Cysteinyl-leukotrienes partly mediate eotaxin-induced bronchial hyperresponsiveness and eosinophilia in IL-5 transgenic mice.
Eotaxin, a selective chemoattractant for eosinophils, induces lung eosinophilia and bronchial hyperresponsiveness (BHR) when administered intratracheally to interleukin-5 (IL-5) transgenic mice. We determined whether these effects of eotaxin were mediated through the production of cysteinyl-leukotrienes. IL-5 transgenic mice were administered eotaxin (5 micrograms) intratracheally after pretreatment with either diluent or a selective 5-lipoxygenase inhibitor SB210661 or a cysteinyl-leukotriene receptor antagonist, pranlukast. Twenty-four hours later, bronchial responsiveness to acetylcholine was measured and the degree of eosinophil influx was determined in bronchoalveolar lavage fluid (BALF) or in lung tissue. Both pranlukast and SB210661 significantly attenuated BHR induced by eotaxin with logPC(50), which is the concentration of acetylcholine needed to increase baseline insufflation pressure 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 attenuation of the eosinophil counts in BALF and in airways. BALF levels of leukotriene C(4) (LTC(4)) 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 both SB210661 (71.2 +/- 21.0) and pranlukast (62.7 +/- 11.5). Concentrations of LTB(4) were not significantly changed. We conclude that eotaxin-induced effects in the airways of IL-5 transgenic mice are partly mediated by the activation of 5-lipoxygenase enzyme leading to the generation of cysteinyl-leukotrienes.
Hisada
T
T
Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom.
Salmon
M
M
Nasuhara
Y
Y
Chung
K F
KF
D000109:Acetylcholine; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001985:Bronchial Provocation Tests; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D003545:Cysteine / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology*; D004802:Eosinophilia / Q000276:immunology*; D004804:Eosinophils / Q000187:drug effects; D015848:Interleukin-5 / Q000235:genetics / Q000502:physiology*; D007958:Leukocyte Count; D020024:Leukotriene Antagonists / Q000494:pharmacology; D015289:Leukotrienes / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D001572:Benzofurans; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D002867:Chromones; D016207:Cytokines; D015848:Interleukin-5; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; C111788:SB 210661; C112381:cysteinyl-leukotriene; D014508:Urea; D003545:Cysteine; D000109:Acetylcholine; C047681:pranlukast