Airway administration of dexamethasone, 3′-5′-cyclic adenosine monophosphate, and isobutylmethylxanthine facilitates compensatory lung growth in adult mice

Abstract

The combination of dexamethasone, 8-bromo-3'-5'-cyclic adenosine monophosphate, and isobutylmethylxanthine, referred to as DCI, has been reported to optimally induce cell differentiation in fetal lung explants and type II epithelial cells. DCI administration is also known to modulate the expression levels of many genes known to be involved in the facilitation of lung growth. Recently, we found that RNA silencing of thyroid transcription factor 1 (TTF-1) delayed compensatory lung growth. DCI is also known to induce TTF-1 expression in pulmonary epithelial cells. From these findings, we hypothesized that DCI administration may facilitate compensatory lung growth. In the present study, using a postpneumonectomy lung growth model in 9-wk-old male mice, we found that compensatory lung growth was significantly facilitated by airway administration of DCI immediately following left pneumonectomy, as indicated by the increase in the residual right lung dry weight index. TTF-1 expression was significantly elevated by DCI administration, and transient knockdown of TTF-1 attenuated the facilitation of compensatory lung growth by DCI. These results suggested that DCI facilitated compensatory lung growth, at least in part, through the induction of TTF-1. Morphological analyses suggested that DCI administration increased the number of alveoli, made each of them smaller, and produced a net increase in the calculated surface area of the alveoli per volume of lung. The effect of a single administration was maintained during the observation period, which was 28 days. DCI with further modifications may provide the material to potentially augment residual lung function after resection.