title: Chronic lung disease in preterm lambs: effect of daily vitamin A treatment on alveolarization.
abstract: Neonatal chronic lung disease is characterized by failed formation of alveoli and capillaries, and excessive deposition of matrix elastin, which are linked to lengthy mechanical ventilation (MV) with O(2)-rich gas. Vitamin A supplementation has improved respiratory outcome of premature infants, but there is little information about the structural and molecular manifestations in the lung that occur with vitamin A treatment. We hypothesized that vitamin A supplementation during prolonged MV, without confounding by antenatal steroid treatment, would improve alveolar secondary septation, decrease thickness of the mesenchymal tissue cores between distal air space walls, and increase alveolar capillary growth. We further hypothesized that these structural advancements would be associated with modulated expression of tropoelastin and deposition of matrix elastin, phosphorylated Smad2 (pSmad2), cleaved caspase 3, proliferating cell nuclear antigen (PCNA), VEGF, VEGF-R2, and midkine in the parenchyma of the immature lung. Eight preterm lambs (125 days' gestation, term approximately 150 days) were managed by MV for 3 wk: four were treated with daily intramuscular Aquasol A (vitamin A), 5,000 IU/kg, starting at birth; four received vehicle alone. Postmortem lung assays included quantitative RT-PCR and in situ hybridization, immunoblot and immunohistochemistry, and morphometry and stereology. Daily vitamin A supplementation increased alveolar secondary septation, decreased thickness of the mesenchymal tissue cores between the distal air space walls, and increased alveolar capillary growth. Associated molecular changes were less tropoelastin mRNA expression, matrix elastin deposition, pSmad2, and PCNA protein localization in the mesenchymal tissue core of the distal air space walls. On the other hand, mRNA expression and protein abundance of VEGF, VEGF-R2, midkine, and cleaved caspase 3 were increased. We conclude that vitamin A treatment partially improves lung development in chronically ventilated preterm neonates by modulating expression of tropoelastin, deposition of elastin, and expression of vascular growth factors.
authors.affiliation: Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah 84158, USA. kurt.albertine@hsc.utah.edu
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Albertine
authors.forename: Mar Janna
authors.initials: MJ
authors.lastname: Dahl
authors.forename: Linda W
authors.initials: LW
authors.lastname: Gonzales
authors.forename: Zheng-Ming
authors.initials: ZM
authors.lastname: Wang
authors.forename: Drew
authors.initials: D
authors.lastname: Metcalfe
authors.forename: Dallas M
authors.initials: DM
authors.lastname: Hyde
authors.forename: Charles G
authors.initials: CG
authors.lastname: Plopper
authors.forename: Barry C
authors.initials: BC
authors.lastname: Starcher
authors.forename: David P
authors.initials: DP
authors.lastname: Carlton
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bland
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002908:Chronic Disease; D019587:Dietary Supplements; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D008168:Lung / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D008171:Lung Diseases / Q000178:diet therapy* / Q000473:pathology / Q000503:physiopathology* / Q000662:veterinary*; D011247:Pregnancy; D047928:Premature Birth; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D011659:Pulmonary Gas Exchange; D012121:Respiration, Artificial; D012756:Sheep; D014333:Tropoelastin / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D014801:Vitamin A / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D014815:Vitamins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D014333:Tropoelastin; D042461:Vascular Endothelial Growth Factor A; D014815:Vitamins; D014801:Vitamin A; D004549:Elastin; D040301:Vascular Endothelial Growth Factor Receptor-2
references.citation: J Biochem. 1997 Aug;122(2):453-8
references.pmid: 9378726
references.citation: Am J Respir Cell Mol Biol. 2000 Sep;23(3):320-6
references.pmid: 10970822
references.citation: Am J Respir Crit Care Med. 2008 Aug 15;178(4):407-18
references.pmid: 18556628
references.citation: Pediatrics. 2000 Dec;106(6):1452-9
references.pmid: 11099603
references.citation: Anat Rec. 1991 Apr;229(4):495-8
references.pmid: 2048754
references.citation: Pediatr Pathol Mol Med. 2001 Sep-Oct;20(5):387-412
references.pmid: 11552739
references.citation: Pediatr Res. 2005 Sep;58(3):549-56
references.pmid: 16148072
references.citation: J Pediatr. 1978 Jan;92(1):101-4
references.pmid: 563434
references.citation: Am J Physiol. 1993 Dec;265(6 Pt 1):L521-48
references.pmid: 8279570
references.citation: Am J Respir Cell Mol Biol. 2001 Oct;25(4):507-14
references.pmid: 11694457
references.citation: Am J Respir Crit Care Med. 2005 Oct 1;172(7):899-906
references.pmid: 15976381
references.citation: Pediatrics. 2005 Mar;115(3):e249-54
references.pmid: 15713907
references.citation: Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1971-80
references.pmid: 11734454
references.citation: Am J Respir Cell Mol Biol. 1990 Oct;3(4):369-76
references.pmid: 2206540
references.citation: Semin Perinatol. 2003 Aug;27(4):281-7
references.pmid: 14510318
