This program project research is a renewal of a 12-year program for studies in Cystic Fibrosis (CF). The current program contains a core facility consisting of more than 400 patients with CF, a pulmonary function laboratory, a computer facility, and a fiberoptic bronchoscopy service. Thirteen research projects are proposed which relate to the core facilities and interrelate with respect to objectives. The clinical studies are designed to elucidate 1) natural history of the disease, emphasizing pathophysiologic alterations in the lung, 2) effect of diagnosis before the onset of significant lung disease on prognosis, and 3) long term effects of complicating events (hyperglycemia, cor pulmonale, hemoptysis, pneumothorax, pregnancy). The efficacy of therapeutic measures including mist tents, aerosols and anti-staphylococcal therapy will be assessed in controlled studies. Improved therapy forpneumothorax and cor pulmonale will be sought. Laboratory studies will 1) attempt to clarify the pathophysiology of pulmonary gas transport employing tests that can be used to study infants, small children and older subjects, 2) study pulmonary lymphocyte and alveolar macrophage defense mechanisms with emphasis on pseudomonas organisms, 3) define biochemical, rheologic, and pharmacologic properties of human respiratory mucous glycoprotein secretions and determine how these properties relate to lung disease in CF, 4) investigate the basis of the excocrine water and electrolyte abnormalities found in CF, and 5) search for morphologic abnormalities of the CF pulmonary system at an ultrastructural level. It is anticipated that these studies will result in: 1) a better understanding of the course of this disease and its complications, 2) improved symptomatic therapy of lung and other complications of CF, 3) a clearer understanding of the pathogenetic mechanisms involved, and ultimately, 4) the design of more specific and effective therapeutic measures based on intervention of these life-threatening pathophysiologic processes.