Impaired accumulation of granulocytes in the lung during ozone adaptation

Respiratory alterations induced by an acute exposure to ozone (O-3) paradox ically resolve during multiday exposure. This adaptation is characteristica lly accompanied by a gradual attenuation of lung neutrophilia. As maintenan ce of neutrophilia at the site of inflammation is due to cytokine-mediated delayed neutrophil apoptosis, which is associated with reduced levels of Ba x, a proapoptotic protein, we sought to determine whether defects in these mechanisms could account for O-3 adaptation. Lung granulocytes obtained at different time points from calves exposed to 0.75 ppm O-3 for 12 h/d for 7 consecutive days neither showed enhancement of survival nor Bax deficiency, when compared to blood granulocytes. To further investigate the effects of an exogenous oxidative stress on neutrophil survival, human granulocytes w ere treated with hydrogen peroxide alone, or in combination with granulocyt e/ macrophage colony-stimulating factor, an antiapoptotic cytokine. Both tr eatments led to rapid apoptosis associated with downregulation of Bcl-x(L) and Bcl-2, two antiapoptotic proteins. This study shows that O-3 adaptation is associated with a failure in the mechanisms leading to accumulation of neutrophils at the site of inflammation, and suggests that this defect is d ue to direct proapoptotic effects of exogenous oxidative stress on granuloc ytes. (C) 2001 Elsevier Science Inc.