TY - JOUR
T1 - Regulation of Heme Oxygenase-1 Expression in Vivo and in Vitro in Hyperoxic Lung Injury
AU - Lee, Patty J.
AU - Alam, Jawed
AU - Sylvester, Sherrie L.
AU - Inamdar, Nilufar
AU - Otterbein, Leo
AU - Choi, Augustine M.K.
PY - 1996
Y1 - 1996
N2 - 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.
AB - 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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U2 - 10.1165/ajrcmb.14.6.8652184
DO - 10.1165/ajrcmb.14.6.8652184
M3 - Article
C2 - 8652184
AN - SCOPUS:0030160391
SN - 1044-1549
VL - 14
SP - 556
EP - 568
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
IS - 6
ER -