Published ahead of print on September 15, 2005, doi:10.1165/rcmb.2005-0172OC
© 2006 American Thoracic Society DOI: 10.1165/rcmb.2005-0172OC Hypoxia-Induced Mitogenic Factor Modulates Surfactant Protein B and C Expression in Mouse LungDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Pathology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Correspondence and requests for reprints should be addressed to Dechun Li, M.D., Ph.D., Department of Internal Medicine, Division of Pulmonary, Critical Care, and Occupational Medicine, Saint Louis University, 7th Floor, Desloge Towers, St. Louis, MO 63110–2539. E-mail: dechunli{at}jhmi.edu 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.
Key Words: gene expression • lung development • lung epithelial cells • mRNA stability • signal transduction This article has been cited by other articles:
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