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Title: The role of thrombin and protease activated receptor-1 in the pathogenesis of pulmonary fibrosis
Author: Howell, David Christopher John
ISNI:       0000 0001 3582 6986
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2004
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Pulmonary fibrosis is characterised by excessive deposition of extracellular matrix proteins within the lung parenchyma. Activation of the coagulation cascade occurs in this condition and thrombin levels are increased in bronchoalveolar lavage fluid (BALF) from patients with this disorder. In addition to its role in blood coagulation, thrombin exerts cellular effects, including promoting fibroblast proliferation, procollagen production and expression of connective tissue growth factor (CTGF) via activation of protease activated receptor-1 (PAR-1). This thesis examined the hypothesis that thrombin plays a role in promoting lung collagen accumulation in pulmonary fibrosis, via activation of PAR-1. To address this hypothesis, the effect of a direct thrombin inhibitor, UK-156406 on bleomycin-induced pulmonary fibrosis was examined in rats. In addition, the effect of bleomycin-induced pulmonary fibrosis in PAR-1 knockout (PAR-1-/-) and wild-type (WT) mice was evaluated. In rats, immunohistochemical expression of thrombin and PAR-1 were dramatically increased in the lung following bleomycin instillation, compared with saline-treated animals. Following bleomycin instillation, lung collagen doubled and was preceded by significant elevations in 1(I) procollagen and CTGF mRNA levels. In bleomycin-treated animals receiving an anticoagulant dose of UK-156046, lung collagen accumulation, 1(I) procollagen and CTGF mRNA levels were all significantly reduced. In WT mice given bleomycin, total lung collagen was increased but in bleomycin-instilled PAR-1-/- mice, lung collagen accumulation was significantly reduced biochemically and histologically. Furthermore, BALF total inflammatory cell number, total protein and CTGF mRNA levels were also significantly reduced in bleomycin-instilled PAR-1-/- mice compared with WT mice receiving bleomycin. In summary, this thesis shows that direct thrombin inhibition attenuates lung collagen accumulation in bleomycin-induced pulmonary fibrosis and also that PAR-1-/- mice are protected from bleomycin-induced lung injury. These data support the hypothesis that thrombin and PAR-1 play a critical role in experimental pulmonary fibrosis and that the pro-fibrotic effects of thrombin in this model, may be mediated, at least in part, via a CTGF-dependent mechanism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available