Abstract 408 Effects of Oxygen on Lung Oxidant/Antioxidant Balance Poster Symposium, Sunday, 5/2

Treatment with supplemental oxygen remains as the mainstay of supportive care in patients with lung disease. Although therapy with supplemental oxygen is life-sustaining, hyperoxia may injure the lung and methods to support or enhance antioxidant defense mechanisms have been sought. Heme oxygenase (HO) catalyzes the first step in metabolism of heme to biliverdin and bilirubin, with concomitant production of CO and liberation of heme-bound iron. Some investigators have proposed that the inducible isoform, HO-1, may contribute to adaptive responses to oxidant stresses, in part through the production of bilirubin, which can exhibit antioxidant activities. In previous studies, lung HO-1 mRNA levels and HO activities were induced in animals exposed to hyperoxia, whereas HO-2 knockout mice were more susceptible to hyperoxic lung injury. To test the hypothesis that increased expression of HO-1 contributes to antioxidant defense functions and resistance to hyperoxic lung injury in vivo, we generated a line of transgenic mice that express the rat spleen HO-1 cDNA driven by a human surfactant protein C promoter. HO activities (1123 ± 204 vs. 407 ± 47 pmol of bilirubin produced/min/g lung) and HO-1 protein and mRNA levels were greater in the lungs of the transgenic animals than in the lungs from control animals. The transgenic animals were more susceptible to lung injury in response to hyperoxia (lung weights, 10.66 ± 0.95 vs. 7.67 ± 0.67 mg lung/g animal by 96 h). Hyperoxia increased lung HO activities and HO-1 mRNA levels in the control animals, as has been reported previously, but message levels and HO activities in the lungs of transgenic animals were diminished by hyperoxia (1238 ± 196, 612 ± 103, and 527 ± 100 pmol/min/g lung at 24, 48 and 72 h of hyperoxia, respectively, n=7-12). HO-1 expression in air-breathing transgenic animals appeared by immunohistochemistry to be predominantly in lung type II cells, but expression in type II cells had largely disappeared by 48 h of hyperoxia. Increased HO-1 expression in both transgenic and wild-type animals exposed to hyperoxia appeared to be associated with alveolar macrophages. These findings suggest that protective effects of HO-1 induction in vivo, if present, may be cell-specific and efforts to enhance antioxidant defense functions will need to be regulated in a cell-specific manner. Supported by HD01124 and HD27823 from the National Institutes of Health.