Inhibition by a novel peptide leukotriene receptor antagonist ONO‐1078 of airway wall thickening and airway hyperresponsiveness to histamine induced by leukotriene C4 or leukotriene D4 in guinea‐pigs

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Abstract
We studied the effect of intravenous administration of leukotriene (LT) C4 or LTD4 on airway responsiveness to histamine and airway wall thickening in guinea-pigs. Guinea-pigs were killed and the lungs were fixed in formalin. Slides from paraffin-embedded section of the lungs were stained and the airways that were cut in transverse section were measured by tracing enlarged images using a digitizer. Moreover, airway resistance (Raw) was determined by a pulmonary mechanics analyser and we calculated two indices, an index of airway wall thickening and the one of airway hyperresponsiveness to histamine, from changes of baseline-Raw and peak-Raw following intravenous administration of histamine before and after the intravenous administration of LTC4 or LTD4. The infusion of LTC4 or LTD4 induced an increase of the relative thickness of the airway wall in peripheral bronchi demonstrable by the histological examination. In analysis of airway function, intravenous administration of LTC4 or LTD4 induced airway hyperresponsiveness to histamine with airway wall thickening. The LTC4 and LTD4 receptor antagonist ONO-1078 inhibited these effects of LTC4 and LTD4, suggesting LTC4 and LTD4 may induce airway wall thickening and airway hyperresponsiveness through LTC4 and LTD4 receptors in the airways.