Endothelin-1 and O2-mediated pulmonary hypertension in neonatal rats:: A role for products of lipid peroxidation

We hypothesized that reactive O-2 species, or their intermediary products, generated during exposure to elevated O-2 lead to pathologic endothelin-l expression in the newborn lung. Endothelin-1 expression and 8-isoprostane content (an in vivo marker of lipid peroxidation) were examined and found to be elevated (p < 0.05) in the lungs of newborn rats with abnormal lung morphology and pulmonary hypertension, as assessed by right ventricular hypertrophy, after a 14-d exposure to 60% O-2. The antioxidant and lipid hydroperoxide scavenger, U74389G (10 mg/kg), given by daily i.p. injection prevented O-2-dependent right ventricular hypertrophy (p < 0.05 compared with vehicle treated controls), but had no effect on abnormal lung morphology. Additionally, we observed that 8-isoprostane caused marked endothelin-l mRNA up-regulation in vitro in primary rat fetal lung cell cultures. We conclude that reactive O-2 species, or their bioactive intermediaries, are causative in O-2-mediated pulmonary hypertension and endothelin-1 up-regulation. It is likely that the bioactive lipid peroxidation product, 8-isoprostane, plays a key role in pathologic endothelin-1 expression and pulmonary hypertension during oxidant stress.