RETINOIC ACID INDUCES CHANGES IN THE PATTERN OF AIRWAY BRANCHING AND ALTERS EPITHELIAL-CELL DIFFERENTIATION IN THE DEVELOPING LUNG IN-VITRO

Retinoids have been shown to influence pattern formation during develo pment and regeneration in numerous systems such as limbs, vertebrae, a nd neural tube although there is little information about the effects of retinoids on pattern formation in visceral organs. We investigated the effects of exogenous retinoic acid on the in vitro pattern of airw ay branching and on lung epithelial cell differentiation, Histology, [ H-3]thymidine autoradiographies and reverse transcriptase/polymerase c hain reaction (RT/PCR) amplification were used to assess the effects o f retinoids and the expression of lung epithelial markers of different iation. We found that retinoic acid interferes, in a dose-dependent fa shion, with the expression of epithelial genes that are found in dista l segments of the fetal lung (surfactant-associated proteins SP-A, SP- B, and SP-C). At high concentrations, retinoic acid (RA) dramatically altered the developmental pattern of the lung, favoring growth of stru ctures that resemble proximal airways and concomitantly suppressing di stal epithelial buds. We hypothesize that this in vitro ''proximalizin g'' effect on the developing lung may be related to alterations in the expression of pattern-related genes.