The risk for proteolysis of lung connective tissue was evaluated in patients with cystic fibrosis (CF) with chronic, severe lung infections by measuring uninhibited elastase activity in sputum samples and urinary excretion of desmosines (cross-linking amino acids in elastin). Of the 16 patients included in the study, 11 were infected with Pseudomonas aeruginosa, 2 with Pseudomonas cepacia, and 2 with both P. aeruginosa and P. cepacia. Uninhibited elastase activity (0.34 to 20.2 micrograms elastin degraded/mg protein/30 min) was detected in the sputum samples from each of 13 patients tested. Serine elastase activity was detected in the sputum of each of 12 patients, and metalloelastase (P. aeruginosa elastase and possibly macrophage elastase) activity was detected in the sputum of 11 of 12 patients tested. Male patients with CF excreted significantly more elastin cross-links (desmosines) in their urine than did control male subjects (3.6 +/- 1.7 micrograms/kg/24 h versus 1.5 +/- 0.6 micrograms/kg/24 h; p less than 0.01), and there was a significant correlation (p less than 0.05) between urine desmosine excretion and the severity of lung disease in the patients with CF as indicated by chest roentgenogram score. In 3 autopsied patients, abnormal elastin fibers were seen by light microscopy in all lung compartments. Fragmented and exfoliated elastin, evidence of active elastolysis, was noted in bronchial ulcers and abscesses. The results of this study suggest that proteolytic destruction of lung connective tissue is an ongoing process in the chronically infected CF lung and that this proteolysis contributes to the pathologic changes observed in airways and alveolar parenchyma.