Akram, Khondoker Mehedi (2013) Idiopathic pulmonary fibrosis: exploration of aberrant epithelial wound repair and stem cell-mediated regenerative approaches. Doctoral thesis, Keele University.

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Idiopathic pulmonary fibrosis (IPF) is a fatal form of fibrotic lung disease. The pathogenesis of IPF is unclear. An aberrant alveolar epithelial wound repair is likely to be involved in the disease process. Alveolar bronchiolisation, a process where bronchiolar Clara cells migrate into the affected alveoli, is a manifestation of abnormal alveolar wound repair. The role of Clara cells during alveolar injury repair in IPF is controversial. This study was undertaken to investigate the role of Clara cells in alveolar epithelial wound repair and pulmonary fibrosis. Currently, there is no curative treatment for IPF; therefore, stem-cell mediated regenerative therapy has been suggested. In this study, the paracrine role hMSC and hESC on pulmonary epithelial wound repair has also been evaluated.

A direct-contact co-culture in vitro model was utilised to evaluate the role of Clara cells on alveolar epithelial cell wound repair. Immunohistochemistry was conducted on IPF lung tissue samples to replicate the in vitro findings ex vivo. The paracrine role of hMSC and hESC on pulmonary epithelial cells was evaluated by utilising the in vitro wound repair system.

This study demonstrates that Clara cells induce apoptosis in AEC through a TRAILdependent mechanism, resulting in significant inhibition of wound repair. Furthermore in the IPF lungs, TRAIL-expressing Clara cells were detected within the fibrotic alveoli, together with widespread AEC apoptosis. This study also demonstrates that hMSC enhance AEC and SAEC wound repair via a paracrine mechanism through stimulation of cell migration; whereas, secretory factors of differentiated hESC promote AEC wound repair through stimulation of both cell proliferation and migration.

Through this study I propose a novel hypothesis which implies that the extensive profibrotic remodelling associated with IPF could be driven by TRAIL-expressing Clara cells inducing AEC apoptosis through a TRAIL-dependent mechanism. My study also supports the notion of clinical application of hMSC and hESC or their secretory products as regenerative therapeutic modality for IPF.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Contributors: Forsyth, NR (Thesis advisor)
Spiteri, M (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 25 Jul 2017 10:30
Last Modified: 16 Aug 2022 15:01
URI: https://eprints.keele.ac.uk/id/eprint/3804

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