A C-11 substituted PGE 2 analog, DHET-PGE 2 [ ℓ -11-deoxy-11α-(2-hydroxyethylthio)-PGE 2 methyl ester], was demonstrated to exert potent bronchodilator activity in three in vivo models of augmented airway resistance: (1) acute bronchospasms, induced by 5-hydroxytryptamine, histamine and acetylcholine in the anesthetized guinea pig, (2) acute bronchospasm, induced by pilocarpine, in the anesthetized dog, and (3) chronic bronchospasm, induced by SO 2 exposure, in the unanesthetized dog. In acute and 30-day toxicological studies in the dog, no cardiovascular, respiratory or gastrointestinal side effects were observed at aerosol doses at least 1,000 times those required for efficacy. In vitro , DHET-PGE 2 effectively relaxed isolated preparations of dog bronchus that had been contracted with carbachol. In clinical studies, human asthmatics and bronchitics responded consistently to β-agonist bronchodilators but variably to DHET-PGE 2. Overall, increases in pulmonary resistance or decreases in FEV 1 were observed with DHET-PGE 2. Subsequent evaluation in isolated carbachol-contracted human bronchus revealed that, in contrast to the bronchodilator activity of PGE 1 and β-agonists, DHET-PGE 2 and PGE 2 induced contraction. Considered along with results from previous clinical studies on other PGs, these data underscore the difficulties in making extrapolations on this class of compounds from animal models to humans and suggest that human bronchial tissue may provide the only appropriate preclinical test system for predicting the clinical efficacy of PG bronchodilators.