The epithelium probably modulates airway smooth muscle responsiveness by producing relaxing factors, by inactivating agonists, or by acting as a physical barrier. In isolated airway strips, however, only a limited modulatory role of the epithelium has been found, and this may well be due to shortcomings of this airway model. The present study compares the modulatory role of the airway epithelium in human airway tubes and strips. In addition, since oxygen radicals may contribute to epithelial damage in asthma, oxidative damage to the airway epithelium was induced with luminally applied hydrogen peroxide (H2O2), and changes in responsiveness to the agonists histamine, methacholine, and salbutamol were measured. To examine whether intact epithelium acts as a barrier to histamine, the histamine concentration in the organ bath was measured in tubes with intact and damaged epithelium stimulated from the mucosal side. In airway strips, no differences in responsiveness were found between intact and epithelium-denuded airways for any of the three agonists. In contrast, the sensitivity of airway tubes to both histamine and methacholine was significantly lower with mucosal stimulation than with serosal stimulation (-log EC50: 4.87 and 4.92 versus 5.87 and 5.45 for histamine and methacholine, respectively, p < 0.001). No difference was found between the sensitivity to salbutamol of mucosally and serosally stimulated airways (-log EC50: 6.19 and 6.20, respectively). The modulation of the sensitivity to contractile agonists by the epithelium increased with increasing airway size, and was abolished after treatment with H2O2.(ABSTRACT TRUNCATED AT 250 WORDS)