Endothelin-1 and O-2-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 e xpression in the newborn lung. Endothelin-1 expression and 8-isoprostane co ntent (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 morp hology and pulmonary hypertension, as assessed by right ventricular hypertr ophy, after a 14-d exposure to 60% O-2. The antioxidant and lipid hydropero xide scavenger, U74389G (10 mg/kg), given by daily i.p. injection prevented O-2-dependent right ventricular hypertrophy (p < 0.05 compared with vehicl e treated controls), but had no effect on abnormal lung morphology. Additio nally, we observed that 8-isoprostane caused marked endothelin-l mRNA up-re gulation 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 l ikely that the bioactive lipid peroxidation product, 8-isoprostane, plays a key role in pathologic endothelin-1 expression and pulmonary hypertension during oxidant stress.