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Effects of All-Trans-Retinoic Acid in Promoting Alveolar Repair^*

^* From Roche Bioscience, Department of Respiratory Diseases, Palo Alto, CA.

Correspondence to: Paula Belloni, PhD, Roche Bioscience, Respiratory Diseases, 3401 Hillview Ave, Palo Alto, CA 94308

	Introduction

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 

Abbreviations: ATRA = all-trans-retinoic acid; PCNA = proliferating cell nuclear antigen; PDGF = platelet-derived growth factor; RA = retinoic acid; RAR = retinoic acid receptor; RXR = retinoid X receptor; SP = surfactant protein; TGF = transforming growth factor

Emphysema is characterized by airway destruction distal to the terminal bronchioles, gradual loss of lung recoil, decreased alveolar surface area, and impaired gas exchange, leading to a reduced FEV₁.¹ These last two features, impaired gas exchange and reduction in expiratory flow, are characteristic physiologic abnormalities in patients with emphysema. The most common cause of emphysema is cigarette smoking, although other potential environmental toxins also may contribute. These various insulting agents activate destructive processes in the lung, including the release of active proteases and free radical oxidants in excess of protective mechanisms. The imbalance in protease/antiprotease levels leads to the destruction of the elastin matrix and alveolar structure with progressive loss of lung recoil. Removing the injurious agents (ie, quitting smoking) slows the rate of damage; however, unlike the response after acute lung injury, the damaged alveolar structures do not repair and lung function is not regained.

The relationship between vitamin A status and airway obstruction has been examined in cross-sectional studies.^{2 3} These studies established an inverse relationship between plasma retinol status and the degree of airway obstruction (assessed by FEV₁). Recent preclinical studies suggest that an analog of vitamin A, all-trans-retinoic acid (ATRA), may promote the repair and/or realveolarization of parenchymal lesions associated with emphysema.⁴ This study has prompted a surge of new preclinical and clinical research exploring the molecular basis for the function of vitamin A within the lung. In this review article, historical data supporting the role of vitamin A in the differentiation of lung structure and the maintenance of normal function will be reviewed. Experimental evidence elucidating the molecular basis of function via selective gene expression will be discussed. Data supporting the effects of ATRA on the repair of experimental models of emphysema will be presented in the context of their potential therapeutic use in the treatment of COPD.

	Molecular Basis for Action of Retinoic Acid

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 
Retinoids are a class of compounds structurally related to vitamin A that comprise natural and synthetic compounds. Retinoic acid (RA) and its other naturally occurring retinoid analogs (9-Ci-RA, all-trans-3–4 didehydro-RA, 4-oxo-RA, and retinol) are pleiotropic regulatory compounds that modulate the structure and function of a wide variety of inflammatory, immune, and structural cells. These compounds function like hormones to regulate epithelial cell proliferation, pattern formation in developing tissues, morphogenesis in the lung, and cellular differentiation. The current proven clinical uses of selected retinoids are for the treatment of dermatologic diseases (acne, psoriasis, eczema, and photo-damaged skin) and specific forms of cancer. Retinoids exert their biological effects through a series of nuclear receptors that are ligand-inducible transcription factors belonging to the steroid/thyroid receptor superfamily.⁵ The ligand-bound heterodimer binds to RA response elements in the noncoding region of the target gene to repress or enhance expression (Fig 1 ). Retinoids also can modulate gene expression by binding directly to specific transcription factors such as AP-1 that interfere with the protein-protein interactions, similar to the effects of glucocorticoids.⁶

View larger version (63K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Retinoid nuclear hormone receptors.

	Vitamin A Metabolism

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 
Vitamin A is acquired from the diet in the form of retinyl-esters and ß-carotene, converted to retinol in the intestine and stored in the liver after reconversion to retinyl esters. Retinol released from the liver is transported to target tissues complexed to retinyl binding proteins, where it can be stored in the form of esters or converted to the active hormone ATRA. Retinol is converted to RA at the cellular site of action in a highly controlled metabolic pathway.⁷ Retinol is first oxidized to an inactive intermediate, retinal, by members of the alcohol dehydrogenase family (ie, retinol dehydrogenase), which is followed by oxidation of retinol to the active ligand RA by members of the aldehyde dehydrogenases.⁸ Throughout the metabolic processes, retinoid metabolites and ATRA remain complexed to retinoid-binding proteins (retinol binding protein, cellular retinol binding protein, and cellular retinoic acid binding protein) to protect the cells from hormonal action. Much of this highly controlled pathway is autoregulated by local concentrations of ATRA.⁹ Either an excess of ATRA or inadequate maintenance of ATRA can have significant pathologic consequences throughout life.

	Vitamin A in Lung Development and Function

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 
Lung development involves the formation of the primordial lung from the foregut and sequential branching morphogenesis into small airways, which are followed by three maturation phases: phase 1 is pseudoglandular, with continued airway branching; phase 2 is canalicular, with thinning of the epithelium and cell differentiation; and phase 3 is the terminal saccular stage, with rapid proliferation of interstitial fibroblasts, alveolar budding, septation, and differentiation of type II and type I epithelia.^{10 11} On completion of septation, the alveolar walls become thinner and apoptotic processes reduce the number of interstitial fibroblasts.^{12 13} Throughout this development process, the lung is composed of the following two primary tissue layers: the epithelium and the mesenchyme. The mesenchyme produces growth factors (epidermal growth factor, transforming growth factor [TGF]-, human growth factor, fibroblast growth factor-7, and TGF-ß) and matrix molecules (collagen, elastin, and proteoglycans) that stimulate epithelial cell proliferation and differentiation, promoting branching. Similarly, the epithelium produces growth factors (platelet-derived growth factor [PDGF], insulin-like growth factor, TGF-ß₂, and proteases such as matrix metalloproteinases) as well as cell-cell contacts, direct fibroblast proliferation, and matrix deposition. RA is known to be one of the primary morphogens that regulates the temporal and spatial expression of many of these factors in both tissue layers.^{14 15 16 17 18}

	Relationships Among RARs, RA, and Alveolar Septation

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 
ATRA has been shown to modulate various aspects of cellular differentiation and matrix metabolism by interacting with specific RARs. Expression of the RARs is highly regulated both temporally and spatially at various times during lung development. RAR- is associated with instructing epithelial cell differentiation and driving structural changes during the transition from the glandular to the canalicular stage of development. In contrast, RAR-ß increases significantly in the terminal saccular stage, with the induction of both type II and type I epithelial cells. RAR- tends to be restricted to cells of the mesenchyme throughout this process.^{19 20} RA storage granules are most abundant in the fibroblastic mesenchyme surrounding alveolar walls, where levels peak prior to alveolar septation.^{21 22 23 24} Depletion of these retinyl-ester stores parallels the deposition of a new elastin matrix and septation. In neonatal rats fed a vitamin A-deficient diet or treated with dexamethasone, alveolar septation is significantly reduced. At the molecular level, the expression of cellular retinol binding protein and RAR-ß messenger RNA is diminished in the lungs of vitamin A-deficient rat pups.^{25 26} In contrast, the treatment of neonatal rat pups with ATRA increases lung alveolarization and can reverse the effects of dexamethasone.²⁷

The effects of dexamethasone and ATRA on the late stages of branching morphogenesis have also been demonstrated ex vivo.^{18 28} In these studies, terminal branching and type II epithelial cell proliferation were inhibited in gestational day 14/15 lungs when cultured in the presence of dexamethasone and were normalized by costimulation with ATRA. The authors related the changes in transcription of fibroblast growth factor-7 and human growth factor to the structural observations induced by dexamethasone with or without ATRA.

In adult animals deficient in retinol, the conducting airways undergo squamous metaplasia, the transformation of the mucociliary epithelium into squamous cells.^{29 30 31} Similar changes are observed in bronchopulmonary dysplasia, a chronic lung disease encountered by infants after ventilation therapy for respiratory distress. In addition to delayed septation, lung function is impaired in these infants by inadequate levels of surfactant phospholipids, which normally line alveoli. Vitamin A deficiency is thought to mediate some of the lung pathology associated with these neonates.

Preclinical studies indicated that the supplementation of vitamin A-deficient rat pups with physiologic levels of ATRA not only promotes septation, but also promotes the expression of surfactant protein (SP) genes.^{32 33} In this study, levels of SP- and SP-ß were correlated directly with plasma retinol concentrations. Although the molecular basis for action has not been investigated clinically, results from recent clinical studies suggest that supplementation with retinol enhances the survival rate of these rat pups.³⁴

Elastin deposition in the saccule wall is instrumental to alveolar septal formation. Elastin is the primary structural protein in the alveolar wall that is the basis for its recoil properties. Tropoelastin is the soluble elastin gene product that becomes insoluble on polymerization. ATRA has been shown to effect the transcription of elastin in fetal lung fibroblasts directly.^{21 22 23 24 35} The critical need for elastin deposition during septation is borne out in genetic knock-out studies. PDGF- null mice are homozygous lethal, with restriction points before E-10 and one postnatally. In PDGF--deficient mice that survive, emphysema develops secondary to the failure to septate. The failure to septate was due to a loss of alveolar myofibroblasts and the associated elastin fibers.¹⁵ The deficiency in myofibroblasts and elastin was restricted to the lung parenchyma, which appear healthy in the bronchi and blood vessels. Preclinical investigations of repair mechanisms after acute lung injury suggest that similar profiles of growth factors and receptors promote the structural repair of damaged alveoli.

	Tissue Repair and Matrix Deposition in the Adult Lung

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 
Wound healing occurs in the following three phases: inflammatory, proliferative, and remodeling.³⁶ The first phase of inflammation is characterized by an infiltration of polymorphonuclear neutrophils and macrophages. The second phase requires fibroblast proliferation, angiogenesis, and the production of a provisional matrix of collagen/elastin. Wound contraction and reepithelialization constitute the final phase of repair. Evidence supporting the capacity for self-renewal or repair in adult tissue stems from studies examining the alveolar microenvironment of patients or animals after acute lung injury. In acute lung injury, the process begins with massive inflammatory infiltration in the alveolar wall after exposure of a noxious environmental or endogenous biological agent, followed by significant tissue destruction. Repair is initiated by an extensive fibroproliferative response, leading to granulation of the alveolar airspaces, which is a classic wound-healing response. The granulation tissue is composed of fibroblasts, endothelial cells, residual macrophages, and a provisional collagen matrix.^{37 38} PDGF (- and ß-chains), TGF-ß₁, and TGF-ß₂ are rapidly induced into alveolar epithelial cells in response to an injury.³⁹ PDGF is a potent mitogen for mesenchymal cells, whereas TGF-ß retards fibroblast growth but promotes matrix deposition. PDGF receptor- expression is markedly enhanced in lung myofibroblasts within 24 h of injury and subsides prior to the deposition of fibrotic matrix proteins.^{40 41} In patients or animals that survive, there is resolution of the granulation tissue with subsequent restoration of the gas-exchange apparatus. The reduction in cell mass occurs via apoptosis,⁴² which is similar to the final stages of septation in development,¹³ as well as in normal wound healing.⁴³ The effects of RA and PDGF on dermal wound repair are well documented.^{36 44} Additional studies are required to determine whether ATRA may activate a similar gene expression cascade in the repair of emphysema.

	Retinoid Agonists in the Treatment of Experimental Emphysema

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 
Numerous studies have demonstrated that the instillation of elastolytic enzymes into the lung can induce experimental emphysema. Elastase treatment leads to rapid destruction of the elastin content and to permanent disruption of the elastin fiber architecture within the alveolus.⁴⁵ Airspace enlargement and partial loss of lung capacity have been measured in the rat. The loss of lung structure and function in elastase-induced emphysema are thought to be representative of the changes that occur in mild-to-moderate human emphysema.

The studies reported by Massaro and Massaro⁴ suggest that ATRA can reverse the effects of elastase-induced damage in the rat. In the reported study, lungs were damaged by a single instillation of pancreatic elastase. Three weeks after injury, the rats were treated with ATRA (0.5 mg/kg) or a vehicle for an additional 14 days. Lung volumes were determined by volume displacement. Changes in alveolar structure were determined by the selector method using serial sections and classic methods of morphometry. In these studies, the treatment of rats with elastase plus vehicle resulted in an 18% increase in alveolar volume and 45% fewer alveoli, relative to healthy rats or those treated with elastase and ATRA.

We have repeated these studies and analyzed changes in alveolar area and density using computer-assisted image analysis. Lung tissue is nearly ideal for computer-assisted morphometry. Alveoli are represented histologically as empty spaces surrounded by tissue. The alveolar lining cells can be stained using standard histochemical dies (hematoxylin-eosin), so therefore, alveoli can be differentiated clearly from surrounding tissue when the image is converted to a gray scale. The image threshold can be set within a narrow range of pixel intensities, and the areas of interest are defined by contiguous pixels. As such, areas of alveolar wall destruction result in larger alveoli and in fewer alveoli per field.

Using these methods, the average alveolar area in rats treated with elastase and the vehicle was threefold larger than that in untreated rats (pixel density, 5,200 vs 1,800, respectively). The average alveolar area of rats treated with elastase and ATRA was 3,200 pixels, which represents an approximately 50% reversal of damage (Fig 2 ). The treatment of elastase-injured rats with another nonselective RAR agonist, 9-cis RA, had a similar effect; a 70% improvement in alveolar area. Lung volumes were determined in experimental emphysema by volume displacement and were found to be increased by 15% in elastase-treated rats, as reported by Massaro and Massaro⁴ ; however, in these studies, lung volumes were not corrected by treatment with ATRA. The results from these studies suggest that the repair of the alveolar structure does not necessarily confer an improvement in elastic recoil.

View larger version (60K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Experimental emphysema with and without ATRA treatment. IT = intratracheal; Veh = vehicle.

	Cellular Changes in Alveoli Indicative of Wound-Healing Response

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Immunolocalization of cell proliferation/PCNA.

	Relationship Between Lung Structure and Function

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 
A primary issue raised in response to the initial publications by Massaro and Massaro^{4 27} is whether improvements in lung structure would translate to changes in lung function. We have used both invasive and nonrestrained plethysmography to assess lung capacity and compliance. No differences have been detected in compliance with or without ATRA treatment relative to naive animals. In contrast, there was a measurable change in the ratio of the alveolar-arterial oxygen pressure difference to PO₂, suggesting there is improved diffusion capacity in ATRA-treated rats. The effects of elastase treatment, with or without ATRA, on lung function in the rat also have been reported by Tepper et al.⁴⁶ In these early studies, lung volumes (total lung capacity, residual volume, vital capacity, and functional residual capacity) were increased by elastase treatment, while FEV₁ and the diffusing capacity of the lung for carbon monoxide were decreased. Treatment with ATRA for 2 weeks partially reversed these changes. Taken together, the results of current studies suggest that ATRA treatment may promote repair, regenerate, or both damaged alveoli, resulting in improvement of selected functional parameters.

	Summary

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 
An appreciation of the central role of RAs in embryogenesis, tissue homeostasis, and aging was greatly expanded during the last decade by the discovery that its actions are mediated by a subgroup of nuclear hormone receptors, the RARs. It is now recognized that ATRA is a potent embryonic morphogen that has defined roles in the development and postnatal maintenance of many tissues, including the lung. While many of the responses to ATRA both in vitro and in vivo appear to be contradictory, the effects reflect the capacity of this molecule to "normalize" cellular behavior rather than to stimulate or inhibit them specifically.

ATRA currently is used clinically to treat promyelocytic leukemia and is used cosmetically in the treatment and prevention of photo-aging and epidermal atrophy. ATRA is thought to reverse epidermal atrophy in photo-aging by inducing gene expression profiles that are similar to those observed earlier in development. The initial report by Massaro and Massaro⁴ showing that ATRA can reverse experimental emphysema by inducing new alveoli suggests that ATRA may have similar activity in the adult lung. The remarkable effects of ATRA in experimental models of COPD have stimulated significant hope that ATRA or selective chemical analogs will bring some benefit to those with emphysema. If one considers the limited epidemiologic data indication and the inverse relationship between plasma retinol in smokers and the degree of airway obstruction, then it may be reasonable to assume that inadequate levels of RA may contribute to the chronic injury observed in COPD (Fig 4 ). The National Institutes of Health have sponsored clinical proof-of-concept studies that will be initiated in the year 2000. Results from these studies, as well as from preclinical projects addressing more fundamental mechanism driving lung restructuring, will likely stimulate additional therapeutic approaches to improve the health of COPD patients.

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Role of ATRA in alveolar repair. See Figure 2 for abbreviation. EGFr = epidermal growth factor receptor; PDGFr = PDGF receptor; TIMP = tissue inhibitor matrix metalloproteinase; CRABP = cellular retinoic acid binding protein; ROH = retinol; RoDH = retinol dehydrogenase; RAL = retinal; RalDH = retinal dehydrogenase; LRAT = lecithin retinol acyl transferase; RE = retinyl ester; REH = retinyl ester hydrolase.

	References

TOP Introduction Molecular Basis for Action... Vitamin A Metabolism Vitamin A in Lung... Relationships Among RARs, RA,... Tissue Repair and Matrix... Retinoid Agonists in the... Cellular Changes in Alveoli... Relationship Between Lung... Summary References

 

1. Cosio, M, Ghezo, H, Hogg, JC, et al (1978) The relationship between structural changes in small airways and pulmonary function tests. N Engl J Med 298,1277-1281[Abstract]
2. Morabia, A, Menkes, M, Comstock, G, et al (1990) Serum retinol and airway obstruction. Am J Epidemiol 132,77-82[Abstract/Free Full Text]
3. Paiva, S, Goday, I, Vannucchi, H, et al (1996) Assessment of vitamin A status in chronic obstructive pulmonary disease patients and healthy smokers. Am J Clin Nutr 64,928-934[Abstract/Free Full Text]
4. Massaro, G, Massaro, D (1997) Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med 3,675-677[CrossRef][ISI][Medline]
5. Chambone, P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10,940-954[Abstract]
6. Nagpal, S, Athanikar, J, Chandraratna, R (1995) Separation of transactivation and AP-1 antagonism functions of retinoic acid receptor . J Biol Chem 270,923-927[Abstract/Free Full Text]
7. Napoli, J (1996) Retinoic acid biosynthesis and metabolism. FASEB J 10,993-1001[Abstract]
8. Duester, G (1996) Involvement of alcoholdehydrogenase, short chain dehydrogenase/reductase, aldehyde dehydrogenase, and cytochrome P450 in the control of retinoic acid synthesis. Biochemistry 35,12221-12227[CrossRef][Medline]
9. Haq, R, Pfahl, M, Chytil, F (1991) Retinoic acid affects the expression of nuclear retinoic acid receptors in tissues of retinol deficient rats. Proc Natl Acad Sci USA 88,8272-8276[Abstract/Free Full Text]
10. Kauffman, SSL, Burri, P, Weibel, E (1974) The postnatal growth of the rat lung: II. Autoradiography. Anat Rec 180,63-76[CrossRef][Medline]
11. Farrell, P (1981) Morphological aspects of lung maturation. Farrell, P eds. Lung development: biological and clinical perspectives (vol 1) ,13-25 Academic Press New York, NY.
12. Kresch, M, Christian, C, Wu, F, et al (1998) Ontogeny of apoptosis during lung development. Pediatr Res 43,426-431[ISI][Medline]
13. Bruce, M, Honaker, C, Cross, R (1999) Lung fibroblasts undergo apoptosis following alveolarization. Am J Respir Cell Mol Biol 20,228-236[Abstract/Free Full Text]
14. Souza, P, Tanswell, K, Post, M (1996) Different roles for PDGF- and ß receptors in embryonic lung development. Am J Respir Cell Mol Biol 15,551-562[Abstract]
15. Bostrom, H, Willetts, K, Pekny, M, et al (1996) PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85,863-873[CrossRef][ISI][Medline]
16. Zachman, R (1995) Role of vitamin A in lung development. J Nutr 125(suppl),1634S-1638S
17. Afink, G, Nister, M, Stassen, B, et al (1995) Molecular cloning and functional characterization of human platelet derived growth factor receptor gene promoter. Oncogene 10,1667-1672[ISI][Medline]
18. Schuger, L, Varani, J, Mitra, R, et al (1992) Retinoic Acid stimulates mouse lung development by a mechanism involving epithelial-mesenchymal interaction and epidermal growth factor. Dev Biol 159,462-473
19. Dolle, P, Ruberte, R, Leroy, P, et al (1990) Retinoic acid receptors and cellular retinoid binding proteins: I. A systematic study of their differential pattern of transcription during mouse organogenesis. Development 110,1133-1151[Abstract/Free Full Text]
20. Grummer, M, Zachman, R (1994) Expression of retinoic acid receptors in fetal and newborn rat lung. Pediatr Pulmonol 17,234-238[ISI][Medline]
21. Liu, R, Harvey, C, McGowan, S (1993) Rintinoic acid increases elastin in rat lung fibroblast cultures. Am J Physiol 265,L430-L437[Abstract/Free Full Text]
22. McGowan, S, Harvey, C, Jackson, S (1995) Retinoids, retinoic acid and cytoplasmic retinoid binding proteins in perinatal rat lung fibroblasts. Am J Physiol 269,L463-L472[Abstract/Free Full Text]
23. McGowan, S, Dora, M, Jackson, S (1997) Endogenous retinoids increase perinatal elastin gene expression in rat lung fibroblasts and fetal explants. Am J Physiol 273,L410-L416[Abstract/Free Full Text]
24. Okabe, T, Yorifuji, H, Yamada, E, et al (1984) Isolation and characterization of vitamin A storing lung cells. Exp Cell Res 154,125-135[CrossRef][ISI][Medline]
25. Ong, D, Chytil, F (1976) Changes in levels of cellular retinol and retrinoic acid binding proteins of liver and lung during perinatal development of rat. Proc Natl Acad Sci USA 73,3976-3978[Abstract/Free Full Text]
26. Grummer, M, Zachman, R (1995) Postnatal rat lung retinoic acid receptor (RAR) mRNA expression and effects of dexamethasone on RARß mRNA. Pediatr Pulmonol 20,234-240[ISI][Medline]
27. Massaro, G, Massaro, D (1996) Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats. Am J Physiol 270,L305-L310[Abstract/Free Full Text]
28. Cardosa, W, Williams, M, Mitsialis, A, et al (1995) Retinoic acid induces changes in the pattern of airway branching and alters epithelial cell differentiation in the developing lung in vitro. Am J Respir Cell Mol Biol 12,464-476[Abstract]
29. Wolbach, S, Howe, P (1925) Tissue changes following deprivation of fat soluble A vitamin. J Exp Med 43,753-758
30. Wolbach, S, Howe, P (1933) Epithelial repair in recovery from vitamin A deficiency. J Exp Med 57,511-517[Abstract]
31. Macdowell, E, Keenan, K, Huang, M (1984) Effects of vitamin A deprivation on hampster tracheal epithelium: a quantitative morphologic study. Virchows Arch B Cell Pathol 45,197-219[ISI][Medline]
32. Bogue, C, Jacobs, D, Dynia, C, et al (1996) Retinoic acid increases surfactant protein mRNA in fetal rat lung in culture. Am J Physiol 271,L862-L868[Abstract/Free Full Text]
33. Chailley-Heu, B, Chelly, N, Pergorier, M, et al (1999) Mild vitamin A deficiency delays fetal lung maturation in the rat. Am J Respir Cell Mol Biol 21,89-96[Abstract/Free Full Text]
34. Tyson, J, Wright, L, Oh, W, et al (1999) Vitamin A supplementation for extremely low birth weight infants. N Engl J Med 340,1962-1968[Abstract/Free Full Text]
35. Swee, M, Parks, W, Pierce, R (1995) Developmental regulation of elastin production. J Biol Chem 270,14899-14906[Abstract/Free Full Text]
36. Anstead, G (1998) Steroids, retinoids, and wound healing. Adv Wound Care 11,277-285[Medline]
37. Fukuda, Y, Ishizake, M, Masuda, Y, et al (1987) The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. Am J Pathol 126,171-182[Abstract]
38. Katzenstein, A, Myers, J, Mazur, M (1986) Acute interstitial pneumonia: a clinicopathologic, ultrastructural and cell kinetic study. Am J Surg Pathol 10,256-267[ISI][Medline]
39. Brody, A, Liu, J-y, Brass, D, et al (1997) Analyzing the genes and peptide growth factors expressed in lung cells in vivo consequent to asbestos exposure and in vitro. Environ Health Perspect 105,1165-1171
40. Coin, P, Lindroos, P, Bird, G, et al (1996) Lipopolysaccharide up-regulates platelet-derived growth factor (PDGF) alpha-receptor expression in rat lung myofibroblasts and enhances response to all PDGF isoforms. J Immunol 56,4797-4806
41. Bonner, J, Lindroos, P, Rice, A, et al (1998) Induction of PDGF receptor: a in rat myofibroblasts during pulmonary fibrogenesis in vivo. Am J Physiol 274,L72-L80[Abstract/Free Full Text]
42. Tesfaigz, J, Wood, M, Johnson, N, et al (1998) Apoptosis is a pathway responsible for the resolution of endotoxin-induced alveolar type II cell hyperplasia in the rat. Int J Exp Pathol 79,303-311[CrossRef][ISI][Medline]
43. Greenhalgh, D (1998) The role of apoptosis in wound healing. Int J Biochem Cell Biol 30,1019-1030[CrossRef][ISI][Medline]
44. Hunt, T (1986) Vitamin A and wound healing. J Am Acad Dermatol 15,817-821[ISI][Medline]
45. Snider, G (1992) Emphysema: The first two centuries and beyond. Am Rev Respir Dis 146,1615-1622[ISI][Medline]
46. Tepper J, Pfeiffer J, Aldrich M, et al. Can retinoic acid ameliorate the physiologic and morphologic effects of elastase instillation in the rat? Chest 2000; 117(suppl)

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				D. Massaro and G. D. Massaro Pre- and Postnatal Lung Development, Maturation, and Plasticity: Invited Review: Pulmonary alveoli: formation, the "call for oxygen," and other regulators Am J Physiol Lung Cell Mol Physiol, March 1, 2002; 282(3): L345 - L358. [Abstract] [Full Text] [PDF]

				E. Nabeyrat, S. Corroyer, V. Besnard, V. Cazals-Laville, J. Bourbon, and A. Clement Retinoic Acid Protects against Hyperoxia-Mediated Cell-Cycle Arrest of Lung Alveolar Epithelial Cells by Preserving Late G1 Cyclin Activities Am. J. Respir. Cell Mol. Biol., October 1, 2001; 25(4): 507 - 514. [Abstract] [Full Text] [PDF]

				G. D. C. MASSARO, D. MASSARO, W.-Y. CHAN, L. B. CLERCH, N. GHYSELINCK, P. CHAMBON, and R. A. S. CHANDRARATNA Retinoic acid receptor-{beta}: an endogenous inhibitor of the perinatal formation of pulmonary alveoli Physiol Genomics, November 9, 2000; 4(1): 51 - 57. [Abstract] [Full Text] [PDF]

				M. Hind, J. Corcoran, and M. Maden Pre- and Postnatal Lung Development, Maturation, and Plasticity: Temporal/spatial expression of retinoid binding proteins and RAR isoforms in the postnatal lung Am J Physiol Lung Cell Mol Physiol, March 1, 2002; 282(3): L468 - L476. [Abstract] [Full Text] [PDF]

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