Retinoid receptors in the developing human lung

Nuclear receptors and their ligands are known to play very important roles in lung development. Among these receptors, retinoid receptors, members of the steroid/thyroid hormone receptor superfamily, are classified into retinoic acid receptor (RAR) isoforms α, β, and γ and retinoid X receptor (RXR) isoforms α, β, and γ. In addition, isoforms I and II of the orphan receptor chicken ovalbumin upstream promoter-transcription factor (COUP-TF) have been shown to negatively regulate the activation of retinoid receptors. Both of these receptors have been shown to regulate lung development in the mouse. In the present study we utilized immunohistochemistry and real-time quantitative PCR to examine the expression of RAR-α, -β and -γ, RXR-α, -β and -γ and COUP-TFII in the human fetal lung at 13–16 gestational weeks, a very critical stage of human pulmonary development, in order to study possible roles in pulmonary morphogenesis by comparing these findings with those of the adult lung. RXR-γ immunoreactivity was detected at both proximal (epithelia and mesenchyme of the trachea and bronchi associated with cartilage) and distal (epithelia and mesenchyme of smaller distal bronchi) sites in the fetal lung, but was markedly weaker in the adult lung. RAR-β immunoreactivity was detected in distal mesenchymal cells of the fetal lung, but was not discernible in distal mesenchymal cells in the adult lung (bronchioles, alveolar ducts and alveolus). Relatively intense RAR-γ immunoreactivity was detected in the chondrocytes of bronchial cells. COUP-TFII immunoreactivity was detected with a similar pattern to that of RAR-β. Real-time quantitative PCR analyses revealed that mRNA levels of RXR-γ at proximal and distal sites (ratio of fetal lung/adult lung: 3.4±0.05-fold and 3.1±0.03-fold respectively; P<0.01), RAR-β at distal sites (2.4±0.01-fold; P<0.05) and RAR-γ at proximal sites (2.2±0.11-fold; P<0.05) were significantly higher in the fetus than in the adult.