GLUTATHIONE LEVELS PLAY A ROLE IN CIGARETTE SMOKE-INDUCED CELL-PROLIFERATION IN THE RAT LUNG

To investigate the role of glutathione (GSH), an important cellular ox idant defense mediator, in cellular proliferation induced by cigarette smoke exposure, we utilized two experimental protocols. The first pro tocol was designed with four groups of rats. Two groups were pretreate d with diethyl maleate (DEM) to reduce tissue GSH levels. One nontreat ed and one DEM-treated group received cigarette smoke exposure; the ot her two groups received sham smoke exposure only. For the second proto col we used a lung explant system, and in addition to smoke- and sham smoke-exposed groups, we supplemented cellular GSH levels with GSH add ed to the medium. Cell proliferation was assessed by cell labeling wit h 5-bromo-2'-deoxyuridine (BrdU). We found that, in the intact rat, ci garette smoke induced cell proliferation in the airway epithelium and walls and in the vessel walls; GSH depletion induced or increased this proliferative effect in airway walls and in the vascular endothelium and walls. In the lung explants, cigarette smoke also induced cell pro liferation in airway epithelium and airway and vessel walls, and GSH s upplementation reduced proliferation in both control and smoke-exposed airway epithelium. In the intact animals, smoke had no effect on tiss ue GSH either immediately or after 24 h. However, exposure of the expl ants to cigarette smoke exposure increased GSH after 24 h. We conclude that (I) cigarette smoke-induced cellular proliferation is a direct e ffect of cigarette smoke that probably does not require the presence o f smoke-evoked inflammatory cells, and (2) smoke-induced cell prolifer ation is related, at least partially, to the level of GSH and, by impl ication, to the balance between oxidants and antioxidants in the tissu es.