Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with poor survival, limited treatment options and no known cure. Early detection and treatment is a promising approach that could potentially improve clinical outcomes of patients affected with this devastating disease. Cigarette smoking is the most important environmental risk factor for the development of ILD; we have recently shown that smokers without a prior diagnosis of ILD have radiographic interstitial lung abnormalities (ILA) that are associated with physiologic, functional and molecular changes. Although these findings suggest that a subset of smokers with subclinical ILD will progress to develop clinically significant pulmonary fibrosis, large prospective longitudinal studies are required to define clinical and molecular features associated with subclinical ILD in smokers. In this proposal we will prospectively study a large cohort of smokers enrolled in the Pittsburgh Lung Screening Study (PLuSS). We aim to define clinical and molecular determinants that predict development and longitudinal progression of ILA detected by computed tomography over a 10-year mean follow-up period. We hypothesize that select clinical and molecular features that portend a poor prognosis in IPF patients predict development and progression of subclinical ILD in smokers. To test this hypothesis we will address the following specific aims: Specific Aim 1: Determine prevalence and long-term longitudinal progression of subclinical ILD in smokers enrolled in PLuSS. Specific Aim 2: Define clinical and molecular determinants that predict progression of subclinical ILD in smokers. Specific Aim 3: Identify clinical and molecular determinants that predict the development of subclinical ILD in smokers. The successful completion of this research will provide us with a better understanding of the characteristics and natural history of subclinical ILD and novel non- invasive ways to identify smokers at risk for progression of subclinical ILD.