The LTRC study population has already been established by the NHLBI (http://www.ltrcpublic.com) and we have received approval to access all biological specimens (see letter of support). The LTRC enrolls donor subjects who are anticipating lung surgery, collects blood and extensive phenotypic data from the prospective donors, and then processes their surgical waste tissues for research use. Most donor subjects have COPD/emphysema or pulmonary fibrosis. A standardized clinical data collection protocol to assure uniformity of the data and a standardized tissue collection and processing protocol is followed to assure high quality biospecimens, and to allow for pathological study, immunohistochemistry, gene expression analyses, biomarker measurements, genetic analyses, and electron microscopy. Phenotype data is discussed in Aim 2. We plan to conduct the proposed study in all LTRC subjects, including at least 1261 patients with chronic lung disease (fibrotic interstitial lung disease (N=393; 31%), COPD/emphysema (N=545; 43%), other chronic lung disease (N=323; 26%)) and 176 control lungs (obtained from individuals with lung cancer). Since the LTRC is continuing to enroll subjects at a rate of at least 250/year, we anticipate that we will be able to include at least 1500 LTRC study subjects. In addition, we have access to 100 flash frozen and formalin fixed samples from normal lung. These lungs were donor lungs for transplantation. Single whole-lung samples from 100 individuals were obtained from Tissue Transformation Technologies (Edison, NJ). All individuals had suffered brain death and were evaluated for organ transplantation before research consent. Informed consent was obtained at the time of transplant evaluation. All specimens failed regional lung selection criteria for transplantation. For inclusion in this proposal, subjects had to demonstrate no evidence of active infection or chest radiographic abnormalities, mechanical ventilation < 48 h, PaO2/FiO2 ratio > 200, and no past medical history of underlying lung disease or systemic disease that involves the lungs (e.g., rheumatoid arthritis). Lung samples were procured within 34 h after brain death (mean, 16.2 h; range, 4.5-33.25 h), and DNA/RNA has been extracted and quality checked.