Tachykinins Mediate the Acute Increase in Airway Responsiveness Caused by Toluene Diisocyanate in Guinea Pigs

Exposing guinea pigs to toluene diisocyanate (TDI) causes an acute increase in airway responsiveness to inhaled acetylcholine. The mechanism of this increase in airway responsiveness is unknown. Capsaicin-sensitive afferent nerves and the tachykinins they release upon activation are important in controlling bronchomotor tone in guinea pigs. To determine whether tachykinins are important in TDI-induced airway hyperresponsiveness, we studied the effects of tachykinin depletion, using capsaicin, and competitive tachykinin antagonism, using (D-Arg1, D-Pro2, D-Trp7,9, Leu11) substance P, on TDI-induced airway hyperresponsiveness. In 9 of 9 untreated animals, TDI exposure caused a large and significant increase in airway responsiveness to acetylcholine. The mean concentration of acetylcholine required to decrease specific airway conductance by 50% below baseline (the PD50) was 1.51% before TDI exposure and 0.17% after TDI exposure (p < 0.0005). Capsaicin treatment had no effect on the PD50 but prevented the TDI-induced increase in airway responsiveness in 10 of 12 animals. (The PD50 was 1.03% before TDI and 1.27% after TDI exposure.) Treatment with the tachykinin antagonist (D-Arg1, D-Pro2, D-Trp7,9, Leu11) substance P also abolished the TDI-induced increase in airway responsiveness in all 5 animals treated Although TDI exposure also causes airway edema, the effect of capsaicin treatment on TDI-induced airway hyperresponsiveness did not result from prevention of airway edema. TDI exposure caused a marked increase in tracheal extravasation of intravenously administered Evans blue dye that was not prevented by capsaicin treatment. Untreated animals exposed to TDI had 116 ± 13 µg (mean ± SEM) Evans blue per g of tracheal tissue, whereas capsaicin-treated animals exposed to TDI had 139 ± 15 µg/g). The results of this study suggest that tachykinins are important in TDI-induced airway hyperresponsiveness and that this effect is not due to the known effect of tachykinins on airway vascular permeability.