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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2004 May 29;359(1445):799–808. doi: 10.1098/rstb.2004.1470

Retinoic acid in alveolar development, maintenance and regeneration.

Malcolm Maden 1, Matthew Hind 1
PMCID: PMC1693372  PMID: 15293808

Abstract

Recent data suggest that exogenous retinoic acid (RA), the biologically active derivative of vitamin A, can induce alveolar regeneration in a rat model of experimental emphysema. Here, we describe a mouse model of disrupted alveolar development using dexamethasone administered postnatally. We show that the effects of dexamethasone are concentration dependent, dose dependent, long lasting and result in a severe loss of alveolar surface area. When RA is administered to these animals as adults, lung architecture and the surface area per unit of body weight are completely restored to normal. This remarkable effect may be because RA is required during normal alveolar development and administering RA re-awakens gene cascades used during development. We provide evidence that RA is required during alveologenesis in the mouse by showing that the levels of the retinoid binding proteins, the RA receptors and two RA synthesizing enzymes peak postnatally. Furthermore, an inhibitor of RA synthesis, disulphiram, disrupts alveologenesis. We also show that RA is required throughout life for the maintenance of lung alveoli because when rats are deprived of dietary retinol they lose alveoli and show the features of emphysema. Alveolar regeneration with RA may therefore be an important novel therapeutic approach to the treatment of respiratory diseases characterized by a reduced gas-exchanging surface area such as bronchopulmonary dysplasia and emphysema for which there are currently no treatments.

