Role of lung endothelial cells during fibrotic lung remodeling

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Summary Chronic epithelial or vascular injuries followed by dysregulated repair are the trigger mechanisms in pathogenesis of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). Multiple cell types are involved in lung fibrogenesis, with fibroblasts and epithelial cells given the most attention. Role of endothelial cells and microvasculature remain unclear. Dysregulated repair causes vascular remodeling, associated with increased vessel permeability, partial loss of capillaries, focal increase in pathological angiogenesis and endothelial dysfunction. Normal endothelial cells (EC) are transcriptionally re-programmed into fibrosis- associated endothelial cells (FEC), that support activated fibroblasts and promote lung inflammation. Our long- term goal is to identify key regulators of EC-to-FEC re-programming and clarify molecular mechanisms of the crosstalk between endothelial cells and other cell types during pulmonary fibrogenesis. In our preliminary data, we used endothelial cells from lungs of patients with IPF and mouse lung fibrosis models to identify FOXF1 as a key transcriptional regulator of EC-to-FEC re-programming during lung fibrogenesis. Using transgenic mouse models with endothelial-specific deletion or over-expression of Foxf1 gene, we propose to test the hypothesis that endothelial FOXF1 decreases activation of fibroblasts and prevents macrophage accumulation in fibrotic foci. We propose two specific aims: (1) identify molecular mechanisms whereby endothelial FOXF1 inhibits lung fibrogenesis, (2) establish whether restoring FOXF1 in FECs will prevent or reduce fibrotic lung remodeling after chronic lung injury. Understanding the regulation of EC-to-TEC re-programming, and the molecular mechanisms utilized by pulmonary endothelial cells to control pulmonary fibrosis, will provide new approaches for treatment of interstitial lung diseases.