We previously reported that exposure of mice to hyperoxia is characterized by extensive lung cell necrosis and apoptosis, mild inflammatory response and by raised circulating levels of corticosterone. Administration of hydroxycortisone acetate during hyperoxia aggravated lung injury. Using adrenalectomized (ADX) and SHAM mice we studied the role of the glucocorticoids (GC) in hyperoxia-induced lung injury. Lung damage was attenuated in ADX mice as measured by lung weight, protein and cell content in bronchoalveolar lavage and as seen by light microscopy. Mortality was delayed by 10 hours. NF-B activity was significantly decreased in lungs of SHAM mice exposed to hyperoxia, but was preserved in ADX mice. Conserved NF-B activity in ADX mice correlated with decreased levels of IB-. In contrast, activator protein (AP)-1 activity increased similarly in both groups of mice. Levels of interleukin (IL)-6, a transcriptional target of NF-B, were higher in bronchoalveolar lavage (BAL) and serum of ADX compared to SHAM mice. However, the protective effect of adrenalectomy was not mediated by IL-6, since administration of recombinant human (rh) IL-6 to SHAM mice did not prevent lung damage. These results demonstrate that the adrenal response aggravates alveolar injury and is likely to be mediated by the decrease in NF-B function involved in cell survival.