Harnessing FGF-10 signaling to protect ER-stress alveolar epithelial cells against viral infection - impact on regenereration versus fibrosis

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal parenchymal lung disease, which is proposed to originate from chronic injury to aged alveolar epithelial type 2 cells (AT2) such as pro-apoptotic endoplasmic reticulum (ER) stress. Fibroblast Growth Factor 10 (FGF-10) has been shown to be important for the formation of the alveolar epithelial lineage development and for survival of AT2 in response to injury. Viral infection is known to trigger progression of IPF and to aggravate the disease. In the preceding funding period, we identified the microRNA miR-142 to be linked with the formation of AT2 during lung development and to be regulated by FGF-10. We also showed that viral infection in the ER-stressed AT2 augments apoptosis and boosts lung fibrosis. Moreover, we found that FGF-10 prevents influenza (PR8) amplification in AT2 and that a knockout of miR-142 makes AT2 more resistant to PR8. Additionally, we showed that the first-line antidiabetic drug metformin impacts FGF-10 signaling and accelerates lung regeneration after injury. Based on these results, we propose, in the forthcoming funding period, that the newly discovered FGF-10-FGFR2b-miR-142 signaling axis in the adult lung decreases viral infection of ER-stressed AT2 cells, and we envision that targeting this axis including metformin administration beneficially impacts virus-induced lung injury and regeneration.