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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.
AuthorsFumihiko Namba, Hayato Go, Jennifer A Murphy, Ping La, Guang Yang, Shaon Sengupta, Amal P Fernando, Mekdes Yohannes, Chhanda Biswas, Suzanne L Wehrli, Phyllis A Dennery
JournalPloS one (PLoS One) Vol. 9 Issue 3 Pg. e90936 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID24599172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Poly Adenosine Diphosphate Ribose
  • DNA
  • Heme Oxygenase-1
  • Poly(ADP-ribose) Polymerases
Topics
  • Animals
  • Animals, Newborn
  • Apoptosis
  • Carcinogenesis (pathology)
  • Cell Proliferation
  • Cytoprotection
  • DNA (metabolism)
  • DNA Damage
  • Disease Models, Animal
  • Epithelial Cells (enzymology, pathology)
  • Heme Oxygenase-1 (metabolism)
  • Humans
  • Hydrolysis
  • Hyperoxia (enzymology, pathology, physiopathology)
  • Lung (enzymology, pathology, physiopathology)
  • Lung Injury (enzymology, pathology, physiopathology)
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Transgenic
  • Oxidation-Reduction
  • Oxidative Stress
  • Poly Adenosine Diphosphate Ribose (metabolism)
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Pulmonary Alveoli (enzymology, pathology, physiopathology)
  • Respiratory Function Tests
  • Subcellular Fractions (drug effects, enzymology)

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