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Role of prostaglandin E2 in the pathogenesis of pulmonary fibrosis

Keerthisingam, Carmel Beulin; (2000) Role of prostaglandin E2 in the pathogenesis of pulmonary fibrosis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The biosynthesis of lung extracellular matrix proteins is under tight homeostatic control, loss of which leads to changes in connective tissue metabolism. Pulmonary fibrosis is characterised by increased fibroblast proliferation and deposition of extracellular matrix proteins, including collagen. Prostaglandin (PG) E2 inhibits fibroblast proliferation and collagen production and its synthesis is induced by profibrotic mediators including transforming growth factor (TGF)-β1. However, in patients with pulmonary fibrosis, PGE2 levels are decreased, despite elevated levels of TGF-β1. This thesis addressed the hypothesis that PGE2 modulates fibroblast proliferation and collagen synthesis and that in the presence of pro-inflammatory mediators, a reduced capacity to synthesize PGE2 leads to unopposed fibroblast proliferation and collagen synthesis. Firstly, the effect of TGF-β1 on fibroblast PGE2 synthesis, proliferation and collagen production was examined in fibroblasts from non-fibrotic and fibrotic lung. This identified a subset of non-PGE2 synthesizing, control cell lines derived from non-fibrotic lung (group II). In fibroblasts that synthesized PGE2 (group I), TGF-β1stimulated PGE2 synthesis further, however, levels were reduced in group II cell lines and in fibroblasts from fibrotic lung (group III). Impaired PGE2 synthesis correlated with loss of the anti-proliferative response to TGF- β1 and increased TGF-β1-induced collagen synthesis. In group I fibroblasts, the anti-proliferative response to TGF- β1 was mediated by PGE2. Secondly, selective inhibition of cyclooxygenase (COX) suggested a role for COX-2 in TGF- β1-induced PGE2 synthesis. Furthermore, the inability to upregulate PGE2 synthesis in fibroblasts from groups II and III was due to a failure to upregulate COX-2 mRNA levels. These results support the hypothesis that fibroblasts from fibrotic lung have a limited capacity to synthesise PGE2 due to aberrant COX-2 expression. In addition, a group of non-fibrotic cell lines were identified exhibiting a similar phenotype to the fibrosis cell lines. These individuals may be predisposed to developing pulmonary fibrosis. Finally, the role of COX-2 in bleomycin-induced pulmonary fibrosis was assessed. COX-2 expression was upregulated in bleomycin-injured lungs. In COX-2 deficient mice, bleomycin-induced pulmonary fibrosis was associated with an enhanced inflammatory reaction suggesting an anti-inflammatory role for COX-2.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Role of prostaglandin E2 in the pathogenesis of pulmonary fibrosis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; Pulmonary fibrosis
URI: https://discovery.ucl.ac.uk/id/eprint/10103216
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