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 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
Reed
J A
JA
Children's Hospital Medical Center, Cincinnati, Ohio 43229-3039, USA.
Ikegami
M
M
Robb
L
L
Begley
C G
CG
Ross
G
G
Whitsett
J A
JA
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000493:pharmacokinetics; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D006023:Glycoproteins / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D006706:Homeostasis / Q000502:physiology; D015848:Interleukin-5 / Q000032:analysis; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D010713:Phosphatidylcholines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011510:Proteolipids / Q000493:pharmacokinetics; D011650:Pulmonary Alveoli / Q000378:metabolism; D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism; D018121:Receptors, Cytokine / Q000172:deficiency* / Q000235:genetics; D011994:Recombinant Proteins
D006023:Glycoproteins; D015848:Interleukin-5; D010713:Phosphatidylcholines; D010743:Phospholipids; D011498:Protein Precursors; D011510:Proteolipids; D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; C114668:beta C receptor; D015060:1,2-Dipalmitoylphosphatidylcholine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor