Topical delivery of 13-cis-retinoic acid by inhalation up-regulates expression of rodent lung but not liver retinoic acid receptors

Chemopreventive retinoids may be more effective if delivered to the lung ep ithelium by inhalation, 13-cis-Retinoic acid (13-cis-RA) was comparable to all-trans-retinoic acid (RA) in inducing transglutaminase II (TGase II) in cultured human cells. Inhaled 13-cis-RA had a significant stimulatory activ ity on TGase II in rat lung (P < 0.001) but not in liver tissue (P < 0.544) , Furthermore, inhaled 13-cis-RA at daily deposited doses of 1.9 mg/kg/day up-regulated the expression of lung retinoic acid receptors (RARs) alpha, b eta, and gamma at day 1 (RAR alpha by 3.4-fold, RAR beta by 7.2-fold, and R AR alpha by 9.7-fold) and at day 17 (RAR alpha by 4.2-fold, RAR beta by 10. 0-fold, and RAR gamma by 12.9-fold). At a lower aerosol concentration, dail y deposited doses of 0.6 mg/kg/day were also effective at 28 days. Lung RAR alpha was induced by 4.7-fold, RAR beta by 8.0-fold, and RAR gamma by 8.1- fold. Adjustment of dose by exposure duration was also effective; thus, inh alation of an aerosol concentration of 62.2 mu g/liter, for durations from 5 to 240 min daily for 14 days, induced all RARs from 30.6- to 74-fold at t he shortest exposure time. None of the animals exposed to I3-ris-RA aerosol s showed RAR induction in livers. By contrast, a diet containing pharmacolo gical RA (30 mu g/g of diet) failed to induce RARs in SENCAR mouse lung, al though it induced liver RARs (RAR alpha, 21.8-fold; RAR beta, 13.5-fold; RA R gamma, 12.5-fold); it also failed to induce lung TGase II. A striking inc rease of RAR alpha expression was evident in the nuclei of hepatocytes, Pha rmacological dietary RA stimulated RAR alpha, RAR beta, and RAR gamma as ea rly as day 1 by 2-, 4-, and 2.1-fold, respectively, without effect on lung RARs, Therefore, 13-cis-RA delivered to lung tissue of rats is a potent sti mulant of lung but not liver RARs, Conversely, dietary RA stimulates liver but not lung RARs, These data support the concept that epithelial delivery of chemopreventive retinoids to lung tissue is a more efficacious way to at tain up-regulation of TGase II and the retinoid receptors and possibly to a chieve chemoprevention.