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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 4, April, 2002 430-437

Dose-Related Protection from Nickel-Induced Lung Injury in Transgenic Mice Expressing Human Transforming Growth Factor-alpha

William D. Hardie, Daniel R. Prows, Alyssa Piljan-Gentle, Michelle R. Dunlavy, Scott C. Wesselkamper, George D. Leikauf, and Thomas R. Korfhagen

Division of Pulmonary Medicine, Children's Hospital Medical Center, Cincinnati, Ohio; Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio; and Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio

To determine the role of transforming growth factor-alpha (TGF-alpha ) in protecting the lung from aerosolized nickel injury, transgenic mouse lines expressing human TGF-alpha in the pulmonary epithelium, under control of the human surfactant protein-C gene promoter, were tested. Higher expressing TGF-alpha transgenic mouse lines, expressing distinct levels of TGF-alpha , survived longer than nontransgenic control mice. Increased survival correlated with levels of TGF-alpha expression in the lung. After 72 h of nickel exposure (70 µg Ni/m3), transgenic lines with intermediate levels of the TGF-alpha expression demonstrated attenuation of lung injury. The highest expressing line (line 28) demonstrated reduced lung inflammation and edema, reduced lung wet-to-dry weight ratios, decreased bronchoalveolar lavage (BAL) protein and neutrophils, reduced interleukin (IL)-1beta , interleukin-6, and macrophage inflammatory protein-2, and maintained surfactant protein-B (SP-B) levels compared with nontransgenic controls. In the TGF-alpha transgenic mouse model, TGF-alpha protects against nickel-induced acute lung injury, at least in part, by attenuating the inflammatory response, reducing pulmonary edema, and preserving levels of SP-B.

Abbreviations: bronchoalveolar lavage, BAL; epidermal growth factor, EGF; EGF receptor, EGF-R; enzyme-linked immunosorbent assay, ELISA; Hanks' balanced salt solution, HBSS; interleukin, IL; lipopolysaccharide, LPS; macrophage inflammatory protein-2, MIP-2; phosphate-buffered saline, PBS; polytetrafluoroethylene, PTFE; quantitative trait locus, QTL; surfactant protein, SP; transforming growth factor-alpha , TGF-alpha .




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