Effect of a leukotriene B4 receptor antagonist SC-53228 on ozone-induced airway hyperresponsiveness and inflammation in dogs.
The importance of the potent neutrophil chemoattractant leukotriene (LT)B4 in causing ozone-induced bronchoconstriction, airway inflammation, and airway hyperresponsiveness in dogs was studied using the LTB4-receptor antagonist SC-53228. Seven dogs from random sources were studied three times, at least 2 wk apart. On each occasion, acetylcholine (Ach) airway responsiveness was measured before and 1 h after ozone (3 ppm, 30 min) or dry air inhalation, followed by a bronchoalveolar lavage (BAL). On the first day, dogs were treated with SC-53228 (0.4 mg/kg intravenously) followed by a continuous intravenous infusion of 1.2 mg/kg/h before ozone inhalation. On the other two days, diluent was infused followed by ozone or dry air inhalation. Cell counts were measured in BAL and cell activation was measured by spontaneous and by phorbol myristate acetate-stimulated (PMA) (2.4 mumol/L) oxygen radical release, measured from washed BAL cells (4 x 10(6) cells) by lucigenin-enhanced chemiluminescence. Ozone inhalation caused bronchoconstriction and airway hyperresponsiveness. SC-53228 inhibited the ozone-induced airway hyperresponsiveness (p = 0.006), but not the bronchoconstriction. Spontaneous (p = 0.004) and PMA-stimulated (p = 0.04) lucigenin-enhanced chemiluminescence were increased after ozone inhalation. The ozone-induced increases in PMA-stimulated chemiluminescence were significantly attenuated by treatment with SC-53228 (p = 0.04). These results suggest that LTB4 is involved in the pathogenesis of ozone-induced airway hyperresponsiveness, possibly through activation of airway inflammatory cell.
Stevens
W H
WH
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Vanderheyden
C
C
Wattie
J
J
Lane
C G
CG
Smith
W
W
O'Byrne
P M
PM
D000109:Acetylcholine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000503:physiopathology; D001985:Bronchial Provocation Tests / Q000379:methods; D001991:Bronchitis / Q000139:chemically induced* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D005260:Female; D008163:Luminescent Measurements; D008297:Male; D010126:Ozone / Q000633:toxicity*; D011897:Random Allocation; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D016897:Respiratory Burst / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D001578:Benzopyrans; D018102:Receptors, Leukotriene B4; C082206:7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid; D010126:Ozone; D000109:Acetylcholine