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Selected References

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  1. Abu-Abed S. S., Beckett B. R., Chiba H., Chithalen J. V., Jones G., Metzger D., Chambon P., Petkovich M. Mouse P450RAI (CYP26) expression and retinoic acid-inducible retinoic acid metabolism in F9 cells are regulated by retinoic acid receptor gamma and retinoid X receptor alpha. J Biol Chem. 1998 Jan 23;273(4):2409–2415. doi: 10.1074/jbc.273.4.2409. [DOI] [PubMed] [Google Scholar]
  2. Amy R. W., Bowes D., Burri P. H., Haines J., Thurlbeck W. M. Postnatal growth of the mouse lung. J Anat. 1977 Sep;124(Pt 1):131–151. [PMC free article] [PubMed] [Google Scholar]
  3. Baybutt R. C., Hu L., Molteni A. Vitamin A deficiency injures lung and liver parenchyma and impairs function of rat type II pneumocytes. J Nutr. 2000 May;130(5):1159–1165. doi: 10.1093/jn/130.5.1159. [DOI] [PubMed] [Google Scholar]
  4. Belloni P. N., Garvin L., Mao C. P., Bailey-Healy I., Leaffer D. Effects of all-trans-retinoic acid in promoting alveolar repair. Chest. 2000 May;117(5 Suppl 1):235S–241S. doi: 10.1378/chest.117.5_suppl_1.235s. [DOI] [PubMed] [Google Scholar]
  5. Bruce M. C., Honaker C. E., Cross R. J. Lung fibroblasts undergo apoptosis following alveolarization. Am J Respir Cell Mol Biol. 1999 Feb;20(2):228–236. doi: 10.1165/ajrcmb.20.2.3150. [DOI] [PubMed] [Google Scholar]
  6. Burri P. H., Dbaly J., Weibel E. R. The postnatal growth of the rat lung. I. Morphometry. Anat Rec. 1974 Apr;178(4):711–730. doi: 10.1002/ar.1091780405. [DOI] [PubMed] [Google Scholar]
  7. Delva L., Bastie J. N., Rochette-Egly C., Kraïba R., Balitrand N., Despouy G., Chambon P., Chomienne C. Physical and functional interactions between cellular retinoic acid binding protein II and the retinoic acid-dependent nuclear complex. Mol Cell Biol. 1999 Oct;19(10):7158–7167. doi: 10.1128/mcb.19.10.7158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dubick M. A., Rucker R. B., Cross C. E., Last J. A. Elastin metabolism in rodent lung. Biochim Biophys Acta. 1981 Feb 5;672(3):303–306. doi: 10.1016/0304-4165(81)90297-x. [DOI] [PubMed] [Google Scholar]
  9. Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur J Biochem. 2000 Jul;267(14):4315–4324. doi: 10.1046/j.1432-1327.2000.01497.x. [DOI] [PubMed] [Google Scholar]
  10. Fujii H., Sato T., Kaneko S., Gotoh O., Fujii-Kuriyama Y., Osawa K., Kato S., Hamada H. Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos. EMBO J. 1997 Jul 16;16(14):4163–4173. doi: 10.1093/emboj/16.14.4163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Geevarghese S. K., Chytil F. Depletion of retinyl esters in the lungs coincides with lung prenatal morphological maturation. Biochem Biophys Res Commun. 1994 Apr 15;200(1):529–535. doi: 10.1006/bbrc.1994.1480. [DOI] [PubMed] [Google Scholar]
  12. Helms J. A., Kim C. H., Eichele G., Thaller C. Retinoic acid signaling is required during early chick limb development. Development. 1996 May;122(5):1385–1394. doi: 10.1242/dev.122.5.1385. [DOI] [PubMed] [Google Scholar]
  13. Hind Matthew, Corcoran Jonathan, Maden Malcolm. Alveolar proliferation, retinoid synthesizing enzymes, and endogenous retinoids in the postnatal mouse lung. Different roles for Aldh-1 and Raldh-2. Am J Respir Cell Mol Biol. 2002 Jan;26(1):67–73. doi: 10.1165/ajrcmb.26.1.4575. [DOI] [PubMed] [Google Scholar]
  14. Hind Matthew, Corcoran Jonathan, Maden Malcolm. Temporal/spatial expression of retinoid binding proteins and RAR isoforms in the postnatal lung. Am J Physiol Lung Cell Mol Physiol. 2002 Mar;282(3):L468–L476. doi: 10.1152/ajplung.00196.2001. [DOI] [PubMed] [Google Scholar]
  15. Karlinsky J. B., Goldstein R. H., Ojserkis B., Snider G. L. Lung mechanics and connective tissue levels in starvation-induced emphysema in hamsters. Am J Physiol. 1986 Aug;251(2 Pt 2):R282–R288. doi: 10.1152/ajpregu.1986.251.2.R282. [DOI] [PubMed] [Google Scholar]
  16. Kerr J. S., Riley D. J., Lanza-Jacoby S., Berg R. A., Spilker H. C., Yu S. Y., Edelman N. H. Nutritional emphysema in the rat. Influence of protein depletion and impaired lung growth. Am Rev Respir Dis. 1985 Apr;131(4):644–650. doi: 10.1164/arrd.1985.131.4.644. [DOI] [PubMed] [Google Scholar]
  17. Kotton D. N., Ma B. Y., Cardoso W. V., Sanderson E. A., Summer R. S., Williams M. C., Fine A. Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development. 2001 Dec;128(24):5181–5188. doi: 10.1242/dev.128.24.5181. [DOI] [PubMed] [Google Scholar]
