Alveolarization in Retinoic Acid Receptor-β–Deficient Mice

Abstract

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...

All‐Trans Retinoic Acid and Intra‐Amniotic Endotoxin‐Mediated Effects on Fetal Sheep Lung

“…The cytosolic and nuclear receptors for RA were differentially affected by IL-1 beta overexpression with a decrease in the expression of RA receptor (RAR) gamma 2 in inflamed lungs, but the expression of other subtypes of RA receptors was not affected (Bry and Lappalainen, 2006). In another mouse model, deletion of RAR gamma 2 resulted in decreased numbers of alveoli, increased alveolar size, and decreased elastin content (McGowan et al, 1995(McGowan et al, , 2000Hind et al, 2002;Snyder et al, 2005). In the current study, antenatal administration of a large single intramuscular dose of RA 3 hr before endotoxin administration increased RA levels in the fetal lung but did not prevent changes in lung structure induced by antenatal inflammation.…”

Antenatal betamethasone attenuates intrauterine infection-aggravated hyperoxia-induced lung injury in neonatal rats

“…For the morphometric analysis of the lungs, the alveolarization was assessed by measuring radial alveolar count according to the method of Emery and Mithal (36); mean linear intercept was assessed as described by Cooney and Thurlbeck (37); and mean alveolar volume was calculated using the method reported by Snyder et al (38). A minimum of two sections per rat and six fields per section were examined in each analysis, with the examiner blinded to the groups.…”

Lung function in infants and young children with chronic lung disease of infancy: The next steps?

“…(a) genetic predisposition, including sex, race 27,28 and the effect of various genetic polymorphisms, such as those associated with the b2 adrenoceptor, Angiotensin Converting Enzyme (ACE) and glutathione S transferase alleles, [29][30][31][32] (b) preterm delivery per se, [33][34][35] (c) neonatal respiratory disorders and the various treatment strategies on the growing and differentiating lung, [1][2][3][4]27,[36][37][38][39][40] and (d) interactions between neonatal lung disease and the environment (including exposure to tobacco smoke, allergens and infections). 15,41 This in turn requires international consensus on which essential details should be recorded for infants recruited to such studies.…”

“…17,26,30,42,43 Improved methods of assessing alveolar hypoplasia, pulmonary blood flow, parenchymal lung damage and ventilation-perfusion mismatch are essential if we are to evaluate the effects of therapeutic interventions such as the use of retinoids to promote new alveolar growth. 44 …”