Published ahead of print on March 30, 2006, doi:10.1165/rcmb.2005-0340OC Am. J. Respir. Cell Mol. Biol., Volume 35, Number 3, September 2006, 277-288 A more recent version of this article appeared on September 1, 2006
Submitted on September 2, 2005 DNA Damage Induced by Hyperoxia: Quantitation and Correlation with Lung InjuryGeorge F Barker1*,1 Pulmonary and Critical Care Unit, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA * To whom correspondence should be addressed. E-mail: GBarker{at}Partners.org.
Inspired oxygen, an essential therapy for cardiorespiratory disorders, has the potential to generate reactive oxygen species which damage cellular DNA. Although DNA damage is implicated in diverse pulmonary disorders, including neoplasia and acute lung injury, the type and magnitude of DNA lesion caused by oxygen in vivo is unclear. We used single cell gel electrophoresis (SCGE) to quantitate two distinct forms of DNA damage, base adduction and disruption of the phosphodiester backbone, in the lungs of mice. Both lesions were induced by oxygen, but a marked difference between the two was found. With 40 hours of oxygen exposure, oxidized base adducts increased three to four-fold in the entire population of lung cells. This lesion displayed temporal characteristics (a progressive increase over the first 24 hours) consistent with a direct effect of reactive oxygen species attack upon DNA. DNA strand breaks, on the other hand, occurred in less than 10% of pulmonary cells, which acquired severe levels of the lesion; dividing cells were preferentially affected. Characteristics of these cells suggested that DNA strand breakage was secondary to cell death, rather than a primary effect of reactive oxygen species attack on DNA. By analysis of IL-6 and IL-11 overexpressing transgenic animals, which are resistant to hyperoxia, we found that DNA strand breaks, but not base damage, correlated with acute lung injury. Analysis of purified alveolar type 2 preparations from hyperoxic mice indicated that strand breaks preferentially affected this cell type.
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