title: Sustained hyperoxia-induced NF-κB activation improves survival and preserves lung development in neonatal mice.
abstract: Oxygen toxicity contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Neonatal mice exposed to hyperoxia develop a simplified lung structure that resembles BPD. Sustained activation of the transcription factor NF-κB and increased expression of protective target genes attenuate hyperoxia-induced mortality in adults. However, the effect of enhancing hyperoxia-induced NF-κB activity on lung injury and development in neonatal animals is unknown. We performed this study to determine whether sustained NF-κB activation, mediated through IκBβ overexpression, preserves lung development in neonatal animals exposed to hyperoxia. Newborn wild-type (WT) and IκBβ-overexpressing (AKBI) mice were exposed to hyperoxia (>95%) or room air from day of life (DOL) 0-14, after which all animals were kept in room air. Survival curves were generated through DOL 14. Lung development was assessed using radial alveolar count (RAC) and mean linear intercept (MLI) at DOL 3 and 28 and pulmonary vessel density at DOL 28. Lung tissue was collected, and NF-κB activity was assessed using Western blot for IκB degradation and NF-κB nuclear translocation. WT mice demonstrated 80% mortality through 14 days of exposure. In contrast, AKBI mice demonstrated 60% survival. Decreased RAC, increased MLI, and pulmonary vessel density caused by hyperoxia in WT mice were significantly attenuated in AKBI mice. These findings were associated with early and sustained NF-κB activation and expression of cytoprotective target genes, including vascular endothelial growth factor receptor 2. We conclude that sustained hyperoxia-induced NF-κB activation improves neonatal survival and preserves lung development. Potentiating early NF-κB activity after hyperoxic exposure may represent a therapeutic intervention to prevent BPD.
authors.affiliation: Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado;
authors.forename: Sarah
authors.initials: S
authors.lastname: McKenna
authors.affiliation: Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado;
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Michaelis
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
authors.forename: Fadeke
authors.initials: F
authors.lastname: Agboke
authors.affiliation: Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado;
authors.forename: Thanh
authors.initials: T
authors.lastname: Liu
authors.affiliation: Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado;
authors.forename: Kristie
authors.initials: K
authors.lastname: Han
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Dennery
authors.affiliation: Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado; clyde.wright@ucdenver.edu.
authors.forename: Clyde J
authors.initials: CJ
authors.lastname: Wright
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005786:Gene Expression Regulation / Q000502:physiology; D018496:Hyperoxia / Q000378:metabolism* / Q000401:mortality; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000254:growth & development* / Q000473:pathology; D055370:Lung Injury / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: IκBβ hyperoxic lung injury; NF-κB; bronchopulmonary dysplasia; lung development
references.citation: Pediatr Res. 2006 Feb;59(2):185-90
references.pmid: 16439576
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1014-9
references.pmid: 10655476
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Jul;293(1):L142-50
references.pmid: 17400600
references.citation: J Immunol. 2011 Sep 1;187(5):2740-7
references.pmid: 21775686
references.citation: Birth Defects Res B Dev Reprod Toxicol. 2003 Apr;68(2):121-4
references.pmid: 12866703
references.citation: Pediatrics. 2011 Jul;128(1):111-26
references.pmid: 21646264
references.citation: Am J Physiol Lung Cell Mol Physiol. 2002 Sep;283(3):L555-62
references.pmid: 12169575
references.citation: Circulation. 2005 Oct 18;112(16):2477-86
references.pmid: 16230500
references.citation: Exp Lung Res. 1998 Sep-Oct;24(5):685-702
references.pmid: 9779377
references.citation: Free Radic Biol Med. 2004 Mar 15;36(6):782-801
references.pmid: 14990357
references.citation: Science. 1996 Nov 1;274(5288):782-4
references.pmid: 8864118
references.citation: Development. 1999 Mar;126(6):1149-59
references.pmid: 10021335
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Mar;296(3):L296-306
