Experimental Studies on Mechanisms of Eosinophil Infiltration in Airways in Bronchial Asthma and on its Modulation by Drugs

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There is now considerable evidence that eosinophils participate in the sathma process as proinflammatory effector cells, and recent attention has been focused on the mechanisms of airway eosinophil accumulation in ongoing disease. This study was dedigned to determine which mediators are actually responsible for attracting eosinophils to the airway mucosa and examine the effect of suppression of airway eosinophilia on the pathophysiology of asthma. Guinea pigs sensitized by intraperitoneal injection of ovalbumin (OA) responded to a single exposure to aerosolized OA with biphasic infiltration of eosinophils in the airways ; a striking early-phase which peaked at 6 hr and a delayed-phase which peaked at 24 hr and persisted for as long as 5 days. The early-phase infiltration was suppressed by the precious administration ofPAF antagonist, and the delayed-phase was inhibited when animals were treated with Cyclosporin A (CyA) or FK-506 (FK), T lymphocyte-selective immunosuppressive agents. Th … More ese results suggested that PAF may contribute to early-phase and T cell factor (s) may contribute to delayed-phase eosinophil infiltration of the airways. To look at whether PAF generation really occurs in the lungs of guinea pigs after antigen challenge, we determined PAF activity in bronchoalveolar lavage (BAL) fluids and found that there existedl pmol of PAF ler 1 kg body weight. Suppression of airway eosinophilia by CyA and FK resulted in the inhivition of antigen-induced late asthmatic response and a subsequent increase in bronchial hyperresponsiveness in guineapigs immunized by repeated exposure to aerosolized OA, raising the possibility that drugs precenting eosinophil migration into the airways would be useful in the treatment of asthma.Finally, we tested whether PAF- or lymphokine-like substance might be also important in the antigeninduced eosinophil infiltration in humans. Basophils and mononuclear cells were separated from the peripheral blood of Dermatophagoides farinae (DF) -sensitive asthmatic subjects, cultured in the presence of DF antigen and eosinophil chemotactic activity (ECA) in the supernatants was tested using a modified Boyden chamber technique. Basophils produced ECA which was blocked by a specific PAF antagonist, whereas mononuclear cells produced heat-stable ECA with a MW 30,000, presumably lymphokine, which peaked at 3-5 day. These results suggest that PAF- and lymphokine-like substance may play a key role in the airway eosinophils in asthmatic subjects. Less