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Published ahead of print on July 15, 2004, doi:10.1165/rcmb.2002-0300OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 5, November 2004, 483-490

A more recent version of this article appeared on November 1, 2004
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Submitted on December 17, 2002
Revised on July 14, 2004

Reversible cigarette smoke extract-induced DNA damage in human lung fibroblasts

Huijung Kim1, Xiangde Liu2, Tetsu Kobayashi2, Heather Conner2, Tadashi Kohyama3, Fu-Qiang Wen2, Qiuhong Fang2, Shinji Abe2, Peter Bitterman4, and Stephen I Rennard2*

1 Department of Internal Medicine, Seoul Adventist Hospital and WonKwang University Kunpo Medical Center, Seoul, Korea, Republic of, 2 Department of Internal Medicine, Pulmonary Section, University of Nebraska Medical Center, Omaha, NE, USA, 3 Department of Respiratory Medicine, University of Tokyo, Tokyo, Japan, 4 Department of Medicine, University of Minnesota, Minneapolis, MN, USA

* To whom correspondence should be addressed. E-mail: srennard{at}unmc.edu.

Cigarette smoke contains thousands of chemicals, many of which may contribute to cytotoxicity and carcinogenesis. Using assays detecting DNA strand breaks (TUNEL) and DNA content (flow cytometry), we evaluated the genotoxic effect of cigarette smoke extract (CSE) on human fetal lung fibroblasts (HFL-1) cultured in three-dimensional collagen gels as well as in monolayer culture. When HFL-1 cells were exposed to CSE, DNA strand breaks were detected in most, as determined by TUNEL. This effect was dependent on CSE concentration, duration of CSE exposure and the density of HFL-1 cells cast into the collagen gels. Buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, significantly increased DNA damage induced by 1% CSE, and N-acetylcysteine (NAC), a glutathione precursor, blocked 5% CSE from inducing DNA damage. Following CSE exposure, most cells were TUNEL-positive, but DNA quantification revealed no hypodiploid cells, indicating that apoptosis was not occurring during the CSE exposure. CSE-induced DNA damage was reversible, and cells proliferated when CSE was removed after 24-hour exposure. These results demonstrate that cigarette smoke can induce DNA damage in HFL-1 cells cultured in both three-dimensional collagen gels and monolayer cultures, and that oxidants likely play a role in this damage. Moreover, this DNA damage is reversible, with cells surviving and TUNEL positivity reversing when CSE is removed within 24 hours.




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