Involvement of Tachykinins in Endotoxin-Induced Airway Hyperresponsiveness

Inhaled endotoxin, lipopolysaccharide (LPS), has been shown to result in bronchial hyperresponsiveness (BHR) to endogenous bronchoconstrictive mediators such as histamine. To determine the role of sensory neuropeptides released from bronchopulmonary C-fibers in LPS-induced BHR, 24 guinea pigs were allocated randomly to the following four groups. Animals in Groups I and IV were challenged with intratracheal instillation of 100 μl of saline vehicle, and those in Groups II and III with 1 mg of LPS (Escherichia coli, 0111:B4) in 100 μl of saline. Groups III and IV also received a high dose capsaicin (HDC) treatment to deplete tachykinins from C-fibers 1–2 weeks prior to the experiment. Animals were anesthetized and paralyzed, and total lung resistance (R_L) and compliance (C_dyn) were measured continuously during the experiment. Dose responses of R_L and C_dyn to histamine (0–8 μg/kg, intravenously) and capsaicin (0–1.6 μg/kg, intravenously), a specific C-fiber stimulant, were obtained prior to and at 1, 2, and 3 h following LPS/saline vehicle challenge. At 2 h after LPS, ΔR_L caused by histamine (8 μg/kg) was significantly higher in Group II (1.145%) than that in Group I (280%; p < 0.05); similarly, ΔR_L caused by capsaicin (1.6 μg/kg) was also increased after LPS (Group I, 107%; Group II, 267%; p < 0.05). Although HDC treatment completely abolished the bronchomotor response to capsaicin in both Groups III and IV, it enhanced the LPS-induced BHR to histamine (8 μg/kg; Group III, 1.834%; p < 0.05). In conclusion, these results suggest that the role of tachykinins in LPS-induced BHR may be dependent upon the type and the route of administration of the bronchoactive substance studied. Accepted for publication: 13 December 1996