CATIONIC PROTEIN-INDUCED SENSORY NERVE ACTIVATION - ROLE OF SUBSTANCE-P IN AIRWAY HYPERRESPONSIVENESS AND PLASMA-PROTEIN EXTRAVASATION

We have previously reported that human eosinophil granule major basic protein and synthetic cationic proteins such as poly-L-arginine and po ly-L-lysine, can increase airway responsiveness in vivo. In the presen t study, we have investigated whether activation of sensory C-fibers i s important in this phenomenon. Dose-response curves to methacholine w ere constructed before and 1 h after intratracheal instillation of pol y-L-lysine in anaesthetized spontaneously breathing rats, and the conc entration of methacholine required to induce a doubling in total lung resistance was calculated. Poly-L-lysine induced a fivefold increase i n airway responsiveness, which was inhibited by neonatal capsaicin tre atment and potentiated by phosphoramidon (100 mu g/ml). Furthermore, p retreatment with either CP, 96-345, or RP-67580 two selective NK-1 rec eptor antagonists inhibited poly-L-lysine-induced airway hyperresponsi veness and plasma protein extravasation. In vitro, cationic proteins s timulated the release of calcitonin gene-related peptidelike immunorea ctivity from perfused slices of the main bronchi. Our results demonstr ate that cationic proteins can activate sensory C-fibers in the airway s, an effect which is important in the subsequent development of airwa y hyperresponsiveness and plasma protein extravasation. Cationic prote ins may therefore function as a link between inflammatory cell accumul ation and sensory nerve activation.