p53-independent induction of GADD45 and GADD153 in mouse lungs exposed to hyperoxia

Previous studies have shown that lungs of adult mice exposed to >95% oxygen have increased terminal deoxyribonucleotidyltransferase dUTP nick end-labe l staining and accumulate p53, the expression of which increases in cells e xposed to DNA-damaging agents. The present study was designed to determine whether hyperoxia also increased expression of the growth arrest and DNA da mage (GADD) gene 45 and GADD153, which are induced by genotoxic stress thro ugh p53-dependent and -independent pathways. GADD proteins have been shown to inhibit proliferation and stimulate DNA repair and/or apoptosis. GADD45 and GADD153 mRNAs were not detected in lungs exposed to room air but were d etected after 48 and 72 h of exposure to hyperoxia. In situ hybridization a nd immunohistochemistry revealed that hyperoxia increased GADD45 and GADD15 3 expression in the bronchiolar epithelium and GADD45 expression predominan tly in alveolar cells that were morphologically consistent with type II cel ls. Hyperoxia also increased GADD expression in p53-deficient mice. Termina l deoxyribonucleotidyltransferase dUTP nick end-label staining of lung cell s from p53 wild-type and p53-null mice exposed to hyperoxia for 48 h reveal ed that hyperoxia-induced DNA fragmentation was not modified by p53 deficie ncy. These studies are consistent with the hypothesis that hyperoxia-induce d DNA fragmentation is associated with the expression of GADD genes that ma y participate in DNA repair and/or apoptosis.