THE ROLE OF NEUTROPHIL AND EOSINOPHIL IN BRONCHIAL ASTHMA.

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In this project two studies were performed. First study was to see the effect of specific neutrophil elastase inhibitors, ONO-5046 and FRl34043, on antigen-induced asthmatic responses in allergic dual responded sheep. Ascaris suum inhalation over 20 min induced early (IAR) and late (LAR) bronchoconstriction, airway hyperreactivity to methacholine (AHR), increases in recovered neutrophils and eosinophils and the concentrations of leukotriene B_4 (LTB_4) and thromboxane B_2 (TXB_2) in bronchoalveolar lavage fluid (BALF) during LAR.Continuous infusion of ONO-5046 before antigen challenge signficantly reduced both early and late bronchoconstriction. The inhibitory effect was marked in late bronchoconstriction. Also, the drug significantly reduced the antigen-induced AHR,neutrophil accumulation in the airway and increase in LTB_4 during LAR.Another neutrophil elastase inhibitor, FR134043, also reduced both IAR and LAR.These findings suggest that neutrophil elastase is involved in antigen-induced bronchoconstriction and AHR mediated by neutrophil accumulation and 5-lipoxygenase products in allergic sheep. Second study was to see the effects of specific LTB_4 receptor antagonist, ONO-4057, on asthmatic responses in the same allergic sheep model. The oral administration of the drug before antigen challenge significantly reduced the late phase bronchoconstriction along with the inhibition of eosinophil accumulation in the airway. Also, the drug treatment significantly reduced AHR 8h after antigen challenge. These finding suggest that LTB_4 is an important chemotactic factor for eosinophils and the accumulated eosinophil Plays an important role in the development of LAR and AHR.