CATIONIC PROTEINS ALTER SMOOTH-MUSCLE FUNCTION BY AN EPITHELIUM-DEPENDENT MECHANISM

Using a perfused guinea pig tracheal tube preparation, which allows th e selective application of agonists to either the serosal or luminal s urface, we have investigated whether two synthetic cationic proteins, poly-L-arginine and poly-L-lysine, can modify epithelium-dependent res ponses. With an intact epithelium, methacholine was approximately 150 times less potent when applied intraluminally than when applied extral uminally. This difference was abolished by chemically removing the epi thelium with the detergent CHAPS. Intraluminal application of KCl indu ced a dose-related relaxation of a precontracted trachea, which was al so abolished by epithelium removal. Perfusion of the luminal surface w ith cationic proteins for 1 h (10 mug/ml) increased the potency of int raluminally applied methacholine without modifying the responses to ex traluminally applied methacholine. Cationic proteins also attenuated t he relaxant effects of intraluminally applied KCl. These effects occur red in the absence of any overt epithelial cell damage. in contrast, w hen the serosal surface of the trachea was treated with poly-L-arginin e, there was no modification of either methacholine-induced contractio n or KCl-induced relaxation. The effects of poly-L-arginine were inhib ited by coperfusion with the polyanions albumin (10 mug/ml) or heparin (100 mug/ml). In contrast to cationic proteins, intraluminal perfusio n with a polyanion, poly-L-aspartate (10 mug/ml), failed to modify eit her methacholine-induced contraction or KCl-induced relaxation. Our da ta demonstrate that cationic proteins can modify epithelium-dependent responses in the airways. Although the precise mechanisms are unclear, a role is suggested for a charge-mediated interaction with the respir atory epithelium, resulting in airway smooth musele dysfunction.