A Possible Therapy for Smoke‐Induced Lung Injuries by Inhalation of All‐Trans Retinoic Acid in a Guinea Pig Model System

Abstract

Smoking is known to be linked with various cardiovascular and pulmonary diseases. Cigarette smoke (CS) not only affects smokers but also contributes to the health problems of non-smokers. We have recently described a clinical relevant model system for mainstream (MS) and sidestream (SS) CS exposure in guinea pigs. Retinoic acid (RA) is necessary for the maintenance of respiratory epithelial cell differentiation in vivo and thus have prospects as preventive agents for some forms of cancer. Systemic applications of retinoids as therapy of smoke-induced lung injuries carry the risks of toxic side effects and may not accumulate in the target tissue. Therefore, we adapted a PARI LC Star nebulizer (Pari, Richmond, VA) to a tubical system, which allows the inhalation treatment of six guinea pigs at the same time. As a bolus, we applied a water-miscible formulation, consisting of Cremophor EL (ethoxylated castor oil), all-trans retinoic acid, butylated hydroxyl toluene (BHT) in PBS or without the retinoid as vehicle. Over a period of 5 weeks, 3 mL of this solution was nebulized for 20 minutes once a day. HPLC analysis of lung samples of sacrificed animals showed an increase in 13-cis retinoic acid of 23.85% (control) and 31.81% in MS animals. Other RA isomers could not be detected. (Supported by DAMD17-03-1-0352 & DAMD17-03-2-0054 grants)