Smoktunowicz, N; (2014) Procoagulant Signalling In Lung Injury And Fibrosis. Doctoral thesis , UCL (University College London).

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Abstract

Coagulation proteinases, such as thrombin, exert a plethora of cellular effects via activation of proteinase-activated receptors (PARs). Abnormal activation of the coagulation cascade has been widely implicated in the pathology of fibroproliferative lung disease, including the most common form idiopathic pulmonary fibrosis (IPF). The high-affinity thrombin receptor PAR-1 is over-expressed in the lungs of IPF patients, particularly by the hyperplastic epithelium and fibroblasts within fibrotic foci. Moreover, viral infections are implicated in aberrant coagulation activation and accumulating evidence points to viruses as contributory factors to acute exacerbations that lead to deterioration of lung function in IPF patients. This thesis focuses on investigating and extending our current understanding of the role of PAR-1 in driving lung injury and fibrosis. The data show that primary human lung fibroblasts and microvascular endothelial cells express abundant PAR-1 and elicit robust calcium signalling responses following thrombin stimulation. In contrast, normal human alveolar and bronchial epithelial cells express low levels of PAR-1 but high levels of PAR-2. Exposure of the alveolar epithelial cell line, A549, to TGFβ increases PAR-1 expression and functional responses but this was not seen in freshly isolated primary human alveolar and bronchial epithelial cells. The role of TGFβ and pro-coagulant signalling responses was also investigated in an in vivo model of viral infection on a background of pulmonary fibrosis. Herpesvirus infection in the fibrotic lung promoted robust inflammatory responses characterized by extensive pulmonary consolidation but did not lead to an increase in lung collagen deposition. Importantly, viral infection was associated with the local upregulation of key components of the extrinsic coagulation pathway. Although PAR-1 is known to contribute to lung injury and fibrosis in a single hit experimental model of pulmonary fibrosis by promoting the activation of latent TGFβ, systemic targeting of TGFβ and the coagulation cascade does not impact on inflammation induced by viral infection in the fibrotic lung.

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