Oxidative stress has been increasingly implicated in the pathogenesis of lung diseases. Antioxidant mechanisms and their regulation are poorly characterized in the human lung, but they may be important in the development and progression of pulmonary diseases. The present study was designed to investigate the regulation of the most important antioxidant enzymes (AOEs), superoxide dismutases (MnSOD, CuZnSOD), catalase, and glutathione peroxidase (GPx), in human lung cells by exposing them to agents and states (cytokines, asbestos fibers, oxidants, and hyperoxia), which may play an important role in the pathogenesis of lung diseases.
Enzyme regulation was investigated in cultured human bronchial epithelial cells (BEAS-2B), pleural mesothelial cells (MET-5A), alveolar macrophages, monocytes, and neutrophils. Enzyme expression was assessed at the level of mRNA, protein, and/or activity. Cell injury was measured by lactate dehydrogenase (LDH) release and/or depletion of high-energy nucleotides. Copper-zinc superoxide dismutase was constitutively expressed in all cell types investigated. The specific activity of MnSOD was quite low, but similar in all cell types. It was induced by TNF-α but not by high oxygen tension or asbestos fibers in BEAS-2B and MET-5A cells, respectively. Induction of MnSOD by TNF-α offered no protection against subsequent oxidant exposure. Catalase, glutathione peroxidase and reductase were constitutively expressed in BEAS-2B cells, with no change during exposure to any agent. The activity of catalase was highest in neutrophils, whereas glutathione levels and enzymes of the glutathione cycle were highest in monocytes. Catalase was the main scavenger of exogenous H2O2 in alveolar macrophages and also appeared to explain the high resistance of neutrophils against exogenous H2O2. During the respiratory burst of alveolar macrophages, the glutathione redox cycle was mainly responsible for the maintenance of cellular integrity. Low levels of glutathione and related enzymes may account for the short survival of human neutrophils.
In conclusion, MnSOD is induced by TNF-α, but cytokine-induced MnSOD does not protect lung cells against oxidant-induced damage. The enzymes associated with the scavenging of H2O2 are not upregulated by cytokines or oxidants, but they play an important role in scavenging of both exogenous H2O2 and endogenous oxidants in a cell-specific manner. Because transformed cell lines or cell culture conditions for primary cells were used, the results should be extrapolated with caution with respect to the situation in vivo.