Distinct changes in pulmonary surfactant homeostasis in common beta-chain-and GM-CSF-deficient mice

Pulmonary alveolar proteinosis (PAP) is caused by inactivation of either gr anulocyte-macrophage colony-stimulating factor (GMCSF) or GM receptor commo n beta-chain (beta(c)) genes in mice [GM(-/-), beta(c)(-/-)], demonstrating a critical role of GM-CSF signaling in surfactant homeostasis. To distingu ish possible phenotypic differences in GM(-/-) and beta(c)(-/-) mice, surfa ctant metabolism was compared in beta(c)(-/-), GM(-/-), and wild-type mice. Although lung histology in beta(c)(-/-) and GM(-/-) mice was indistinguish able, distinct differences were observed in surfactant phospholipid and sur factant protein concentrations and clearance from lungs of beta(c)(-/-) and GM(-/-) mice. At 1-2 days of age, lung saturated phosphatidylcholine (Sat PC) pool sizes were higher in wild-type, beta(c)(-/-), and GM(-/-) mice com pared with wild-type adult mice. In wild-type mice, Sat PC pool sizes decre ased to adult levels by 7 days of age; however, Sat PC increased with advan cing age in beta(c)(-/-) and GM(-/-) mice. Postnatal changes in Sat PC pool sizes were different in GM(-/-) compared with beta(c)(-/-) mice. After 7 d ays of age, the increased lung Sat PC pool sizes remained constant in beta( c)(-/-) mice but continued to increase in GM(-/-) mice, so that by 56 days of age, lung Sat PC pools were increased three- and sixfold, respectively, compared with wild-type controls. After intratracheal injection, the percen t recovery of [H-3]dipalmitoylphosphatidylcholine and I-125-recombinant sur factant protein (SP) C was higher in beta(c)(-/-) compared with wild-type m ice, reflecting decreased clearance in the receptor-deficient mice. The def ect in clearance was significantly more severe in GM(-/-) than in beta c(-/ -) mice. The ratio of SP Sat PC to SP-A, -B, and -C was similar in bronchoa lveolar lavage fluid (BALF) from adult mice of all genotypes, but the ratio of SP-D to Sat PC was markedly increased in beta(c)(-/-) and GM(-/-) mice (10- and 5-fold, respectively) compared with wild-type mice. GM-CSF concent rations were increased in BALF but not in serum of beta(c)(-/-) mice, consi stent with a pulmonary response to the lack of GM-CSF signaling. The observ ed differences in surfactant metabolism suggest the presence of alternative clearance mechanisms regulating surfactant homeostasis in beta(c)(-/-) and GM(-/-) mice and may provide a molecular basis for the range in severity o f PAP symptoms.