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Role of transforming growth factor β isoforms in the pathogenesis of pulmonary fibrosis

Coker, Robina Kate; (1997) Role of transforming growth factor β isoforms in the pathogenesis of pulmonary fibrosis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Pulmonary fibrosis is a disease of the lung interstitium characterised by excessive deposition of extracellular matrix proteins including collagen. The aetiology is frequently unclear, but the last decade has generated significant advances in our understanding of the pathogenesis. One current hypothesis is that polypeptide mediators, released by resident lung cells and recruited inflammatory cells, stimulate fibroblast replication and increased collagen synthesis. Interstitial collagen deposition then impedes gas exchange. Of the cytokines studied so far, current evidence strongly implicates transforming growth factor B1 (TGFB1). However, it is now known that there are at least five TGFB isoforms, of which TGFB1-3 are found in mammals. The role of TGFB2 and TGFB3 in the pathogenesis of pulmonary fibrosis is currently unclear. The overall aim of this thesis was to examine the role of the three different TGFB isoforms in the pathogenesis of pulmonary fibrosis. In so doing, I addressed the hypothesis that TGFB1, TGFB2 and TGFB3 play distinct but overlapping roles in the pathogenesis of this disease. To address this hypothesis, the effect of TGFB2 and TGFB3 on human lung fibroblast procollagen metabolism was examined in vitro, TGFB1-3 all stimulated fibroblast procollagen production. TGFB3 was the most potent and also reduced intracellular procollagen degradation. Secondly, a non-isotopic in situ hybridisation technique was developed for use in lung tissue. This enabled the localisation of TGFB isoform gene expression in normal and fibrotic murine and human lung. TGFB1 and TGFB3 mRNA transcripts were demonstrated in a wide variety of lung cells not hitherto recognised to express these genes, and TGFB3 gene expression was demonstrated in human lung for the first time. TGFB1 but not TGFB3 gene expression was enhanced during bleomycin-induced lung injury in mice, and TGFB1 gene expression was more consistently enhanced in human lung fibrosis than was that of TGFB3. Taken together, these data suggest that TGFB1 is the predominant isoform implicated in the pathogenesis of this disease. Finally, results with the TGFB2 riboprobes yielded positive hybridisation signal using the sense probe, but little or no signal using the antisense probe. These results and further studies involving characterisation of the TGFB2 probes and Northern analysis of rat lung and murine lung cells suggested that a natural TGFB2 antisense transcript is present in mammalian lung.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Role of transforming growth factor β isoforms 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.
URI: https://discovery.ucl.ac.uk/id/eprint/10099397
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