title: DHA suppresses chronic apoptosis in the lung caused by perinatal inflammation.
abstract: We have previously shown that an adverse perinatal environment significantly alters lung growth and development and results in persistently altered cardiopulmonary physiology in adulthood. Our model of maternal LPS treatment followed by 14 days of neonatal hyperoxia exposure causes severe pulmonary disease characterized by permanent decreases in alveolarization and diffuse interstitial fibrosis. The current investigations tested the hypothesis that dysregulation of Notch signaling pathways contributes to the permanently altered lung phenotype in our model and that the improvements we have observed previously with maternal docosahexaenoic acid (DHA) supplementation are mediated through normalization of Notch-related protein expression. Results indicated that inflammation (IL-6 levels) and oxidation (F2a-isoprostanes) persisted through 8 wk of life in mice exposed to LPS/O2 perinatally. These changes were attenuated by maternal DHA supplementation. Modest but inconsistent differences were observed in Notch-pathway proteins Jagged 1, DLL 1, PEN2, and presenilin-2. We detected substantial increases in markers of apoptosis including PARP-1, APAF-1, caspase-9, BCL2, and HMGB1, and these increases were attenuated in mice that were nursed by DHA-supplemented dams during the perinatal period. Although Notch signaling is not significantly altered at 8 wk of age in mice with perinatal exposure to LPS/O2, our findings indicate that persistent apoptosis continues to occur at 8 wk of age. We speculate that ongoing apoptosis may contribute to persistently altered lung development and may further enhance susceptibility to additional pulmonary disease. Finally, we found that maternal DHA supplementation prevented sustained inflammation, oxidation, and apoptosis in our model.
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Mehboob
authors.initials: M
authors.lastname: Ali
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Heyob
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Rheinische Friedrich-Wilhlems-University, University Medical Center, Bonn, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Velten
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Trent E
authors.initials: TE
authors.lastname: Tipple
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University, Columbus, Ohio; lynette.rogers@nationwidechildrens.org.
authors.forename: Lynette K
authors.initials: LK
authors.lastname: Rogers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism; D018496:Hyperoxia / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology*; D008171:Lung Diseases / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018384:Oxidative Stress / Q000187:drug effects; D053764:Presenilin-1 / Q000378:metabolism; D053766:Presenilin-2 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C580804:presenilin 1, mouse; D004281:Docosahexaenoic Acids
keywords: docosahexaenoic acid, apoptosis; maternal inflammation; neonatal hyperoxia