EFFECT OF EPITHELIAL DENUDATION, INFLAMMATORY MEDIATORS AND MAST-CELL ACTIVATION ON THE SENSITIVITY OF ISOLATED HUMAN AIRWAYS TO METHACHOLINE

In asthmatics, both the continuous release of mast cell-derived inflammatory mediators and damage of the airway epithelium may be related to the degree of bronchial responsiveness. We therefore evaluated the effect of inflammatory mediators and mast cell activation on the cholinergic responsiveness of strips of human bronchioles with and without epithelium. Cumulative concentration-response curves to methacholine were generated from strips with or without epithelium before, during and after incubation with threshold doses of either methacholine (3 x 10(-7) M, controls), histamine (3 x 10(-7) M), the thromboxane A2 analogue, U46619 (10(-9) M), prostaglandin (PG) D2 (3 x 10(-7) M), PGF2-alpha (3 x 10(-7) M), leukotriene (LT) C4 (10(-9) M), or anti-human immunoglobulin E (24.4 +/- 4.0-mu-g . ml-1). Strips without epithelium were 1.6 times more sensitive to methacholine than strips with epithelium (-log EC50: 5.76 +/- 0.04 vs. 5.97 +/- 0.04, P < 0.0001). The average contraction in response to identical doses of anti-IgE in strips without epithelium was 3 times greater than the contraction in strips with epithelium (P < 0.05). Threshold concentrations of histamine, U44619 and PGD2 caused a similar non-parallel leftward shift of the concentration-response curve of strips with or without epithelium to methacholine (P < 0.05). Together, epithelial denudation and low levels of mediators caused a 4.0- to 9.1-fold increase in sensitivity based on the -log EC10 and a 1.8- to 3.0-fold increase in sensitivity based on the -log EC50. It is concluded that removal of the epithelium and the presence of inflammatory mediators increase additively the cholinergic sensitivity of peripheral human airways, especially to low concentrations of an acetylcholine agonist and that the epithelium may be an important determinant of the magnitude of the response to inhaled allergens.