Project Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the peripheral lung parenchyma that affects ~0.5% of older adults in the US and carries a median survival time of only 3.8 years. While pirfenidone and nintedanib slow the decline of lung function in IPF, neither drug reverses fibrosis or prevents the ongoing alveolar epithelial cell injury that leads to fibrosis in IPF. The identification of interventions that prevent alveolar epithelial cell injury in IPF would have a paradigm-shifting impact. A recent novel hypothesis suggests that “tractional” injury in the periphery of the lung may be responsible for the development of IPF. Our central hypothesis is that obstructive sleep apnea (OSA), which affects up to 88% of adults with IPF, is a prevalent cause of recurrent peripheral tractional stress in the lung that leads to alveolar epithelial cell injury and, in susceptible individuals, lung fibrosis. We believe that the Müeller maneuvers induced during obstructive apneas and hypopneas lead to stretch and injury alveolar epithelial cells, contributing to fibrosis in susceptible adults over the course of 10-20 years. In mice, inspiratory resistive loading (a model of obstructive hypopnea) induces alveolar epithelial cell injury and results in increased alveolar-capillary membrane permeability. In humans, we and others have shown that adults with OSA have higher circulating levels of surfactant protein-A and Krebs von den Lungen-6, markers of alveolar epithelial cell injury, and higher serum matrix metalloproteinase-7 levels, a marker of extracellular matrix remodeling, suggesting that subclinical alveolar epithelial cell injury and extracellular matrix remodeling occurs in OSA in otherwise healthy adults. Alveolar epithelial and endothelial injury is also detectable by measurement of serum surfactant protein-D, and angiopoetin-2, respectively. In IPF, alveolar epithelial cell injury is detectable by elevations in some of these markers, and matrix metalloproteinase-7 levels are a key diagnostic and prognostic biomarker in IPF. We propose to establish OSA as a contributor to alveolar epithelial cell injury in adults with and without IPF, and to obtain data that will inform and justify a phase 2 clinical trial of continuous positive airway pressure (CPAP) to improve outcomes in adults with IPF and OSA. We will investigate associations between OSA and biomarkers of alveolar epithelial & endothelial cell injury and extracellular matrix remodeling a multi-ethnic population- based cohort of adults who underwent home polysomnography in 2010-2012. We will also investigate whether treatment with CPAP is associated with reductions in serum markers of alveolar epithelial cell injury and extracellular matrix remodeling in adults with OSA both with and without IPF, including measurement of CPAP- induced changes in the proteome of bronchoalveolar lavage fluid in adults with IPF. Our study will provide strong evidence for or ag...