To determine the potential role of neuropeptides in acrolein-induced airway responses, capsaicin-treated guinea pigs were exposed to acrolein aerosol in a regimen causing increased airway sensitivity to substance P. Acrolein exposure resulted in 100% mortality after capsaicin pretreatment compared with only 14% mortality in guinea pigs not pretreated with capsaicin. Acrolein exposure by itself caused marked pulmonary inflammation and large airway epithelial necrosis and denudation. Pretreatment with capsaicin exacerbated these responses throughout the lung. Intravenous acrolein caused an acute dose-related bronchoconstriction in naive guinea pigs that was diminished by capsaicin treatment and potentiated by thiorphan pretreatment, which suggests that arolein exposure causes an acute release of capsaicin-sensitive C-fiber neuropeptides. To determine whether acrolein-induced C-fiber release altered neuronal viability, either rhodamine or Fast Blue dye was instilled intratracheally into vehicle- or acrolein-exposed guinea pigs. Acrolein exposure did not reduce the neuronal uptake or retrograde transport of these dyes, as indicated by the number of fluorescent cell bodies in the nodose ganglia. To determine the functional state of airway neurons, the dose response to intravenous capsaicin was measured in vehicle-exposed and acrolein-exposed guinea pigs; no differences were observed. Thus, acrolein appears to activate airway C-fibers, which release neuropeptides that are protective against this insult, with no suggestion of an accompanying reduction in C-fiber function.