references.pmid: 19074556
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Mar;298(3):L315-23
references.pmid: 20008116
references.citation: Am J Physiol Heart Circ Physiol. 2009 May;296(5):H1296-304
references.pmid: 19304943
references.citation: Semin Fetal Neonatal Med. 2010 Aug;15(4):223-9
references.pmid: 20430708
references.citation: Biochim Biophys Acta. 1999 Jan 11;1448(3):349-62
references.pmid: 9990287
references.citation: Pediatr Res. 1999 Dec;46(6):641-3
references.pmid: 10590017
references.citation: J Thorac Cardiovasc Surg. 2003 Mar;125(3):650-60
references.pmid: 12658209
references.citation: J Biol Chem. 2012 Feb 24;287(9):6230-9
references.pmid: 22223647
references.citation: Nat Cell Biol. 2005 Sep;7(9):921-3
references.pmid: 16136188
references.citation: Cell. 1995 Feb 24;80(4):573-82
references.pmid: 7867065
references.citation: Free Radic Biol Med. 2006 Jul 1;41(1):4-18
references.pmid: 16781448
references.citation: Am J Respir Cell Mol Biol. 1998 Apr;18(4):538-47
references.pmid: 9533942
references.citation: Annu Rev Physiol. 1986;48:721-31
references.pmid: 3518622
references.citation: Exp Lung Res. 1997 Nov-Dec;23(6):537-52
references.pmid: 9358235
references.citation: J Clin Invest. 2000 Sep;106(6):783-91
references.pmid: 10995789
references.citation: Science. 2002 Nov 8;298(5596):1241-5
references.pmid: 12424381
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Aug 15;305(4):L301-11
references.pmid: 23812632
references.citation: Am J Physiol. 1999 May;276(5):L776-85
references.pmid: 10330034
references.citation: J Immunol. 2010 Oct 15;185(8):4896-903
references.pmid: 20861353
references.citation: Isr Med Assoc J. 2000 May;2(5):365-9
references.pmid: 10892391
references.citation: N Engl J Med. 2013 May 30;368(22):2094-104
references.pmid: 23642047
references.citation: Annu Rev Physiol. 2005;67:623-61
references.pmid: 15709973
references.citation: Free Radic Biol Med. 2004 Nov 15;37(10):1670-9
references.pmid: 15477018
references.citation: Arch Dis Child. 1960 Dec;35:544-7
references.pmid: 13726619
references.citation: Am J Physiol. 1998 Jul;275(1):L110-7
references.pmid: 9688942
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Sep;279(3):L600-7
references.pmid: 10956636
references.citation: Thorax. 1982 Aug;37(8):580-3
references.pmid: 7179186
references.citation: J Exp Med. 1998 Sep 21;188(6):1055-62
references.pmid: 9743524
references.citation: Paediatr Respir Rev. 2013 Sep;14(3):173-9
references.pmid: 23523392
references.citation: Respir Res. 2011 Oct 10;12:134
references.pmid: 21985298
references.citation: J Clin Invest. 2004 Sep;114(5):669-78
references.pmid: 15343385
references.citation: Lancet. 1993 Oct 23;342(8878):1023-4
references.pmid: 8105265
references.citation: Am J Respir Cell Mol Biol. 2013 May;48(5):578-88
references.pmid: 23328640
references.citation: J Exp Med. 2010 Nov 22;207(12):2621-30
references.pmid: 20975042
references.citation: Pediatrics. 2010 Sep;126(3):443-56
references.pmid: 20732945
references.citation: Nature. 2010 Aug 26;466(7310):1115-9
references.pmid: 20740013
references.citation: Pediatrics. 2009 Jun;123(6):1562-73
references.pmid: 19482769
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Jul;291(1):L119-27
references.pmid: 16443642
references.citation: Am J Respir Cell Mol Biol. 2014 Feb;50(2):429-38
references.pmid: 24066808
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Feb;278(2):L393-8
references.pmid: 10666124
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Mar;278(3):L492-503
references.pmid: 10710521
references.citation: Lab Invest. 1975 May;32(5):619-35
references.pmid: 1092910
references.citation: J Biol Chem. 2001 Jan 5;276(1):569-75
references.pmid: 11034997
references.citation: Dev Dyn. 2008 Feb;237(2):328-38
references.pmid: 18161062
references.citation: N Engl J Med. 2010 May 27;362(21):1959-69
references.pmid: 20472937
references.citation: Am J Physiol Lung Cell Mol Physiol. 2012 May 15;302(10):L1023-36
references.pmid: 22367785
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1978 Nov;45(5):699-704
references.pmid: 730565
references.citation: J Biol Chem. 1997 Aug 15;272(33):20646-9
references.pmid: 9252381
references.citation: Nat Med. 2003 May;9(5):575-81
references.pmid: 12692538
references.citation: Cell. 2008 Feb 8;132(3):344-62
references.pmid: 18267068
references.citation: Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
references.pmid: 17183360