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(American Journal of Pathology. 2006;169:1633-1642.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060501

Insulin-Like Growth Factor-Binding Protein-5 Induces Pulmonary Fibrosis and Triggers Mononuclear Cellular Infiltration

Hidekata Yasuoka^*, Zhihong Zhou^*, Joseph M. Pilewski^*, Tim D. Oury, Augustine M.K. Choi^* and Carol A. Feghali-Bostwick^*

From the Division of Pulmonary, Allergy, and Critical Care Medicine,^* the Department of Medicine, Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, and the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

We have recently shown that insulin-like growth factor-binding protein (IGFBP)-5 is overexpressed in idiopathic pulmonary fibrosis lung tissues and increases collagen and fibronectin deposition. Here, we further examined the effect of IGFBP-5 in vivo by intratracheal administration of replication-deficient adenovirus expressing human IGFBP-5 (Ad5), IGFBP-3 (Ad3), or no cDNA (cAd) to wild-type mice. Increased cellular infiltration and extracellular matrix deposition were observed in mice after Ad5 administration compared with Ad3 and cAd. Mononuclear cell infiltration consisted predominantly of T lymphocytes at day 8. By day 14, the number of infiltrating T cells decreased, whereas that of B cells and monocytes/macrophages increased. IGFBP-5 also induced migration of peripheral blood mononuclear cells in vitro, suggesting that in vivo mononuclear cell infiltration may be the direct result of IGFBP-5 expression. -Smooth muscle actin and Mucin-1 co-localized in cells of mice treated with Ad5, suggesting that IGFBP-5 induced epithelial-mesenchymal transition. In addition, exogenous IGFBP-5 induced -smooth muscle actin expression in primary fibroblasts and epithelial-mesenchymal transition of pulmonary epithelial cells in vitro. In conclusion, our results suggest that overexpression of IGFBP-5 in mouse lung results in fibroblast activation, increased extracellular matrix deposition, and myofibroblastic changes. Thus, the IGFBP-5-induced fibrotic phenotype in vivo may represent a novel model to better understand the pathogenesis of fibrosis.

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