Cysteinyl-leukotrienes partly mediate eotaxin-induced bronchial hyperresponsiveness and eosinophilia in IL-5 transgenic mice

Eotaxin, a selective chemoattractant for eosinophils, induces lung eosinoph ilia and bronchial hyperresponsiveness (BHR) when administered intratrachea lly to interleukin-5 (IL-5) transgenic mice. We determined whether these ef fects of eotaxin were mediated through the production of cysteinyl-leukotri enes. IL-5 transgenic mice were administered eotaxin (5 mu g) intratracheal ly after pretreatment with either diluent or a selective 5-lipoxygenase inh ibitor SB210661 or a cysteinyl-leukotriene receptor antagonist, pranlukast. Twenty-four hours later, bronchial responsiveness to acetylcholine was mea sured and the degree of eosinophil influx was determined in bronchoalveolar lavage fluid (BALF) or in lung tissue. Both pranlukast and 5B210661 signif icantly attenuated BHR induced by eotaxin with logPC(50), which is the conc entration of acetylcholine needed to increase baseline insufflation pressur e by 50%, from -0.43 +/- 0.16 to 0.39 +/- 0.10 and from -0.22 +/- 0.10 to 0 .53 +/- 0.10, respectively (p < 0.05). There was also a significant attenua tion of the eosinophil counts in BALF and in airways. BALF levels of leukot riene C-4 (LTC4) showed a significant increase after eotaxin from 23.9 +/- 6.7 to 165.0 +/- 35.0 pg/ml (p < 0.05) but were partially suppressed by bot h SB210661 (71.2 +/- 21.0) and pranlukast (62.7 +/- 11.5). Concentrations o f LTB4 were not significantly changed. We conclude that eotaxin-induced eff ects in the airways of IL-5 transgenic mice are partly mediated by the acti vation of 5-lipoxygenase enzyme leading to the generation of cysteinyl-leuk otrienes.