title: Lipid hydroperoxide formation regulates postnatal rat lung cell apoptosis and alveologenesis.
abstract: An acute increase in oxygen tension after birth imposes an oxidative stress upon the lung. We hypothesized that the resultant increase in reactive oxygen species, specifically lipid hydroperoxides, would trigger postnatal alveologenesis and physiological lung cell apoptosis in the neonatal rat. Neonatal rats were either untreated or treated daily with subcutaneous vehicle or diphenyl phenyl diamine, a scavenger of lipid hydroperoxides and inhibitor of lipid peroxidation, from day 1 to 6 of life. Alveolar formation and physiological lung cell apoptosis were assessed by morphometry, immunohistochemistry, and Western blot analyses on day 7 samples. Substitution experiments were conducted using the prototypic lipid hydroperoxide t-butylhydroperoxide. At a minimum effective dose of 15μg/g body wt, treatment with diphenyl phenyl diamine resulted in a significant increase in tissue fraction and mean linear intercept and significant reductions in small peripheral blood vessels, secondary crest formation, lung and secondary crest cell DNA synthesis, and estimated alveolar number. Decreased numbers of apoptotic type II pneumocytes and mesenchymal cells, and decreased contents of proapoptotic cleaved caspase-3 and -7 and cytoplasmic cytochrome c, and an increase in antiapoptotic Bcl-xL were found in lungs treated with diphenyl phenyl diamine. A prevention of selected changes induced by diphenyl phenyl diamine was observed with concurrent treatment with intraperitoneal t-butylhydroperoxide, at a minimally effective dose of 187μg/g body wt. We conclude that oxidative stress after birth induces lipid hydroperoxide formation, which, in turn, triggers postnatal alveologenesis and physiological lung cell apoptosis in the neonatal rat.
authors.affiliation: Lung Biology Programme, Physiology & Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada.
authors.forename: Mobin
authors.initials: M
authors.lastname: Jamal
authors.forename: Azhar
authors.initials: A
authors.lastname: Masood
authors.forename: Rosetta
authors.initials: R
authors.lastname: Belcastro
authors.forename: Lianet
authors.initials: L
authors.lastname: Lopez
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Jaques
authors.initials: J
authors.lastname: Belik
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
authors.forename: A
authors.initials: A
authors.lastname: Keith Tanswell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010655:Phenylenediamines / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D051381:Rats
chemical_list: D008054:Lipid Peroxides; D010655:Phenylenediamines; C004845:N,N'-diphenyl-4-phenylenediamine