Inhalation of lipopolysaccharide (LPS) has been associated with increased airway responsiveness and inflammation both in humans and in animals. To investigate the contribution of capsaicin-sensitive nerves to these changes, we compared airway responsiveness and inflammation after intratracheal administration of 10 micrograms/kg LPS (Escherichia coli O55:B5 lipopolysaccharide) or saline in guinea pigs treated 10 days previously with 50 mg/kg capsaicin and in those pretreated with the capsaicin vehicle. Four hours after LPS, airway responsiveness and cell counts in the bronchoalveolar lavage were assessed. To determine airway responsiveness, guinea pigs were anesthetized, tracheotomized, and mechanically ventilated before exposure to increasing concentrations of aerosolized histamine (10(-4) to 10(-3) M). Capsaicin pretreatment prevented the LPS-induced increase in airway responsiveness in response to aerosolized histamine. It significantly reduced total cell recovery in the bronchoalveolar lavage after LPS (1,167 +/- 167 10(3) cells/ml in capsaicin-treated guinea pigs versus 2,171 +/- 184 10(3) in vehicle-treated guinea pigs) by reducing the LPS-induced influx of neutrophils and macrophages. Additional experiments demonstrated that the activity of neutral endopeptidase (NEP) in the tracheal epithelium was not significantly different in guinea pigs injected with LPS from that in the saline-treated control animals, and that the pretreatment with the NEP inhibitor phosphoramidon did not increase the LPS-induced influx of neutrophils into the bronchoalveolar lavage. These results demonstrate that in the guinea pig, capsaicin-sensitive nerves are involved in LPS-induced airway hyperresponsiveness and inflammation.