McNulty, K; (2013) Genetically modified cell therapy for the reduction of lung injury. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Pulmonary fibrosis is a feature of a number of important lung diseases, the commonest of which is idiopathic pulmonary fibrosis (IPF). IPF is refractory to current treatments and has a poor prognosis, so development of novel therapeutic strategies is paramount. Injury to the alveolar epithelium plays a central role in the pathogenesis of IPF, and represents a logical therapeutic target. Keratinocyte growth factor (KGF) exerts protective effects on the alveolar epithelium and is a potential therapeutic candidate. There is growing interest in combined gene and cell therapy approaches, and in this study the therapeutic potential of macrophages genetically modified to express KGF was explored in the mouse bleomycin model of pulmonary fibrosis. Lentiviral vectors were generated expressing KGF, and used to transduce murine BMDM and the IC-21 murine macrophage cell line. KGF-transduced IC-21 cells were characterised and were shown to induce proliferation in mouse lung epithelial cells in vitro. A luciferase-expressing lentiviral vector was produced, and IC-21 cell were transduced to express luciferase. Luciferase-transduced IC-21 cells were tracked in vivo using bioluminescence imaging after delivery to the lungs of mice, and were retained in the lungs of bleomycin-treated mice, but not saline-treated controls, and localised to injured areas. KGF-transduced IC-21 cells were delivered to mice during both the inflammatory and fibrotic phases of the mouse bleomycin model, and no improvements in outcomes reflecting alveolar-capillary membrane permeability, inflammation, cytotoxicity and fibrosis were demonstrated. The reasons for the lack of therapeutic efficacy of KGF-transduced macrophages were unclear, but delivery of macrophages per se was associated with an increase in inflammatory mediators. In conclusion, exogenously delivered macrophages were shown to localise to sites of lung injury, but KGF-transduced macrophages were not found to have therapeutic efficacy in bleomycin-treated mice. Future work should better characterise the effects of exogenous macrophage delivery in pulmonary fibrosis.

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