METALLOTHIONEIN IN THE LUNG--THE ROLE AS AN ANTIOXIDANT

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This project proposes to evaluate the roles of lung metallothioneins (MTs) as free radical scavengers and lipid peroxidation inhibitors. We have obtained preliminary data that multiple interferon inducers not only suppress pulmonary hyperoxic lipid peroxidation but also protect rats from hyperoxia. We propose that this protection is associated with increased MTs in lung since MTs content increase with interferon inducers in various organs and probably in lung, too. Although other antioxidants might also increase with these agents, we did not observe a common increase of pulmonary superoxide dismutase (SOD) activities and the increased catalase activities were not expected with these agents examined. The preliminary results also showed that MTs are relatively strong inhibitors of lipid peroxidation as well as being potent hydroxyl radical scavengers. Our first approach will be to correlate the lung damages and hyperoxic (greater than 95% O2) mortality with the quantity of lung MTs which we will attempt to modulate by various agents such as interferon inducers and metals. Secondly, we will estimate the biological activities of MTs such as SOD-like activity, hydroxyl radical activity and lipid peroxidation inhibition activity, after determining the content of each isoform of MT, identifying metal species and quantifying the metal content associated with each isoform. Our third approach is to isolate various cell types from rat lung and determine their MTs contents and susceptibility to hyperoxia after modulating MTs contents. The mechanism by which MTs increase with agents also will be attempted to elucidate by determining the turnover rate of MTs and by measuring the rate of MT mRNA synthesis. We anticipate that the results after performing these approaches give us the solid basis to conclude the role of MTs as a significant antioxidant in lung to protect at least against hyperoxic damage.