EFFECTS OF ZYMOSAN-ACTIVATED HUMAN GRANULOCYTES ON ISOLATED HUMAN AIRWAYS

In asthma a temporal association exists between the late allergic reaction (LAR), the influx of granulocytes into the airway wall, and an increase in bronchial responsiveness. We therefore tested the hypothesis that activated human granulocytes constrict isolated human airways and increase their sensitivity to cholinergic stimuli. Bronchial rings were dissected from 23 lung tissue specimens collected at thoracotomy and studied isotonically in organ baths. Airways were incubated with 1, 2, 5, 10, or 20 x 10(6) granulocytes from normal or atopic donors. Activation of the cells with serum-treated zymosan (STZ, 0.2 mg/ml), which itself did not alter baseline airway caliber, resulted in a bronchoconstriction proportional to the number of zymosan-activated granulocytes (ZAG) present (r(s) = 0.79, p < 0.001). This contraction was reduced by about 70% with the leukotriene C4/D4 receptor antagonist FPL 55712 (11.5-mu-M; p < 0.001) or with the lipoxygenase inhibitor nordihydroguaiaretic acid (10-mu-M; p < 0.001). The scavengers of activated oxygen molecules superoxide dismutase (300 U/ml) and bovine catalase (5,000 U/ml), the cyclooxygenase inhibitor indomethacin (10-mu-M), or the histamine (H1) receptor antagonist mepyramine (2.8-mu-M) had no effect. Granulocyte suspensions from atopic donors contained more eosinophils (p < 0.001), and the magnitude of the contraction to 10 x 10(6) ZAG was related to the proportion of eosinophils (r(s) = 0.66, p < 0.01). The sensitivity of the airways to methacholine was unchanged in the presence of 1, 2, or 5 x 10(6) ZAG and decreased with 10 or 20 x 10(6) ZAG (p < 0.05). The cholinergic twitch and the nonadrenergic relaxation to near maximal electrical field stimulation (EFS) were unchanged in the presence of 5 x 10(6) ZAG, but the slow contractile response to EFS was slightly potentiated (p < 0.01). If during the LAR the number of granulocytes and their activation resemble those used in these in vitro experiments the results suggest that during the LAR granulocytes do not increase airway muscle sensitivity but may contribute to muscle contraction. Most of this muscle contraction seems secondary to the release of LTC4, which is related to the proportion of eosinophils among the granulocytes.