Retinoids offer hope for the treatment of emphysema

Abstract

Is cessation of cigarette smoking the only effective ‘treatment’ for emphysema? Potentially no, according to a recent paper by Massaro and Massaro1xRetinoic acid treatment partially rescues failed septation in rats and in mice. Massaro, G.D. and Massaro, D. Am. J. Physiol. 2000; 278: 955–960See all References1, who found that all-trans retinoic acid rescued alveoli formation in rats, in which septation was blocked pharmacologically with the glucocorticoid dexamethasone, and in mice genetically predisposed to emphysema.In mammals, alveoli are formed, in part, by the developmentally regulated subdivision (septation) of the saccules that comprise the gas-exchange region of the architectually immature lung. There is a critical period in the last month of pregnancy or shortly after birth (depending on the species) during which septation must occur. If septation is prevented or fails to occur at the appropriate time, alveoli will not form and there is no current means of inducing post hoc septation. In a previous study, the authors found that all-trans retinoic acid, a fat-soluble metabolite of vitamin A that exerts its effects by interacting with specific cytosolic receptors that act as ligand-dependent transcription factors, abrogated elastase-induced pulmonary emphysema in adult rats through the re-formation of alveoli. Now Massaro and Massaro have extended those original observations with all-trans retinoic acid to include a rat model in which failure of septation was induced by dexamethasone and in ‘tight-skin’ (Tsk) mice, in which a tandem duplication within the fibrillin-1 gene genetically predisposes the animals to emphysema. In both models of failed septation, all-trans retinoic acid increased the number of alveoli without affecting lung volume and, in the mice, also increased alveolar surface area. To account for the discrepancy between mice and rats, the authors proposed that all-trans retinoic acid regulates the eruption of septa and their spacing, whereas another factor determines the surface area.If a recent Phase II pilot trial of all-trans retinoic acid in patients with emphysema by Mao et al.2xA phase II pilot study of all-trans retinoic acid for the treatment of human emphysema. Mao, J.T. et al. Am. J. Respir. Crit. Care Med. 2000; 161: 583See all References2 proves beneficial, then this pharmacological approach could provide general remedial action in humans with respiratory diseases that are characterized by an inadequate number of alveoli for adequate gas exchange, such as emphysema, interstitial fibrosis and bronchopulmonary dysplasia.