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 oxidant defense mediator, in cellular proliferation induced by cigarette smoke exposure, we utilized two experimental protocols. The first protocol was designed with four groups of rats. Two groups were pretreated with diethyl maleate (DEM) to reduce tissue GSH levels. One nontreated and one DEM-treated group received cigarette smoke exposure; the other two groups received sham smoke exposure only. For the second protocol we used a lung explant system, and in addition to smoke- and sham smoke-exposed groups, we supplemented cellular GSH levels with GSH added to the medium. Cell proliferation was assessed by cell labeling with 5-bromo-2'-deoxyuridine (BrdU). We found that, in the intact rat, cigarette 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 proliferation in airway epithelium and airway and vessel walls, and GSH supplementation reduced proliferation in both control and smoke-exposed airway epithelium. In the intact animals, smoke had no effect on tissue GSH either immediately or after 24 h. However, exposure of the explants to cigarette smoke exposure increased GSH after 24 h. We conclude that (I) cigarette smoke-induced cellular proliferation is a direct effect of cigarette smoke that probably does not require the presence of smoke-evoked inflammatory cells, and (2) smoke-induced cell proliferation is related, at least partially, to the level of GSH and, by implication, to the balance between oxidants and antioxidants in the tissues.