Synergistic effects of pranlukast and leukotriene B4 receptor antagonist on antigen-induced pulmonary reaction.

We now attempted to differentiate effects of cysteinyl-leukotrienes and leukotriene B4 on antigen-induced pulmonary reaction by using a selective leukotriene D4/E4 (CysLT1) receptor antagonist and a selective LTB4 (BLT) receptor antagonist in rats. An intratracheal challenge with ovalbumin to Brown-Norway rats actively sensitized with ovalbumin produced two phases of airway responses which were estimated based on airway resistance, the immediate-type airway response within 30 min, and the delayed-type airway response beginning from 4 to 6 h after the challenge. Pretreatment of the rats with a CysLT1 receptor antagonist (pranlukast) failed to reduce the elevation of airway resistance, and pretreatment with a BLT receptor antagonist (ONO-4057; 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]- oxyphenoxy] valeric acid) also produced no decrease. In contrast, combined pretreatment of the rats with pranlukast and ONO-4057 did not reduce the amplitude of the immediate-type airway response, but did allow the elevated airway resistance to return to its baseline level and also significantly inhibited the delayed-type airway response. Histological examination at 6 h after ovalbumin challenge showed infiltration of inflammatory cells with a predominance of neutrophils and scattered eosinophils in the bronchial submucosa. While pretreatment with neither pranlukast nor with ONO-4057 inhibited the infiltration of inflammatory cells in the bronchial submucosa, pretreatment with the two antagonists combined significantly inhibited the infiltration of granulocytes into the bronchial submucosa. On the contrary, intratracheal administration of either leukotriene D4 or leukotriene B4 up to 10 microg resulted in the infiltration of granulocytes into the bronchial submucosa, but no synergism for the infiltration of granulocytes was observed after combined administration. These results suggest that leukotriene B4 appears to play a significant role in the antigen-induced pulmonary reaction in association with cysteinyl-leukotrienes. Accordingly, the combined antagonism at the CysLT1 receptor and BLT receptor may be a useful intervention for the treatment of bronchial asthma.