Parenteral injection of the cytokines interleukin-1 and tumor necrosis factor, or of endotoxin (lipopolysaccharide), protects rats against lethal pulmonary oxygen toxicity. To determine the potential importance of manganese superoxide dismutase (MnSOD) in this model, we measured MnSOD mRNA and activity in lung. In addition, we confirmed that increases in activities were related to changes in MnSOD protein, which was measured using an enzyme-linked immunosorbentassay (ELISA) technique. After cytokine or endotoxin administration, increases in lung MnSOD mRNA occurred promptly (4 h), with or without hyperoxic exposure. In parallel, lung MnSOD protein and activity were increased after 24 h, and protein levels remained elevated after 52 h. MnSOD activity and protein levels were closely correlated. Neither lung copper-zinc superoxide dismutase (CuZnSOD) mRNA nor activity increased following administration of cytokines. Small increases in CuZnSOD mRNA, which did not exceed those in beta-actin mRNA, occurred early (4 h) after endotoxin, but CuZnSOD activity was unchanged. Immunohistochemistry was used to demonstrate in which cell types the increase in MnSOD protein occurred after cytokine or endotoxin administration. In agreement with ELISA findings, immunoreactive MnSOD appeared to be increased in lung parenchyma, but not in lung neutrophils, 24 h after cytokine or endotoxin treatment. MnSOD was heavily concentrated in alveolar type II cells. However, the numbers of surfactant protein D-positive (type II) cells in lung sections did not appear to be increased after treatment with cytokines or endotoxin. We conclude that early and sustained increases in endogenous MnSOD, but not CuZnSOD or other antioxidant enzymes, are associated with protection of rat lungs against hyperoxic damage by cytokines or endotoxin.