Chronic obstructive lung disease (COPD) is characterized by the presence of airflow obstruction lung destruction and airway inflammation. The factors responsible for disease progression are poorly understood, but infections likely play a role in the initiation or perpetuation of pulmonary inflammation in COPD. Recent data have identified carrier states for Pneumocystis, suggesting that transmission and colonization are the likely mode of acquisition. In COPD patients Pneumocystis colonization is detected at high rates in lung specimens obtained at the time transplantation or lung resection and is also frequently found in respiratory specimens of patients with chronic bronchitis. Whether repeated bouts of Pneumocystis colonization or carriage contribute to lung damage, particularly in conjunction with cigarette smoke, has not been investigated experimentally. Mice exposed to cigarette smoke develop mild emphysema, but the inflammation found with smoke exposure only is mild and there is little data on physiologic changes characteristic of COPD. Thus, this model lacks key features of the human disease. It seems likely that a second "hit" (e.g. infection) may be necessary to better model human disease. We have found that even short-term smoke exposure alters innate host defense responses in the lung. In this setting, exposure to a pulmonary pathogen such as Pneumocystis might result in a more aggressive or prolonged infection, which, over time, could result in lung damage. Central Hypothesis: Tobacco smoke-exposure alters pulmonary innate immune responses that predispose to chronic colonization after environmentally acquired Pneumocystis infection. Once colonized, prolonged infection with Pneumocystis, in concert with continued cigarette smoke exposure, accelerate physiologic and pathologic changes characteristic of human COPD. Specific Aim 1. Determine the effect of cigarette smoke exposure on clearance of Pneumocystis infection. Specific Aim 2. Determine how cigarette smoke exposure and Pneumocystis infection interact to produce pulmonary inflammation. Specific Aim 3. Determine how cigarette smoke exposure and Pneumocystis interact to alter pulmonary physiology. Specific Aim 4. Examine the association of Pneumocystis colonization and the decline in pulmonary function in patients with COPD. COPD is a highly prevalent disease with substantial morbidity and mortality. Advances in understanding the pathogenesis of this disease could lead to new innovative strategies for restoring lung function and have a significant impact on health care outcomes for a large segment of the US population.