PULMONARY APOPTOSIS IN AGED AND OXYGEN-TOLERANT RATS EXPOSED TO HYPEROXIA

Accumulating evidence demonstrates that genotoxic and oxidant stress c an induce programmed cell death or apoptosis in cultured cells. Howeve r, little is known about whether oxidative stress resulting from the d eleterious effects of hyperoxia can induce apoptosis in vivo and even less is known regarding the functional significance of apoptosis in vi vo in response to hyperoxia. Using hyperoxia as a model of oxidant-ind uced lung injury in the rat, we show that hyperoxic stress results in marked apoptotic signals in the lung. Lung tissue sections obtained fr om rats exposed to hyperoxia exhibit increased apoptosis in a time-dep endent manner by terminal transferase dUTP nick end labeling assays. T o examine whether hyperoxia-induced apoptosis in the lung correlated w ith the extent of lung injury or tolerance (adaptation) to hyperoxia, we investigated the pattern of apoptosis with a rat model of age-depen dent tolerance to hyperoxia. We show that apoptosis is associated with increased survival of aged rats to hyperoxia and with decreased level s of lung injury as measured by the volume of pleural effusion, wet-to -dry lung weight, and myeloperoxidase content in aged rats compared wi th young rats after hyperoxia. We also examined this relationship in a n alternate model of tolerance to hyperoxia. Lipopolysaccharide (LPS)t reated young rats not only demonstrated tolerance to hyperoxia but als o exhibited a significantly lower apoptotic index compared with saline -treated rats after hyperoxia. To further separate the effects of agin g and tolerance, we show that aged rats pretreated with LPS did not ex hibit a significant level of tolerance against hyperoxia. Furthermore, similar to the hyperoxia-tolerant LPS-pretreated young rats, the nont olerant LPS-pretreated aged rats also exhibited a significantly reduce d apoptotic index compared with aged rats exposed to hyperoxia alone. Taken together, our data suggest that hyperoxia-induced apoptosis in v ivo can be modulated by both aging and tolerance effects. We conclude that there is no overall relationship between apoptosis and tolerance.