in this process are the abnormal activation of the coagulation cascade and the presence of oxidative stress. The coagulation proteinase FX is produced locally in the lung and plays a role in experimental fibrosis. Preliminary in vitro work suggested a role for oxidative stress, which itself has also been purported to play an aetiological role in IPF. This resulted in the hypothesis that local production of coagulation proteinases by lung epithelium plays a role in the pathogenesis of IPF and is regulated by oxidative stress. In vitro, the cell line A549, primary human alveolar type II cells (ATII), and primary human bronchiolar epithelial cells (HBECs) were shown to produce F10 mRNA and FX protein at baseline. This production was increased in the presence of reactive oxygen species (ROS). Further, NRF2 was demonstrated to play a role in this production, through the use of agonists, ChIP, and siRNA. In vivo, immunohistochemistry and immunocytochemistry showed the localisation of FX, FVII, and tissue factor (TF) to epithelial cells. Treatment of bleomycin-induced fibrosis with the antioxidant NAC, although showing no effect on disease, reduced F10 mRNA levels and showed an effect on markers of epithelial injury. Together, these studies provide strong evidence for local epithelial production of FX and for oxidative stress and NRF2 signalling in this production.

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