Mice Bearing Deletions of Retinoic Acid Receptors Demonstrate Reduced Lung Elastin and Alveolar Numbers

Abstract

In mammals, including rats and mice, the development of pulmonary alveolar septa is primarily limited to late gestation and the early periods of postnatal life. Before this time, the rat lung contains a relatively large supply of endogenous retinyl ester that, together with its metabolite retinoic acid, has been shown to increase elastin gene expression and the number of alveoli. We have hypothesized that mice bearing a deletion of one or more genes encoding for retinoic acid receptors (which are DNA binding proteins that alter transcription of retinoic acid-responsive genes) may demonstrate abnormalities in retinoid-mediated alveolar formation. Our studies demonstrate that the absence of the retinoic acid receptor-gamma (RARgamma) is associated with a decrease in the steady-state level of tropoelastin messenger RNA in a subpopulation of lung fibroblasts at Postnatal Day 12. RARgamma gene deletion also resulted in a decrease in whole lung elastic tissue and alveolar number, and an increase in mean cord length of alveoli (L(m)) at Postnatal Day 28. The additional deletion of one retinoid X receptor (RXR)alpha allele resulted in a decrease in alveolar surface area and alveolar number, and an increase in L (m). These data indicate that RARgamma is required for the formation of normal alveoli and alveolar elastic fibers in the mouse, and that RAR/RXR heterodimers are involved in alveolar morphogenesis.

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.…”

Mechanisms of Lung Development: Contribution to Adult Lung Disease and Relevance to Chronic Obstructive Pulmonary Disease

“…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).…”

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

“…Whereas RA increased alveolar number in newborn rats [77], deletion of RA receptors (RARs) resulted in disrupted alveolar formation [78]. Whereas corticosteroids accelerate microvascular fusion and block septation, RA prevents these effects, which suggests regulatory role of the latter in early mechanisms of alveolarization and of corticosteroids in the later maturation step.…”