Retinoids in Lung Development and Regeneration

Abstract

Abstract This review considers the role that retinoids, the family of molecules derived from vitamin A, play in lung development and regeneration.The stages of lung development are described using rodents and where the information is available, humans, as model systems. Because vitamin A is a dietary component it has long been known that early retinoid deprivation of pregnant animals results in abmormalities such as lung agenesis and later deprivation results in defective alveologenesis. The presence of retinoids, the presence of the transducers of the retinoid signal, and the experiments that have been performed both in vivo and in vitro to investigate the role of retinoids are described for each of the stages of lung development from the initial lung bud stages through to alveologenesis. Recent data on the induction of alveolar regeneration by retinoic acid is also described and its possible modes of action via differing cell types, namely type II pneumocytes or haematopoietic stem cells is discussed. The potential roles of retinoic acid in alleviating human conditons, notably the failure of alveologenesis in premature infants and as a therapy for alveolar regeneration to treat diseases involving the loss of alveoli such as emphysema is considered. The adult lung is a highly efficient gas-exchanging organ whose surface area in humans is approximately 70 m 2 . This surface, across which oxygen diffuses to enter the pulmonary circulation and carbon dioxide leaves to enter the expired air, consists of about 300 million alveoli. The diffusion barrier of the alveolar walls whose thickness varies from 0.1 μm to several microns consists of three tissue layers: capillary endothelium, alveolar epithelium, and interstitial tissue. Lung development is a long and complicated process that takes up 90% of the period of gestation and then continues well into childhood in humans. Once formed, however, the adult lung is not a static, unchanging organ but a dynamic one that rapidly responds to pathogens and can change remarkably rapidly in terms of alveolar number according to environmental influences such as calorific intake (Massaro et al ., 2004) or altitude (Massaro and Massaro, 2002). There is a slow and irrevocable decline in alveolar number with age. If the lung is not given the chance to develop properly, such as in low-birth-weight premature infants, then the reduced number of alveoli present often result in lung disorders such as bronchopulmonary dysplasia. In adults, there is a severe and dramatic decline in alveolar number in diseases such as emphysema, which is irreversible and currently incurable. This review deals with the role that retinoids, the family of molecules derived from vitamin A, play in lung development and regeneration. Because vitamin A is a dietary component, the role of retinoids in lung development is particularly relevant to the respiratory problems of premature infants. Most excitingly, recent data from animal studies suggest that retinoids can induce regeneration of alveoli in young adults, which, if relevant to humans, might be the first potential treatment for diseases such as emphysema or bronchopulmonary dysplasia. Therefore, it is particularly timely to review this subject. The review first describes the events and stages of lung development; then discusses what retinoids are, how they are synthesized, and how they act; then describes the role of retinoids in each stage of lung development; and finally discusses its role in lung regeneration and the clinical implications.