  18. Krause D. S., Theise N. D., Collector M. I., Henegariu O., Hwang S., Gardner R., Neutzel S., Sharkis S. J. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001 May 4;105(3):369–377. doi: 10.1016/s0092-8674(01)00328-2. [DOI] [PubMed] [Google Scholar]
  19. Leid M., Kastner P., Chambon P. Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci. 1992 Oct;17(10):427–433. doi: 10.1016/0968-0004(92)90014-z. [DOI] [PubMed] [Google Scholar]
  20. Li Ting, Molteni Agostino, Latkovich Predrag, Castellani William, Baybutt Richard C. Vitamin A depletion induced by cigarette smoke is associated with the development of emphysema in rats. J Nutr. 2003 Aug;133(8):2629–2634. doi: 10.1093/jn/133.8.2629. [DOI] [PubMed] [Google Scholar]
  21. Lu H. C., Revelli J. P., Goering L., Thaller C., Eichele G. Retinoid signaling is required for the establishment of a ZPA and for the expression of Hoxb-8, a mediator of ZPA formation. Development. 1997 May;124(9):1643–1651. doi: 10.1242/dev.124.9.1643. [DOI] [PubMed] [Google Scholar]
  22. Maden M. Retinoids as endogenous components of the regenerating limb and tail. Wound Repair Regen. 1998 Jul-Aug;6(4):358–365. doi: 10.1046/j.1524-475x.1998.60411.x. [DOI] [PubMed] [Google Scholar]
  23. Maden M. The effect of vitamin A on limb regeneration in Rana temporaria. Dev Biol. 1983 Aug;98(2):409–416. doi: 10.1016/0012-1606(83)90370-6. [DOI] [PubMed] [Google Scholar]
  24. Maden M. Vitamin A and pattern formation in the regenerating limb. Nature. 1982 Feb 25;295(5851):672–675. doi: 10.1038/295672a0. [DOI] [PubMed] [Google Scholar]
  25. Maden Malcolm. Retinoid signalling in the development of the central nervous system. Nat Rev Neurosci. 2002 Nov;3(11):843–853. doi: 10.1038/nrn963. [DOI] [PubMed] [Google Scholar]
  26. Massaro D., Teich N., Maxwell S., Massaro G. D., Whitney P. Postnatal development of alveoli. Regulation and evidence for a critical period in rats. J Clin Invest. 1985 Oct;76(4):1297–1305. doi: 10.1172/JCI112103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Massaro G. D., Massaro D., Chan W. Y., Clerch L. B., Ghyselinck N., Chambon P., Chandraratna R. A. Retinoic acid receptor-beta: an endogenous inhibitor of the perinatal formation of pulmonary alveoli. Physiol Genomics. 2000 Nov 9;4(1):51–57. doi: 10.1152/physiolgenomics.2000.4.1.51. [DOI] [PubMed] [Google Scholar]
  28. Massaro G. D., Massaro D. Formation of pulmonary alveoli and gas-exchange surface area: quantitation and regulation. Annu Rev Physiol. 1996;58:73–92. doi: 10.1146/annurev.ph.58.030196.000445. [DOI] [PubMed] [Google Scholar]
  29. Massaro G. D., Massaro D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med. 1997 Jun;3(6):675–677. doi: 10.1038/nm0697-675. [DOI] [PubMed] [Google Scholar]
  30. Massaro G. D., Massaro D. Retinoic acid treatment partially rescues failed septation in rats and in mice. Am J Physiol Lung Cell Mol Physiol. 2000 May;278(5):L955–L960. doi: 10.1152/ajplung.2000.278.5.L955. [DOI] [PubMed] [Google Scholar]
  31. McGowan S. E., Harvey C. S., Jackson S. K. Retinoids, retinoic acid receptors, and cytoplasmic retinoid binding proteins in perinatal rat lung fibroblasts. Am J Physiol. 1995 Oct;269(4 Pt 1):L463–L472. doi: 10.1152/ajplung.1995.269.4.L463. [DOI] [PubMed] [Google Scholar]
  32. McGowan S., Jackson S. K., Jenkins-Moore M., Dai H. H., Chambon P., Snyder J. M. Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers. Am J Respir Cell Mol Biol. 2000 Aug;23(2):162–167. doi: 10.1165/ajrcmb.23.2.3904. [DOI] [PubMed] [Google Scholar]
  33. Naltner A., Ghaffari M., Whitsett J. A., Yan C. Retinoic acid stimulation of the human surfactant protein B promoter is thyroid transcription factor 1 site-dependent. J Biol Chem. 2000 Jan 7;275(1):56–62. doi: 10.1074/jbc.275.1.56. [DOI] [PubMed] [Google Scholar]
  34. Napoli J. L. Interactions of retinoid binding proteins and enzymes in retinoid metabolism. Biochim Biophys Acta. 1999 Sep 22;1440(2-3):139–162. doi: 10.1016/s1388-1981(99)00117-1. [DOI] [PubMed] [Google Scholar]
  35. Noguchi A., Samaha H. Developmental changes in tropoelastin gene expression in the rat lung studied by in situ hybridization. Am J Respir Cell Mol Biol. 1991 Dec;5(6):571–578. doi: 10.1165/ajrcmb/5.6.571. [DOI] [PubMed] [Google Scholar]
