title: Hypoxia-induced mitogenic factor modulates surfactant protein B and C expression in mouse lung.
abstract: Previous studies have demonstrated a robust pulmonary expression of hypoxia-induced mitogenic factor (HIMF) during the perinatal period, when surfactant protein (SP) synthesis begins. We hypothesized that HIMF modulates SP expression and participates in lung development and maturation. The temporal-spatial expression of HIMF, SP-B, and SP-C in developing mouse lungs was examined by immunohistochemical staining, Western blot, and RT-PCR. The expression and localization of SP-B and SP-C were investigated in mouse lungs after intratracheal instillation of HIMF in adult mice. The effects of HIMF on SP-B and SP-C transcription activity, and on mRNA degradation, were investigated in mouse lung epithelial (MLE)-12 and C10 cells using the promoter-luciferase reporter assay and actinomycin D incubation. The activation of Akt, extracellular signal-regulated kinase (ERK)1/2, and p38 mitogen-activated protein kinase was explored by Western blot. Intratracheal instillation of HIMF resulted in significant increases of SP-B and SP-C production, predominantly localized to alveolar type II cells. In MLE-12 and C10 cells, HIMF enhanced SP-B and SP-C mRNA levels in a dose-dependent manner. Meanwhile, HIMF increased transcription activity and prevented actinomycin D-facilitated SP-B and SP-C mRNA degradation in MLE-12 cells. Incubation of cells with LY294002, PD098059, or U0126 abolished HIMF-induced Akt and ERK1/2 phosphorylation and suppressed HIMF-induced SP-B and SP-C production, whereas SB203580 had no effect. These results indicate that HIMF induces SP-B and SP-C production in mouse lungs and alveolar type II-like cell lines via activations of phosphatidylinositol 3-kinase/Akt and ERK1/2 mitogen-activated protein kinase, suggesting that HIMF plays critical roles in lung development and maturation.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Qiangsong
authors.initials: Q
authors.lastname: Tong
authors.forename: Liduan
authors.initials: L
authors.lastname: Zheng
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Dodd-o
authors.forename: John
authors.initials: J
authors.lastname: Langer
authors.forename: Danming
authors.initials: D
authors.lastname: Wang
authors.forename: Dechun
authors.initials: D
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics / Q000378:metabolism*; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D014158:Transcription, Genetic
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D036341:Intercellular Signaling Peptides and Proteins; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; C413576:Retnla protein, mouse