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Role of proteinase-activated receptor-1-dependent secondary mediators in lung fibrosis.

Johns, R.H.; (2007) Role of proteinase-activated receptor-1-dependent secondary mediators in lung fibrosis. Doctoral thesis , University of London. Green open access

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Persistent local activation of the coagulation cascade typifies tibroproliferative lung disorders such as idiopathic pulmonary fibrosis and the acute respiratory distress syndrome. In addition to its role in coagulation, thrombin exerts potent pro inflammatory and pro-flbrotic effects via activation of its major cellular receptor proteinase-activated receptor-1 (PARi). In this thesis, the relevance of PARi activation to inflammation and fibrosis in a model of lung injury and fibrosis based on the intra-tracheal instillation of bleomycin was examined. Lung inflammation and fibrosis were substantially attenuated in PARi-deficient mice. The attenuated inflammatory response was manifest by substantial reductions in bronchoalveolar lavage protein content, total leukocyte numbers, and lung levels of the chemokine CCL2. The attenuated fibrotic response was manifest by a reduction in lung collagen accumulation of around 60%, and reduced mRNA and/or protein levels of the pro- fibrotic mediators connective tissue growth factor (CTGF) and transforming growth factor-beta-1 (TGF-beta1). These data suggest that PAR may promote inflammation and fibrosis, at least in part, via the expression of CCL2, CTGF, and TGFbeta1. Further studies demonstrated prominent immunostaining for PAR on lung epithelial cells following bleomycin injury, consistent with these cells being a potential source of PARi-dependent secondary mediators in the injured lung. Widespread epithelial injury is a prominent feature of fibroproliferative lung disorders, in which hyperplastic activated epithelial cells represent a major source of pro-inflammatory and pro-fibrotic mediators. The effect of PARi activation on lung epithelial expression of CCL2, CTGF and TGFbeta1 was therefore examined in vitro. Exposure to both thrombin and the PARi agonist peptide TFLLR-NH2 substantially increased mRNA levels of CCL2 and CTGF, but not TGFbeta1 in A549 and BEAS-2B human lung epithelial cells. Increases in CCL2 and CTGF mRNA levels in response to thrombin were attenuated with the PARi antagonist RWJ-58259. PAR 1-dependent increases in CCL2 and CTGF mRNA are apparently protein kinase C-dependent since increases in response to TFLLR-NH2 were inhibited by the protein kinase C inhibitor Ro-31-8425. Increases in CCL2 and CTGF mRNA in response to PARi activation were mirrorred by comparable increases at the protein level. Taken together, these data suggest that epithelial cells may represent a source of PARi-dependent pro-inflammatory and pro-fibrotic mediators following lung injury.

Type: Thesis (Doctoral)
Title: Role of proteinase-activated receptor-1-dependent secondary mediators in lung fibrosis.
Identifier: PQ ETD:592107
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Nephrology
URI: https://discovery.ucl.ac.uk/id/eprint/1444798
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