  36. Okabe T., Yorifuji H., Yamada E., Takaku F. Isolation and characterization of vitamin-A-storing lung cells. Exp Cell Res. 1984 Sep;154(1):125–135. doi: 10.1016/0014-4827(84)90673-6. [DOI] [PubMed] [Google Scholar]
  37. Ong D. E., Chytil F. Changes in levels of cellular retinol- and retinoic-acid-binding proteins of liver and lung during perinatal development of rat. Proc Natl Acad Sci U S A. 1976 Nov;73(11):3976–3978. doi: 10.1073/pnas.73.11.3976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Pauwels R. A., Buist A. S., Calverley P. M., Jenkins C. R., Hurd S. S., GOLD Scientific Committee Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001 Apr;163(5):1256–1276. doi: 10.1164/ajrccm.163.5.2101039. [DOI] [PubMed] [Google Scholar]
  39. Powell J. T., Whitney P. L. Postnatal development of rat lung. Changes in lung lectin, elastin, acetylcholinesterase and other enzymes. Biochem J. 1980 Apr 15;188(1):1–8. doi: 10.1042/bj1880001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Ross S. A., McCaffery P. J., Drager U. C., De Luca L. M. Retinoids in embryonal development. Physiol Rev. 2000 Jul;80(3):1021–1054. doi: 10.1152/physrev.2000.80.3.1021. [DOI] [PubMed] [Google Scholar]
  41. Scadding S. R., Maden M. Retinoic acid gradients during limb regeneration. Dev Biol. 1994 Apr;162(2):608–617. doi: 10.1006/dbio.1994.1114. [DOI] [PubMed] [Google Scholar]
  42. Schittny J. C., Djonov V., Fine A., Burri P. H. Programmed cell death contributes to postnatal lung development. Am J Respir Cell Mol Biol. 1998 Jun;18(6):786–793. doi: 10.1165/ajrcmb.18.6.3031. [DOI] [PubMed] [Google Scholar]
  43. Srinivasan Ganesh, Bruce Eugene N., Houtz Pamela K., Bruce Margaret C. Dexamethasone-induced changes in lung function are not prevented by concomitant treatment with retinoic acid. Am J Physiol Lung Cell Mol Physiol. 2002 Aug;283(2):L275–L287. doi: 10.1152/ajplung.00423.2001. [DOI] [PubMed] [Google Scholar]
  44. Stratford T., Horton C., Maden M. Retinoic acid is required for the initiation of outgrowth in the chick limb bud. Curr Biol. 1996 Sep 1;6(9):1124–1133. doi: 10.1016/s0960-9822(02)70679-9. [DOI] [PubMed] [Google Scholar]
  45. Tepper J., Pfeiffer J., Aldrich M., Tumas D., Kern J., Hoffman E., McLennan G., Hyde D. Can retinoic acid ameliorate the physiologic and morphologic effects of elastase instillation in the rat? Chest. 2000 May;117(5 Suppl 1):242S–244S. doi: 10.1378/chest.117.5_suppl_1.242s. [DOI] [PubMed] [Google Scholar]
  46. Thaller C., Eichele G. Identification and spatial distribution of retinoids in the developing chick limb bud. Nature. 1987 Jun 18;327(6123):625–628. doi: 10.1038/327625a0. [DOI] [PubMed] [Google Scholar]
  47. Thaller C., Eichele G. Isolation of 3,4-didehydroretinoic acid, a novel morphogenetic signal in the chick wing bud. Nature. 1990 Jun 28;345(6278):815–819. doi: 10.1038/345815a0. [DOI] [PubMed] [Google Scholar]
  48. Thurlbeck W. M., Müller N. L. Emphysema: definition, imaging, and quantification. AJR Am J Roentgenol. 1994 Nov;163(5):1017–1025. doi: 10.2214/ajr.163.5.7976869. [DOI] [PubMed] [Google Scholar]
  49. Tschanz S. A., Damke B. M., Burri P. H. Influence of postnatally administered glucocorticoids on rat lung growth. Biol Neonate. 1995;68(4):229–245. doi: 10.1159/000244241. [DOI] [PubMed] [Google Scholar]
  50. Vallari R. C., Pietruszko R. Human aldehyde dehydrogenase: mechanism of inhibition of disulfiram. Science. 1982 May 7;216(4546):637–639. doi: 10.1126/science.7071604. [DOI] [PubMed] [Google Scholar]
  51. Wendel D. P., Taylor D. G., Albertine K. H., Keating M. T., Li D. Y. Impaired distal airway development in mice lacking elastin. Am J Respir Cell Mol Biol. 2000 Sep;23(3):320–326. doi: 10.1165/ajrcmb.23.3.3906. [DOI] [PubMed] [Google Scholar]
  52. Whitney D., Massaro G. D., Massaro D., Clerch L. B. Gene expression of cellular retinoid-binding proteins: modulation by retinoic acid and dexamethasone in postnatal rat lung. Pediatr Res. 1999 Jan;45(1):2–7. doi: 10.1203/00006450-199901000-00002. [DOI] [PubMed] [Google Scholar]
  53. Zeltner T. B., Caduff J. H., Gehr P., Pfenninger J., Burri P. H. The postnatal development and growth of the human lung. I. Morphometry. Respir Physiol. 1987 Mar;67(3):247–267. doi: 10.1016/0034-5687(87)90057-0. [DOI] [PubMed] [Google Scholar]

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