The effects of a specific tachykinin receptor antagonist FK-224 on ozone-induced airway hyperresponsiveness and inflammation.
We have demonstrated previously that tachykinin depletion by capsaicin prevented the ozone-induced airway hyperresponsiveness and the bronchial wall oedema in guinea pigs. To further clarify the role of neurogenic inflammation in ozone-induced airway hyperresponsiveness, we investigated the effects of a specific tachykinin receptor antagonist (FK-224) in guinea pigs. Animals were anaesthetized, tracheostomized and mechanically ventilated. Total pulmonary resistance (RL) was calculated from transpulmonary pressure and box flow in a plethysmograph. Airway responsiveness was assessed by determining the provocative concentration of histamine aerosol that increased RL to twice the baseline value (PC200). Animals were injected with either FK-224 (10 mg/kg, dissolved in 0.2 mL/kg DMSO) or vehicle (0.2 mL/kg DMSO) intravenously, then pre-ozone PC200 was determined. Following this measurement, animals were exposed to 3 ppm ozone for 60 min. Immediately after exposure, the histamine dose response curve was evaluated again. Bronchoalveolar lavage (BAL) was performed in animals treated with FK-224 or vehicle. In animals treated with vehicle, ozone exposure caused significant decrease in PC200 and moderate increase in neutrophils in BAL fluid. FK-224 pre-treatment significantly inhibited ozone-induced hyperresponsiveness. Neutrophils in BAL fluid did not significantly increase after ozone exposure in animals treated with FK-224. By contrast, the degree of epithelial desquamation did not differ significantly between the two groups. We conclude that neurogenic inflammation caused by tachykinin release may be responsible for ozone-induced bronchial hyperresponsiveness, and that tachykinins may play a role in the initiation of airway inflammation.
Aizawa
H
H
Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Koto
H
H
Nakano
H
H
Inoue
H
H
Matsumoto
K
K
Takata
S
S
Shigyo
M
M
Hara
N
N
D000403:Airway Resistance / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D007249:Inflammation / Q000188:drug therapy*; D007262:Infusions, Intravenous; D008297:Male; D010126:Ozone; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D012016:Reference Values
D010456:Peptides, Cyclic; D018039:Receptors, Tachykinin; C075570:FK 224; D010126:Ozone