Human insulin-like growth factor-IA expression in transgenic mice promotes adenomatous hyperplasia but not pulmonary fibrosis

1 Program in Cell Biology, Department of Pediatrics, and 2 Interstitial Lung Disease Program, Department of Medicine, National Jewish Medical and Research Center, and Division of Pulmonary Sciences and Critical Care Medicine, Departments of 3 Medicine, 4 Immunology, and 5 Pathology, University of Colorado Health Sciences Center, Denver, Colorado; and 6 Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Submitted 9 November 2004 ; accepted in final form 17 December 2004 Insulin-like growth factor-I (IGF-I) has been implicated in postnatal alveolar development, pulmonary fibrosis, and non-small cell lung cancer. To further investigate the role of IGF-I, we created a line of transgenic mice in which alveolar type II epithelial cells express human IGF-IA under the control of the surfactant protein C promoter. We determined the effect of pulmonary overexpression of human IGF-IA on 1 ) pulmonary inflammation and fibrosis in response to intratracheal instillation of bleomycin, 2 ) premalignant pulmonary adenomatous hyperplasia, and 3 ) adenoma formation. Transgenic expression of human IGF-IA had no effect on baseline gross lung pathology, cellularity of bronchoalveolar lavage, or total lung collagen content. In addition, there were no significant differences between transgenic mice and nontransgenic littermate controls in the development of pulmonary inflammation or pulmonary fibrosis in response to intratracheal bleomycin instillation. However, pulmonary expression of human IGF-IA in older mice (>12 mo) significantly increased the incidence of premalignant adenomatous hyperplastic lesions compared with littermate controls without affecting adenoma formation. These findings suggest that increased expression of human IGF-IA in alveolar air spaces does not affect the development of pulmonary fibrosis but promotes premalignant changes in the alveolar epithelium. lung; bleomycin Address for reprint requests and other correspondence: D. W. H. Riches, Neustadt D-405, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206 (E-mail: richesd{at}njc.org )