VULNERABILITY OF THE HUMAN AIRWAY EPITHELIUM TO HYPEROXIA - CONSTITUTIVE EXPRESSION OF THE CATALASE GENE IN HUMAN BRONCHIAL EPITHELIAL-CELLS DESPITE OXIDANT STRESS

Although catalase is a major intracellular antioxidant, the expression of the human catalase gene appears to be limited in the airway epithe lium, making these cells vulnerable to oxidant stress. The basis for t his limited gene expression was examined by evaluation of the expressi on of the endogenous gene in human bronchial epithelial cells in respo nse to hyperoxia. Hyperoxia failed to upregulate endogenous catalase g ene expression, in contrast to a marked increase in expression of the heat shock protein gene. Sequence analysis of 1.7 kb of the flanking r egion of the human catalase gene showed features of a ''housekeeping'' gene (no TATA box, high GC content, multiple CCAAT boxes, and transcr iption start sites). Transfection of human bronchial epithelial cells with fusion genes composed of various lengths of the catalase 5'-flank ing region and luciferase as a reporter gene showed low level constitu tive promoter activity that did not change after exposure to hyperoxia . Importantly, using a replication-deficient recombinant adenoviral ve ctor containing the human catalase cDNA, levels of catalase were signi ficantly increased in human airway epithelial cells and this was assoc iated with increased survival of the cells when exposed to hyperoxia. These observations provide a basis for understanding the sensitivity o f the human airway epithelium to oxidant stress and a strategy for pro tecting the epithelium from such injury.