Alveolarization in retinoic acid receptor-beta-deficient mice.

Retinoids bind to nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors]. RARbeta, one of three isoforms of RARs (alpha, beta, and gamma), is expressed in the fetal and adult lung. We hypothesized that RARbeta 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 RARbeta null mice when compared with wild-type controls. The mean cord length of the respiratory airspaces was increased in RARbeta null animals at 42 d postnatal age. Respiratory gas-exchange surface area per unit lung volume was significantly decreased in RARbeta 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 RARbeta null mice. The RARbeta null mice also had impaired respiratory function when compared with wild-type control mice. There was no effect of RARbeta gene deletion on lung platelet-derived growth factor (PDGF) receptor alpha mRNA levels in postnatal lung tissue at several postnatal ages. However PDGF-A protein levels were significantly lower in the RARbeta null mice than in wild-type controls. Thus, deletion of the RARbeta 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.