Reactive oxygen species (ROS) are mediators of chronic tissue damage and fibrosis. Endogenous antioxidants may increase in response to oxidants and reduce tissue injury. We investigated the antioxidant response of the lungs to the chronic release of ROS, as occurs in the immune-specific granulomatous inflammation of chronic beryllium disease (CBD), and compared it with that in healthy controls and individuals exposed to cigarette smoke. The antioxidants superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione (GSH) were quantitated in lung epithelial lining fluid (ELF) and serum from control subjects (n = 10), cigarette smokers (n = 8), and individuals with CBD (n = 9). GPx activity and extracellular GPx (eGPx) protein were increased in the ELF of subjects with CBD in comparison with that of control subjects and smokers (eGPx in ELF: controls, 1.3 +/- 0.2 microgram/ml, smokers, 1.9 +/- 0.3 microgram/ml, CBD, 3.8 +/- 0.8 microgram/ml; p = 0.002; GPx U/ml ELF, controls 1.4 +/- 0.3, smokers 1.8 +/- 0.4, CBD, 4.5 +/- 1, p = 0.02). Smokers' ELF had higher levels of GSH than that of controls, but CBD patients' ELF contained much more GSH than that of either controls or smokers (p < 0.001). Increases in GSH were correlated with eGPx, indicating similar inducing mechanisms for these antioxidants. Thus, coordinate augmentation of the glutathione antioxidant system occurs in granulomatous lung inflammation.