6533b859fe1ef96bd12b7870

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FGF-9 overexpression prevents pleural fibrosis induced by intra-pleural adenovirus injection in mice

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Introduction: Lung fibrosis is associated with the reactivation of molecular pathways involved in lung development. Mesothelial cells are involved in the fibrotic lung process but their exact role is debated. Fibroblast Growth Factor-9 (FGF-9) is expressed by epithelial cells and visceral pleura during embryonic lung development. Mice homozygous for a targeted disruption of FGF-9 exhibit lung hypoplasia with reduced mesenchyme and early postnatal death. The aim of this study was to evaluate the role of FGF-9 expression by mesothelial cells in the adult lung. We used adenovirus-mediated (FGF-9) gene transfer in mesothelial cells in vivo. Material and Methods: AdFGF9 or a control adenovirus (AdCont) (108pfu/mL) was administered in 100 μl of 0.9% NaCl by pleural injection of C56/Bl6 male mice. Mice were studied at day 3, day 5, and day 14.We quantified FGF-9 in pleural fluid by ELISA. The expression of FGF-9, inflammation and pro fibrotic markers were assessed by qPCR, and immunochemistry. Results: Intrapleural injection of AdCont led to pleural inflammation and pleural remodeling beginning at day 5 and maximal at day 14, with pleural thickening, and accumulation of α-SMA+ cells and collagen. AdCont induced murine FGF-9 expression in the pleura. AdFGF-9 led to human FGF-9 overexpression in the pleural fluid and in the lung at day 5. AdFGF-9 completely inhibited the development of pleural remodeling, with a significant decrease of Collagen I, III, fibronectin, PAI-1, CTGF mRNA expression. Conclusion: Intrapleural injection of adenovirus induces pleural fibrosis. It is prevented by pleural overexpression of human FGF-9 suggesting that mesothelial FGF-9 has anti fibrotic properties.