Age-dependent effect of ozone on pulmonary eicosanoid metabolism in rabbits and rats

Abstract

Acute exposures to ozone have previously been shown to cause quantitative changes in the spectrum of arachidonic acid (AA) metabolites in lung lavage fluid. Since age appears to be an important variable in the toxicity of inhaled ozone, we investigated its effect on ozone-induced changes in pulmonary eicosanoid metabolism. Rats and rabbits ranging in age from neonates to young adults were exposed either to air or to 1 ppm ozone for 2 hr. Lung lavage fluid was collected within 1 hr following exposure and analyzed for its content of selected eicosanoids. In both species, there was a pronounced effect of age on ozone-induced pulmonary eicosanoid metabolism. Ozone-exposed animals at the youngest ages examined had severalfold greater amounts of two products of the cyclooxygenase pathway, prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha), than did age-matched controls. This effect lessened and eventually disappeared as the animals grew toward adulthood. In rabbits, ozone also induced increases in 6-keto-prostaglandin F1 alpha and thromboxane B2, but these changes were of lesser magnitude and evident only in the youngest rabbits exposed. There was no observed effect of ozone on lung lavage content of leukothriene B4. Indices of nonspecific pulmonary damage, i.e., protein concentration in lung lavage fluid and total number and viability of lavaged lung cells, were affected by ozone exposure, but not in an age-dependent manner that correlated with changes in pulmonary eicosanoid metabolism. In vitro ozone exposure of lung macrophages from naive rabbits of the same age range as those exposed in vivo demonstrated that ozone is capable of stimulating the elaboration of PGF2 alpha and especially PGE2. However, the increase in lavage fluid PGE2 and PGF2 alpha caused by ozone inhalation could not be attributed to macrophage metabolism conclusively since elaboration of PGE2 and PGF2 alpha by cultured macrophages was not enhanced by prior in vivo ozone exposure. In an ancillary study it was shown that 15-hydroxyprostaglandin dehydrogenase (PGDH) activity in rabbit lung homogenates was not affected by prior exposure to ozone, indicating that the increase in lung lavage fluid eicosanoids that occurred in these animals could not be explained by inhibition of PGDH.