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Published ahead of print on April 3, 2003, doi:10.1165/rcmb.2003-0029OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 3, September 2003, 375-380

A more recent version of this article appeared on September 1, 2003
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Submitted on January 28, 2003
Revised on April 2, 2003

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

Man P Chung1, Martha M Monick1, Nabeel Y Hamzeh1, Noah S Butler1, Linda S Powers1, and Gary W Hunninghake1*

1 Internal Medicine, University of Iowa & Veterans Administration Medical Center, Iowa City, Iowa, USA

* To whom correspondence should be addressed. E-mail: gary-hunninghake{at}uiowa.edu.

Current hypotheses of the pathogenesis of many forms of pulmonary fibrosis suggest that 1) a stimulus results in repeated or prolonged episodes of lung injury and 2) genetic factors modulate the outcome of the injury. The commonly employed single exposure bleomycin model results in only temporary fibrosis. Therefore, we evaluated if repeated bleomycin exposures, in the setting of a genetic background more likely to develop a 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 T helper 2-like environment in both T helper 1-biased C57BL/6J and T helper 2-biased DBA/2 mice. We also found histological 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.




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