title: Expression level and subcellular localization of heme oxygenase-1 modulates its cytoprotective properties in response to lung injury: a mouse model.
abstract: Premature infants exposed to hyperoxia suffer acute and long-term pulmonary consequences. Nevertheless, neonates survive hyperoxia better than adults. The factors contributing to neonatal hyperoxic tolerance are not fully elucidated. In contrast to adults, heme oxygenase (HO)-1, an endoplasmic reticulum (ER)-anchored protein, is abundant in the neonatal lung but is not inducible in response to hyperoxia. The latter may be important, because very high levels of HO-1 overexpression are associated with significant oxygen cytotoxicity in vitro. Also, in contrast to adults, HO-1 localizes to the nucleus in neonatal mice exposed to hyperoxia. To understand the mechanisms by which HO-1 expression levels and subcellular localization contribute to hyperoxic tolerance in neonates, lung-specific transgenic mice expressing high or low levels of full-length HO-1 (cytoplasmic, HO-1-FL(H) or HO-1-FL(L)) or C-terminally truncated HO-1 (nuclear, Nuc-HO-1-TR) were generated. In HO-1-FL(L), the lungs had a normal alveolar appearance and lesser oxidative damage after hyperoxic exposure. In contrast, in HO-1-FL(H), alveolar wall thickness with type II cell hyperproliferation was observed as well worsened pulmonary function and evidence of abnormal lung cell hyperproliferation in recovery from hyperoxia. In Nuc-HO-1-TR, the lungs had increased DNA oxidative damage, increased poly (ADP-ribose) polymerase (PARP) protein expression, and reduced poly (ADP-ribose) (PAR) hydrolysis as well as reduced pulmonary function in recovery from hyperoxia. These data indicate that low cytoplasmic HO-1 levels protect against hyperoxia-induced lung injury by attenuating oxidative stress, whereas high cytoplasmic HO-1 levels worsen lung injury by increasing proliferation and decreasing apoptosis of alveolar type II cells. Enhanced lung nuclear HO-1 levels impaired recovery from hyperoxic lung injury by disabling PAR-dependent regulation of DNA repair. Lastly both high cytoplasmic and nuclear expression of HO-1 predisposed to long-term abnormal lung cellular proliferation. To maximize HO-1 cytoprotective effects, therapeutic strategies must account for the specific effects of its subcellular localization and expression levels.
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Namba
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hayato
authors.initials: H
authors.lastname: Go
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Murphy
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: La
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Shaon
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Amal P
authors.initials: AP
authors.lastname: Fernando
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Mekdes
authors.initials: M
authors.lastname: Yohannes
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Chhanda
authors.initials: C
authors.lastname: Biswas
authors.affiliation: Small Animal Core, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Wehrli
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Dennery
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D063646:Carcinogenesis / Q000473:pathology; D049109:Cell Proliferation; D019610:Cytoprotection; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D018496:Hyperoxia / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D012129:Respiratory Function Tests; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology
chemical_list: D011064:Poly Adenosine Diphosphate Ribose; D004247:DNA; D051547:Heme Oxygenase-1; D011065:Poly(ADP-ribose) Polymerases