The respiratory epithelium produces a variety of inflammatory mediators which may be influencing the bronchial hyperreactivity observed in patients with asthma. Animal studies have demonstrated that removal of the epithelium from tracheal and bronchial smooth muscle causes enhanced responses to cholinergic agonists and histamine (Hist). In this study the effect of epithelium removal on human bronchial smooth muscle response to acetylcholine (ACh) and Hist was assessed. Bronchial smooth muscle was obtained fresh from the operating theatre from 12 patients undergoing thoracotomy. Cumulative concentration effect curves (CCEC) for Hist and ACh were generated for epithelium intact and epithelium denuded muscle strips. All CCEC's were performed in duplicate and all denuded strips were obtained from the same airway immediately adjacent to the intact strip. The mean (+/- SEM) maximum response for Hist for the intact strip was 8.6 +/- 1.1 (grams/gram wet weight) and 12.0 +/- 1.4 (grams/gram wet weight) for the denuded strip (p less than 0.05). For ACh the values were 9.3 +/- 1.3 (g/g wet weight and 14.3 +/- 1.8 (g/g wet weight), respectively (p less than 0.05). The pD2 (-log EC50) for ACh was increased two-fold following epithelium removal (p less than 0.05). For Hist there was a similar increase in pD2 but this did not reach statistical significance. Thus removal of the epithelium from human isolated bronchial smooth muscle appears to modulate responsiveness to ACh and Hist. This enhanced responsiveness consequent to epithelium loss may prove important with respect to the development of worsening asthma.