EOSINOPHIL CHEMOTAXIS INHIBITED BY 5-LIPOXYGENASE BLOCKADE AND LEUKOTRIENE RECEPTOR ANTAGONISM

We studied the effects of the 5-lipoxygenase inhibition and sulfidopep tidyl leukotriene receptor antagonism on lumenal chemotaxis of eosinop hils in 124 guinea pig tracheal explant preparations from 62 animals. Cell migration was assessed histologically and by differential cell co unt, and airway narrowing was measured by calibrated micrometry. Intra lumenal instillation of the chemotaxin, formyl-met-leu-phe (FMLP) caus ed migration of 163,509 +/- 18,103 eosinophils/cm segment (eos/cm) ver sus 15,443 +/- 3,557 eos/cm for segments receiving vehicle only (p < 0 .001). Coincubation of FMLP with zileuton, a selective inhibitor of 5- lipoxygenase, caused a concentration-related inhibition of eosinophil migration. At 10(-10) M zileuton, cell migration caused by FMLP was de creased by 57% and nearly complete reduction to 17,200 +/- 3,620 eos/c m resulted after 10(-6) M zileuton (p < 0.001 versus FMLP). Lumenal na rrowing caused by FMLP (15.3 +/- 3.4%) was attenuated maximally to 1.1 5 +/- 2.51% after 10(-8) M zileuton (p < 0.02). In 36 preparations, co ncentration of leukotriene B-4 (LTB(4)) was measured in treated trache al perfusate. LTB(4) secretion caused by FMLP was 6.4 +/- 0.48 pg/ml v ersus 3.32 +/- 0.89 pg/ml For buffer control at 5 min (p < 0.02) and w as undetectable 120 min after activation with FMLP. Blockade of LTB(4) -receptor with the selective antagonist, LTB(4) dimethyl amide, caused > 90% inhibition of eosinophil migration (p < 0.001). Comparable resu lts were obtained with zafirlukast, an LTD(4)-receptor antagonist. Our data demonstrate that both LTB(4) and LTD(4) facilitate eosinophil mi gration from lamina propria to lumen caused by the chemotaxin, FMLP, a nd that LTB(4)-induced eosinophil migration is accompanied by initial lumenal secretion of LTB(4).