Leukotrienes mediate part of Ova-induced lung effects in mice via EGFR.
Antigen induces murine bronchial hyperreactivity (BHR), inflammation, mucus accumulation, and airway remodeling. To investigate whether leukotrienes (LT) mediate the effects of antigen [ovalbumin (Ova)], we studied 5-lipoxygenase (5-LO) expression in immunized BP2 mice and blocked LT synthesis with the 5-LO inhibitor zileuton or antagonized their effects with receptor antagonists [cysteinyl leukotriene (Cys-LT)-ra MK-571, LY-171883; LTB4-ra PH-163]. Cys-LT content increased in the bronchoalveolar lavage fluid (BALF) as early as 15 min after the intratracheal instillation of Ova. Zileuton inhibited LT release in the BALF and eosinophil recruitment in the lungs, and dose dependently reduced BHR, mucus accumulation, and remodeling, as did the LT-ra. Thus LT, released just after antigen challenge, might constitute the first step in accounting for the effects of Ova. Because mucus accumulation is regulated via the EGF receptor (EGFR), which is also implicated in the effects of LT, we studied this pathway with AG-1478, an EGFR tyrosine kinase inhibitor given at 0.5, 4, and 20 mg/kg. AG-1478 inhibited BHR, inflammation, and lung remodeling induced by Ova or by molecules themselves generated by Ova, such as LT, IL-13, and monocyte chemoattractant protein-1, which promote identical effects, suggesting the involvement of the EGFR pathway in the asthma-like syndrome observed.
Vargaftig
B Boris
BB
Unité de Pathogénie Microbienne Moléculaire, Unité Associée Institut Pasteur-INSERM U389, Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France.
Singer
Monique
M
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002455:Cell Division / Q000502:physiology; D018925:Chemokines / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000473:pathology; D066246:ErbB Receptors / Q000502:physiology*; D015289:Leukotrienes / Q000502:physiology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009093:Mucus / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000473:pathology; D010047:Ovalbumin / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines; D012333:RNA, Messenger / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D018925:Chemokines; D016207:Cytokines; D004791:Enzyme Inhibitors; D015289:Leukotrienes; D011799:Quinazolines; D012333:RNA, Messenger; D020032:Tyrphostins; C101044:RTKI cpd; D010047:Ovalbumin; D003094:Collagen; D001094:Arachidonate 5-Lipoxygenase; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases