Retinoic acid receptor-β: an endogenous inhibitor of the perinatal formation of pulmonary alveoli

Massaro, Gloria D.; Massaro, Donald; Chan, Wai-Yee; Clerch, Linda Biadasz; Ghyselinck, Norbert B.; Chambon, Pierre; Chandraratna, Roshantha A.S.

doi:10.1152/physiolgenomics.2000.4.1.51

Cited by 111 publications

(75 citation statements)

References 33 publications

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“…Until recently, no abnormal lung phenotype had been 388 associated with deletion of any of these genes (8,10,27). However, others have shown that simultaneous deletion of RAR␣ and RAR␤ produces pulmonary hypogenesis or agenesis, which is usually unilateral (28).…”

Section: Discussionmentioning

confidence: 99%

“…The lungs then were filled through the trachea with 2% paraformaldehyde at 20 cm H 2 O pressure and were maintained at this pressure for 18 h at 4°C. This inflation pressure has been used in previous studies describing the influence of retinoids on alveolarization (4,5,10). The lungs were monitored for leakage during this procedure, and only lungs that did not leak were used for further study.…”

Section: Methodsmentioning

confidence: 99%

“…In the present study, we hypothesized that all-trans retinoic acid also binds to RAR␤ in the lung and that activated, ligandbound RAR␤ in turn directly or indirectly regulates genes that promote alveolarization. Massaro et al (10) reported that RAR␤ gene-deleted mice have smaller and more numerous alveoli in their lungs; however, alveolar surface area was not different between the control and RAR␤ null mice. In the present study, we evaluated the effects of RAR␤ gene deletion on morphologic, biochemical, and physiologic aspects of alveolarization in the neonatal mouse lung.…”

mentioning

confidence: 97%

“…Massaro et al (10) reported that the rate of alveolarization is increased in RAR␤ gene-deleted mice. The RAR␤ null animals used in the study by Massaro and co-workers (11,27) were generated by deleting exon 10, whereas the RAR␤ null animals used in the present study were generated by deleting exon 6 of the RAR␤ gene.…”

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Alveolarization in Retinoic Acid Receptor-β–Deficient Mice

et al. 2005

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Retinoids bind to nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors]. RAR␤, one of three isoforms of RARs (␣, ␤, and ␥), is expressed in the fetal and adult lung. We hypothesized that RAR␤ plays a role in alveolarization. Using morphometric analysis, we determined that there was a significant increase in the volume density of airspace in the alveolar region of the lung at 28, 42, and 56 d postnatal age in RAR␤ null mice when compared with wild-type controls. The mean cord length of the respiratory airspaces was increased in RAR␤ null animals at 42 d postnatal age. Respiratory gasexchange surface area per unit lung volume was significantly decreased in RAR␤ null animals at 28, 42, and 56 d postnatal age. In addition, alveolar ducts tended to comprise a greater proportion of the lung airspaces in the RAR␤ null mice. The RAR␤ null mice also had impaired respiratory function when compared with wild-type control mice. There was no effect of RAR␤ gene deletion on lung platelet-derived growth factor (PDGF) receptor ␣ mRNA levels in postnatal lung tissue at several postnatal ages. However PDGF-A protein levels were significantly lower in the RAR␤ null mice than in wild-type controls. Thus, deletion of the RAR␤ gene impairs the formation of the distal airspaces during the postnatal phase of lung maturation in mice via a pathway that may involve PDGF-A. Retinoids regulate the development of the conducting airways and the gas-exchange portion of the lung (1). The major biologically active retinoid, all-trans retinoic acid, is a metabolite of retinol (vitamin A) (2). Retinol can be stored within lung tissue esterified to fatty acids, where it can be released by retinyl ester hydrolases and then be converted to all-trans retinoic acid (1). All-trans retinoic acid binds with high affinity to retinoic acid receptors (RARs), which exist in three isoforms, ␣, ␤, and ␥ (3). Retinoid X receptors (RXRs) primarily bind 9-cis retinoic acid (3). RARs form a heterodimer with RXRs and bind to retinoid responsive elements in target genes (3). RARs and RXRs are members of the steroid hormone receptor superfamily of transcription factors (3).Massaro and co-workers (4,5) reported that all-trans retinoic acid increases the number of alveoli in rat lung. In the first study, postnatal rats that were treated with all-trans retinoic acid had increased numbers of alveoli and increased gas exchange surface area (4). A synthetic glucocorticoid, dexamethasone, decreases the number of alveoli in this animal model. All-trans retinoic acid overcame the inhibitory effects of dexamethasone on alveolarization in the postnatal rats (4). In the second study, elastase was insufflated into the lungs of adult rats to create a model of emphysema, i.e. the damaged lungs in the treated rats were characterized by fewer and larger alveoli and decreased gas exchange area (5). When the elastase-treated rats received an injection of all-trans retinoic acid, the emphysema-like effects of the elastase treatment were almost completely reversed, i...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Alveolarization in Retinoic Acid Receptor-β–Deficient Mice

et al. 2005

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“…Studies in RAR mutant mice suggest that RA can act as a positive or a negative regulator of alveolization depending on the RAR type. RARb-null mice septate earlier and faster than control mice, whereas RARg null have decreased alveolar number and an increase in alveolar volume (40,41).…”

Section: Retinoic Acid From Buds To Alveoli: a Role In Lung Repair Anmentioning

confidence: 95%