6533b852fe1ef96bd12aaa2e

RESEARCH PRODUCT

IL-11 promotes pulmonary vascular remodeling and lung fibrosis through the activation of endothelial to mesenchymal transition

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Background: Pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) portends a poor prognosis and currently there is no approved therapy for hypoxemic PH. IL-11 is a novel lung fibrosis mediator but its role on vascular function is unknown. Objective: To analyze the role of IL-11 on pulmonary artery remodeling and lung fibrosis in vitro and in vivo. Methods: IL-11 expression was evaluated in pulmonary arteries and lung sections of control subjects and patients with IPF, IPF+PH and idiopathic PH (PAH). Human pulmonary artery endothelial cells and smooth muscle cells were stimulated with IL-11. Endothelial to mesenchymal transition was evaluated measuring the increase of mesenchymal markers and decrease of endothelial markers. Transgenic Tie2-GFP mice were subjected to daily subcutaneous injections of IL-11 or saline for 20 days to evaluated the contribution of pulmonary endothelial cells to pulmonary fibrosis. Results: IL-11 was overexpressed in PAH and PH+IPF pulmonary arteries and in a lesser extent in IPF arteries. Subcutaneous injections of IL-11 into Tie2-GFP reporter mice promoted lung fibrosis, pulmonary artery remodeling and the increase of RV/LV+septo. Tie2-GFP positive cells were observed in the pulmonary endothelium of control animals but also in the muscular layer and parenchyma fibroblast from IL-11 treated mice. Lung fibroblasts isolated from lung parenchyma of IL-11 treated mice expressed α-SMA fibers and Tie-GFP indicating an endothelial origin and contribution to pulmonary artery remodeling and lung fibrosis. Conclusions: IL-11 is overexpressed in patients with PH and promotes pulmonary artery remodeling and fibrosis activating EnMT.