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Role of Repeated Lung Injury and Genetic Background in Bleomycin-Induced Fibrosis

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea; and Division of Pulmonary, Critical Care and Occupational Medicine, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa and Veterans Administration Medical Center, Iowa City, Iowa

Address correspondence to: Gary W. Hunninghake, M.D., Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, 200 Hawkins Drive, C33-GH, Iowa City, Iowa 52242. E-mail: gary-hunninghake{at}uiowa.edu

Current hypotheses of the pathogenesis of many forms of pulmonary fibrosis suggest that (i) a stimulus results in repeated or prolonged episodes of lung injury, and (ii) genetic factors modulate the outcome of the injury. The commonly employed single-exposure bleomycin model results in only temporary fibrosis. Therefore, we evaluated whether repeated bleomycin exposures, in the setting of a genetic background more likely to develop a T helper 2 (Th2) response, would induce prolonged fibrosis. Lung fibrosis was induced by intratracheal bleomycin injection, either as a single exposure or as three consecutive exposures. We found that bleomycin induced a Th2-like environment in both Th1-biased C57BL/6J and Th2-biased DBA/2 mice. We also found histologic changes and collagen increases consistent with lung injury/fibrosis at early time points, but prolonged fibrosis only after multiple exposures in the Th2-biased DBA/2 mice. We also determined if impaired healing of bleomycin-induced injury would prolong fibrosis in the C57BL/6J mice. Endothelial nitric oxide (which protects endothelial cells from oxidant-induced injury) synthase knockout animals on a C57BL/6J background also had prolonged fibrosis, similar to DBA/2 mice, after multiple bleomycin exposures. This was specific to eNOS, as inducible nitric oxide synthase knockout animals cleared the fibrosis as effectively as wild-type C57BL/6J mice. This data indicate that healing of injury/fibrosis after bleomycin is complex and can be determined by a number of genetic and environmental factors.

Abbreviations: endothelial nitric oxide synthase, eNOS • interferon-gamma, IFN- • interleukin, IL • inducible nitric oxide synthase, iNOS, T helper, Th

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