references.citation: Development. 1997 Oct;124(20):3943-53
references.pmid: 9374392
references.citation: Am J Clin Nutr. 1979 Oct;32(10):2143-9
references.pmid: 484533
references.citation: J Pediatr. 2005 Apr;146(4):469-73
references.pmid: 15812448
references.citation: N Engl J Med. 1999 Jun 24;340(25):1962-8
references.pmid: 10379020
references.citation: Am Rev Respir Dis. 1991 Feb;143(2):391-400
references.pmid: 1990959
references.citation: Am J Physiol. 1997 Mar;272(3 Pt 1):L452-60
references.pmid: 9124602
references.citation: Am J Respir Cell Mol Biol. 2000 Aug;23(2):162-7
references.pmid: 10919981
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Mar;288(3):L450-9
references.pmid: 15591412
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Jan;298(1):L23-35
references.pmid: 19854954
references.citation: J Biol Chem. 1996 May 10;271(19):11500-5
references.pmid: 8626709
references.citation: Am J Physiol Lung Cell Mol Physiol. 2002 Apr;282(4):L811-23
references.pmid: 11880308
references.citation: Pediatr Res. 2007 Jun;61(6):703-9
references.pmid: 17426644
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Feb;292(2):L537-49
references.pmid: 17071723
references.citation: J Appl Physiol (1985). 2004 Mar;96(3):1080-9
references.pmid: 14617528
references.citation: Circulation. 2005 Aug 2;112(5):727-36
references.pmid: 16043647
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Jul;285(1):L76-85
references.pmid: 12626336
references.citation: Pediatrics. 2002 Jul;110(1 Pt 1):143-51
references.pmid: 12093960
references.citation: Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1755-6
references.pmid: 11734417
references.citation: J Lab Clin Med. 1991 Mar;117(3):226-33
references.pmid: 2002279
references.citation: Am J Respir Cell Mol Biol. 2003 Jan;28(1):33-41
references.pmid: 12495930
references.citation: Am J Physiol. 1996 Feb;270(2 Pt 1):L305-10
references.pmid: 8780001
references.citation: Arch Dis Child. 1960 Dec;35:544-7
references.pmid: 13726619
references.citation: Pediatrics. 2006 Mar;117(3 Pt 2):S52-6
references.pmid: 16777823
references.citation: Endocrinology. 2007 Mar;148(3):1412-23
references.pmid: 17170094
references.citation: Am J Respir Crit Care Med. 1999 Oct;160(4):1333-46
references.pmid: 10508826
references.citation: Am J Respir Crit Care Med. 2006 Dec 15;174(12):1352-60
references.pmid: 17023731
references.citation: Pediatr Res. 2008 Mar;63(3):245-50
references.pmid: 18287961
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Sep;279(3):L600-7
references.pmid: 10956636
references.citation: Pediatr Res. 1997 Dec;42(6):744-9
references.pmid: 9396552
references.citation: Dev Dyn. 2008 Jan;237(1):62-74
references.pmid: 18058915
references.citation: J Appl Physiol (1985). 2004 Mar;96(3):1090-6
references.pmid: 14506099
references.citation: Respir Res. 2009 Aug 21;10:77
references.pmid: 19698107
references.citation: Pediatr Res. 2000 Jul;48(1):64-74
references.pmid: 10879802
references.citation: Am J Physiol Lung Cell Mol Physiol. 2002 Jul;283(1):L219-33
references.pmid: 12060580
references.citation: Am Rev Respir Dis. 1992 Jul;146(1):204-12
references.pmid: 1626805
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 Feb;286(2):L411-9
references.pmid: 14607780
references.citation: Am J Pathol. 2003 Dec;163(6):2575-84
references.pmid: 14633629
references.citation: Pediatr Res. 1985 Feb;19(2):185-8
references.pmid: 3982875
references.citation: Int J Exp Pathol. 2007 Dec;88(6):393-401
references.pmid: 18039276
references.citation: J Dermatol Sci. 1998 Jul;17(3):182-9
references.pmid: 9697046
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Jul;293(1):R314-22
references.pmid: 17428897
references.citation: Am J Physiol. 1997 Aug;273(2 Pt 1):L410-6
references.pmid: 9277454
references.citation: Biol Neonate. 2003;84(1):31-6
references.pmid: 12890933
references.citation: Am J Respir Crit Care Med. 2010 Feb 15;181(4):394-418
references.pmid: 20130146
references.citation: J Biol Chem. 2001 Feb 16;276(7):5395-402
references.pmid: 11098056
references.citation: Annu Rev Physiol. 2001;63:471-94
references.pmid: 11181964
references.citation: Pediatr Pulmonol. 2005 Aug;40(2):113-34
references.pmid: 15965895
references.citation: Am J Respir Cell Mol Biol. 2003 Mar;28(3):271-4
references.pmid: 12594052
references.citation: J Appl Physiol (1985). 2005 Nov;99(5):1681-8
references.pmid: 15961609
references.citation: Am J Obstet Gynecol. 2010 Feb;202(2):186.e1-7
references.pmid: 20022315
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Oct;281(4):L1011-20
references.pmid: 11557605
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Jun;292(6):L1370-84
references.pmid: 17293375
references.citation: Anat Rec. 1981 Dec;201(4):655-67
references.pmid: 7340570
references.citation: Connect Tissue Res. 1980;7(4):263-7
references.pmid: 6450027
references.citation: Am J Respir Cell Mol Biol. 2004 Dec;31(6):650-6
references.pmid: 15333328
references.citation: Am J Pathol. 2002 Nov;161(5):1783-96
references.pmid: 12414525
references.citation: Am J Respir Crit Care Med. 1999 Mar;159(3):945-58
references.pmid: 10051278
references.citation: J Nutr Sci Vitaminol (Tokyo). 1992;Spec No:485-7
references.pmid: 1297793
references.citation: Semin Perinatol. 2006 Aug;30(4):179-84
references.pmid: 16860157
references.citation: J Biol Chem. 2006 Mar 31;281(13):8724-31
references.pmid: 16377626