Contributions of Retinoids to the Generation and Repair of the Pulmonary Alveolus: Retinoids Influence Alveolar Formation
When cultures of rat LIF are supplemented with ATRA, there is a 2.5-fold to threefold increase in the steady-state level of tropoelastin messenger RNA. Tropoelastin is the soluble precursor of elastin, a major component of the elastic fiber. In the lung, its production is normally limited to late gestational and early postnatal life (up to postnatal day 21 in the rat and 7 years in humans). The RA-mediated increase in tropoelastin messenger RNA results from an approximately twofold increase in elastin gene transcription, rather than an increase in tropoelastin messenger RNA stability. Retinoid-responsive elements within the first 2 kilobases upstream of the transcriptional start site are required for this effect, and multiple elements may be involved. review
During the last 3 days of prenatal life, rat lungs contain an abundant supply of retinyl esters, which is equal in amount to that in the liver, the major reservoir of retinyl esters in the adult.4 Diethylumbelliferyl phosphate inhibits retinyl ester hydrolysis in organ cultures of lungs obtained from fetal rats, whose mothers are given a vitamin A-sufficient diet.8 This results in a decrease in elastin, but not collagen gene expression. Similar decrements in elas-tin gene expression are observed after the addition of citral, an inhibitor of retinaldehye oxidation to RA.8 When cultured LIF were supplemented with retinol, elastin gene expression was increased, in a fashion similar to that observed after ATRA supplementation. These data indicate that endogenous retinoids increase elastin gene expression during late gestation in the rat.
Since interrupting the flux of retinyl esters to RA reduced elastin gene expression in lung explants, we posited that a similar process may occur in vivo. To address this hypothesis, we studied mice bearing specific RAR and RXR gene deletions.