Title: Investigation of the epithelial-mesenchymal trophic unit in idiopathic pulmonary fibrosis
Funder: Medical Research Foundation

Abstract: IPF is a chronic fibroproliferative disease of unknown aetiology; no therapy has been shown to improve mortality of IPF patients who usually die within 2‐4 years after diagnosis. The increase in numbers of clinical trials in IPF in the last decade has helped improve general understanding about this devastating disease, and has resulted in a shift in focus away from detrimental immunosuppressive treatments to new anti-­‐fibrotic therapies for treatment of mild-­‐moderate IPF. However, there remains an unmet need as failure rate due to lack of response or side-­‐effects is sizeable, and additional costs are incurred by transplantation and long-­‐term oxygen for those with more advanced disease. Current paradigms suggest that abnormal alveolar epithelial injury and repair responses contribute to ongoing fibrosis, leading to excessive deposition of extracellular matrix (ECM) and disruption of the fine alveolar architecture in the lungs of IPF patients. While the focus of current therapies is to control of fibrosis, there is an under appreciation of the role(s) of the alveolar epithelium in IPF pathogenesis even though it is upstream of the cascade of events leading to fibrosis. Thus, better characterization of mechanisms of lung epithelial injury should lead to development of more efficient therapeutic strategies that complement anti-­‐fibrotic therapies by promoting restoration of normal epithelial integrity, helping to limit the progression of fibrosis in IPF patients. The epithelial-­‐ mesenchymal trophic unit (EMTU) describes the functional interactions between epithelial cells and mesenchymal cells and the ECM which are necessary to initiate numerous cellular functions of the lung. The most common of these functions include ifferentiation during lung development, repair of damaged tissue, and regulation of inflammatory responses. The EMTU therefore plays a central role in the control of normal tissue homeostasis and its dysregulation has been implicated in disease pathogenesis. Many studies suggest that the abnormal secretory phenotype of IPF fibroblasts plays an important role in the development and progression of the disease. Therefore, in this proposal, I wish to test the hypothesis that the alveolar EMTU is dysregulated in IPF as a consequence of the abnormal secretory phenotype of IPF fibroblasts. This maintains persistent activation of the alveolar epithelium and prevents induction of normal epithelial repair responses to restore tissue homeostasis. I will test my hypotheses in novel ex-­‐vivo co-­‐culture models of primary alveolar cells and fibroblasts to mimic the alveolar EMTU, and I will characterize the secretory phenotype of IPF fibroblasts and their crosstalk with the alveolar cells in these models. I will also investigate the main pathways that involved in the injury-­‐repair responses in the EMTU and the ability of growth factors such as hepatocyte growth factor or keratinocyte growth factor to help restore epithelial integrity. Finally, I will assess the expression of the different factors detected during my study in BAL fluid, serum and lung biopsies from IPF patients. An accurate characterization of the complex network of feedback signalling in the EMTU in IPF will help to identify pathways as well as markers of the pathogenesis and progression of the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY