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Distinct changes in pulmonary surfactant homeostasis in common beta-chain- and GM-CSF-deficient mice
Abstract:
Pulmonary alveolar proteinosis (PAP) is caused by inactivation of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM receptor common beta-chain (beta(c)) genes in mice [GM(-/-), beta(c)(-/-)], demonstrating a critical role of GM-CSF signaling in surfactant homeostasis. To distinguish possible phenotypic differences in GM(-/-) and beta(c)(-/-) mice, surfactant metabolism was compared in beta(c)(-/-), GM(-/-), and wild-type mice. Although lung histology in beta(c)(-/-) and GM(-/-) mice was indistinguishable, distinct differences were observed in surfactant phospholipid and surfactant 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 compared with wild-type adult mice. In wild-type mice, Sat PC pool sizes decreased to adult levels by 7 days of age; however, Sat PC increased with advancing 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 days 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 percent recovery of [(3)H]dipalmitoylphosphatidylcholine and (125)I-recombinant surfactant protein (SP) C was higher in beta(c)(-/-) compared with wild-type mice, reflecting decreased clearance in the receptor-deficient mice. The defect 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 bronchoalveolar 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 concentrations were increased in BALF but not in serum of beta(c)(-/-) mice, consistent with a pulmonary response to the lack of GM-CSF signaling. The observed 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 of PAP symptoms. surfactant metabolism; alveolar macrophage; granulocyte-macrophage colony-stimulating factor
Insights
Granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling is crucial for lung surfactant homeostasis. Genetic inactivation of GM-CSF or its receptor in mice revealed distinct impacts on surfactant metabolism and clearance, offering insights into pulmonary alveolar proteinosis.
Area of Science:
- Pulmonary medicine
- Cell biology
- Genetics
Background:
- Pulmonary alveolar proteinosis (PAP) is linked to impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling.
- GM-CSF plays a vital role in maintaining surfactant homeostasis in the lungs.
Purpose of the Study:
- To investigate phenotypic differences in surfactant metabolism between mice lacking GM-CSF (GM(-/-)) and those lacking its receptor's common beta-chain (beta(c)(-/-)).
- To elucidate the role of GM-CSF signaling in surfactant clearance and homeostasis.
Main Methods:
- Comparative analysis of surfactant phospholipid and protein metabolism in wild-type, GM(-/-), and beta(c)(-/-) mice.
- Assessment of surfactant pool sizes, clearance rates after intratracheal injection, and protein-to-lipid ratios in bronchoalveolar lavage fluid (BALF).
Main Results:
- Histology was similar, but surfactant metabolism and clearance differed significantly between GM(-/-) and beta(c)(-/-) mice.
- Lung saturated phosphatidylcholine (Sat PC) levels increased with age in mutant mice, with a more pronounced effect in GM(-/-) mice.
- Clearance defects were more severe in GM(-/-) than beta(c)(-/-) mice, and SP-D to Sat PC ratios were elevated in both mutant groups.
Conclusions:
- GM-CSF signaling critically regulates surfactant homeostasis and clearance.
- Distinct differences in surfactant metabolism between GM(-/-) and beta(c)(-/-) mice suggest alternative clearance pathways.
- Findings provide a molecular basis for varying PAP symptom severity.