Abstract

BACKGROUND: Progressive pulmonary dysfunction is a characteristic symptom of cystic fibrosis (CF) and is associated with functional impairment and biochemical alterations of surfactant phospholipids in the airways. However, the fundamental question of whether surfactant alterations in the CF lung are secondary to the pulmonary damage or are present before initiation of chronic infection and inflammation has yet to be resolved in patients with cystic fibrosis but can now be addressed in CF mice that exhibit the basic defect in the airways. A study was therefore undertaken to investigate the pool sizes, composition, and function of lung surfactant in the non-infected cftrm1HGU/m1HGU mouse. METHODS: The amount and composition of phospholipid classes and phosphatidylcholine molecular species were determined in bronchoalveolar lavage (BAL) fluid and lavaged lungs by high performance liquid chromatography (HPLC). Surfactant protein A (SP-A) levels in BAL fluid were determined by ELISA and surfactant for functional measurements was isolated from BAL fluid by differential ultracentrifugation. Equilibrium and minimal surface tension of surfactant was assessed by the pulsating bubble surfactometer technique. MF1, BALB/c, C57/BL6, and C3H/He mice served as controls. RESULTS: BAL fluid of cftrm1HGU/m1HGU mice contained 1.02 (95% confidence interval (CI) 0.89 to 1.16) mumol phospholipid and 259 (239 to 279) ng SP-A. BAL fluid of MF1, BALB/c, C57BL/6, and C3H/He mice contained 0.69 (0.63 to 0.75), 0.50 (0.42 to 0.57), 0.52 (0.40 to 0.64), and 0.45 (0.27 to 0.63) mumol phospholipid, respectively. After correction for the different body weights of mouse strains, phospholipid levels in BAL fluid of cftrm1HGU/m1HGU mice were increased by 64 (52 to 76)%, 60 (39 to 89)%, 72 (45 to 113)%, and 92 (49 to 163)%, respectively, compared with controls. The amount of SP-A in BAL fluid and the composition of phospholipid as well as phosphatidylcholine molecular species in BAL fluid and lung tissue was unchanged in cftrm1HGU/m1HGU mice compared with controls. The increase in phospholipids in BAL fluid of cftrm1HGU/m1HGU mice resulted from an increased fraction of large aggregates which exhibited normal surface tension function. CONCLUSION: In cftrm1HGU/m1HGU mice surfactant homeostasis is perturbed by an increased phospholipid pool in the alveolar compartment.