meso-IPF

Human idiopathic pulmonary fibrosis (IPF), like many fibrotic disorders, is a chronic, progressive and lethal disease. IPF has an unknown aetiology, and there is presently no effective treatment. In the pathogenesis of the disease, the deposition of extra cellular matrix is a dynamic process with fibroblast/myofibroblasts being the major actors of this process. Interactions between alveolar cells and fibroblasts are critical. Growth factors such as Fibroblast growth Factors play a key role in these interactions. Interestingly, the pathological changes in IPF typically start in the subpleural lung regions. This subpleural predominance of fibrosis is even a characteristic feature of IPF and will persist during the progression of the disease inside the parenchyma. This characteristic and to date unexplained subpleural feature of IPF is the main rationale for the present project. We have previously shown that adenoviral mediated gene transfer of TGF-ß (AdTGF-ß1) to mesothelial cells in vivo induces a severe pleural fibrosis that gradually invades the subpleural parenchyma as observed in IPF. We have also demonstrated in vivo that TGF-ß1 transient overexpression induces mesothelial cells differentiation into myofibroblasts, characterized by the presence of alpha-smooth muscle actin (alpha-SMA), through an epithelio-Mesenchymal transition (EMT)-like process. The EMT process is one of the recent hypotheses for the formation of myofibroblasts in fibrotic processes. In the current proposal we want to analyse factors (proteins, growth factors) that may control mesothelial cells transformation and interaction with other local cells and particularly fibroblasts. Heat shock proteins (HSPs) are crucial in the control of apoptosis but they are also powerful molecular chaperones for other cellular proteins. The small HSP family, which includes HSP27 and alphaB-crystallin are involved in the cell differentiation process and in the maintenance and control of the cytoskeleton. Our preliminary data suggest that HSP27 and alphaB-crystallin may have a critical role in EMT. This project aims to further determine the function of these two chaperones in the EMT process. We will also determine the role of HSP70 inhibition in the process of pulmonary fibrosis by intrapleural administration of HSP70 inhibitors currently in preclinical studies for cancer treatment. Finally we will study the role of fibroblast growth factor-9 (FGF9), produced by mesothelial cells, in cell interactions (mesothelial-fibroblasts) and in the process of EMT. For all the tasks we will verify our hypothesis in vitro, ex vivo in human lung samples and in vivo with our pleural TGF-ß transient overexpression models in rodents. In conclusion, we wish to demonstrate that the mesothelial cell is a key component in the initiation of subpleural fibrosis by its interaction with the local microenvironment for which the involvement of certain chaperones and growth factors is needed.