PJ Lee, J Alam, SL Sylvester, N Inamdar, L Otterbein and AM Choi
Division of Pulmonary and Critical Care, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.

Using hyperoxia as a model of oxidant-induced lung injury in the rat, we explored the regulation of heme oxygenase-1 (HO-1) expression in vivo and in vitro. We demonstrate marked increase of HO-1 messenger ribonucleic acid (mRNA) levels in rat lungs after hyperoxia. Increased HO-1 mRNA expression correlated with increased HO-1 protein and enzyme activity. Immunohistochemical studies of the rat lung after hyperoxia showed increased HO-1 expression in a variety of cell types, including the bronchoalveolar epithelium and interstitial and inflammatory cells. We then examined the regulation of HO-1 expression in vitro after hyperoxia and observed increased HO-1 gene expression in various cultured cells including epithelial cells, fibroblasts, macrophages, and smooth muscle cells. Increased HO-1 mRNA expression correlated with increased HO-1 protein in vitro, and resulted from increased gene transcription and not from increased mRNA stability. We show that transcriptional activation of the HO-1 gene by hyperoxia requires cooperation between the HO-1 promoter and an enhancer fragment located 4 kb upstream from its transcription site. Increased HO-1 gene transcription was associated with increased activator protein-1 (AP-1) binding activity and supershift of the AP-1 complex by antibodies to c- Fos and c-Jun after hyperoxia. Taken together, our data suggest that AP- 1 activation may represent one mechanism mediating hyperoxia-induced HO- 1 gene transcription.

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