PERSISTENT AIRWAY EOSINOPHILIA AFTER LEUKOTRIENE (LT) D-4 ADMINISTRATION IN THE GUINEA-PIG - MODULATION BY THE LTD(4) RECEPTOR ANTAGONIST, PRANLUKAST, OR AN INTERLEUKIN-5 MONOCLONAL-ANTIBODY

Aerosolized cysteinyl leukotrienes (CysLTs) elicit migration of eosino phils into guinea pig lungs and the airways of patients with asthma, T he present studies were designed to analyze the concentration-response relationship, time course, and pharmacologic and histologic character istics of leukotriene D-4 (LTD(4))-induced eosinophil influx into the airways of conscious guinea pigs. Animals were exposed to aerosols of 0.3 to 30 mu g/ml LTD(4) for 1 min, during which specific airway condu ctance (sGaw) was monitored. Bronchoalveolar lavages (BALs) of guinea pig airways were conducted at selected times from 4 h to 4 wk after LT D(4) challenge. LTD(4) produced maximal decreases in sGaw (70 to 90% r eduction) at all concentrations tested and concentration-related incre ases in eosinophil levels in BALs, assessed 24 h after challenge. Incr eased numbers of eosinophils in the bronchial epithelium and subepithe lium were confirmed histologically. Significant eosinophilia was maint ained for up to 4 wk postchallenge. Pretreatment with the LTD(4) recep tor antagonist, pranlukast (ONO-1078, SB 205312) (20 mg/kg, intragastr ically), significantly inhibited both the bronchoconstriction and the eosinophilia at 24 h, whereas the cyclooxygenase inhibitor, meclofenam ic acid (5 mg/kg, intragastrically), had no effect on either parameter . Histologic observations were consistent with BAL results. Pretreatme nt with the rat anti-mouse antibody to interleukin-5 (IL-5), TRFK-5 (1 0-300 mu g, intraperitoneally), produced dose-related inhibition of LT D(4)-induced eosinophilia, measured in 24 h or 3 wk BAL, but did not a ffect the acute bronchoconstriction. These results indicate that LTD(4 ) elicits airway eosinophil influx in guinea pigs which persists as lo ng as 4 wk after a single exposure, and provide the first evidence tha t IL-5 may have a role in LTD(4)-induced airways inflammation. This an d other previously reported proinflammatory effects of LTD(4) may cont ribute significantly to its overall influential role in the pathophysi ology of asthma, and may underlie the therapeutic benefit of CysLT rec eptor antagonists, such as pranlukast, in this disorder.