Am. J. Respir. Crit. Care Med., Vol 152, No. 5, 11 1995, 1443-1448.
Effect of a leukotriene B4 receptor antagonist SC-53228 on ozone- induced airway hyperresponsiveness and inflammation in dogs
WH Stevens, C Vanderheyden, J Wattie, CG Lane, W Smith and PM O'Byrne
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
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.
