Oxidative epithelial damage produces hyperresponsiveness of human peripheral airways.

The epithelium probably modulates ahway 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 shortcomlnqs-ot 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 (H20 2) , and changes in responsiveness to the agonists histamine, methacholine, and salbutamol were measured. Toexamine whether intact epithelium acts as a barrier to histamine, the histamine concentration in the organ bath was mea­ sured 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 signifi­ cantly lower with mucosal stimulation than with serosal stimulation (-log ECso: 4.87 and 4.92 versus 5.87 and 5.45 for histamine and methacholine, respectively, p < 0.001). N6 difference was found between the sensitivity to salbutamol of mucosally and serosally stimulated airways (-log ECso: 6.19 and 6.20, respec­ tively). The modulation of the sensitivity to contractile agonists by the epithelium increased with increasing airway size, and was abolished after treatment with H20 2 • Light microscopic examination of H20 2-treated airway preparations revealed specific damage to the columnar ciliated epithelial cells, with relative preser­ vation of basal cells. The penetration of histamine through the airway wall was similar in intact and Hi 0 2­ treated airways. These results suggest that oxidative damage to the airway epithelium may lead to hyper­ responsiveness to inhaled stimuli; however, this may not be due to a change in barrier function of the damaged epithelium. Hulsmann AR, Raatgeep HR, den Hollander JC, Stijnen T, Saxena PR, Kerrebijn KF, de Jongste JC. Oxidative epithelial damage produces hyperresponsiveness of human peripheral air­ ways. Am J Respir Crit Care Med 1994; 149:519-25.