title: Endothelin-1 and O2-mediated pulmonary hypertension in neonatal rats: a role for products of lipid peroxidation.
abstract: We hypothesized that reactive O2 species, or their intermediary products, generated during exposure to elevated O2 lead to pathologic endothelin-1 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% O2. The antioxidant and lipid hydroperoxide scavenger, U74389G (10 mg/kg), given by daily i.p. injection prevented O2-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-1 mRNA up-regulation in vitro in primary rat fetal lung cell cultures. We conclude that reactive O2 species, or their bioactive intermediaries, are causative in O2-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.
authors.affiliation: Medical Research Council Group in Lung Development and Lung Biology Programme, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
authors.forename: R P
authors.initials: RP
authors.lastname: Jankov
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.forename: J
authors.initials: J
authors.lastname: Cabacungan
authors.forename: R
authors.initials: R
authors.lastname: Belcastro
authors.forename: H
authors.initials: H
authors.lastname: Frndova
authors.forename: S J
authors.initials: SJ
authors.lastname: Lye
authors.forename: A K
authors.initials: AK
authors.lastname: Tanswell
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019332:Endothelin-1 / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism*; D015227:Lipid Peroxidation; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D017382:Reactive Oxygen Species; D010100:Oxygen