title: CysLT1 Receptor Is Protective against Oxidative Stress in a Model of Irritant-Induced Asthma.
abstract: The bronchoconstrictive and proinflammatory properties of cysteinyl leukotrienes (cysLTs) in allergic asthma mediate their effects predominantly through the cysLT1 receptor (cysLT1R). However, the role of cysLTs and cysLT1R in innate immune-triggered asthma is largely unexplored. We explored the synthesis of cysLTs and cysLT1R as determinants of airway responses in an oxidative stress-induced model of irritant asthma. Wild-type (WT) mice exposed to 100 ppm Cl2 for 5 min had airway neutrophilia, increased cysLT production, and pulmonary expression of cysLT-related biosynthetic genes. CysLT1R-deficient (CysLTr1(-/-)) mice that were exposed to Cl2 demonstrated airway hyperresponsiveness to inhaled methacholine significantly greater than in WT BALB/c mice. Compared to WT mice, airway neutrophilia and keratinocyte chemoattractant production levels were higher in CysLTr1(-/-) mice and airway hyperresponsiveness was ameliorated using a granulocyte depletion Ab. CysLTr1(-/-) mice also demonstrated prolonged bronchial epithelial cell apoptosis following Cl2 WT mice showed increased antioxidant and NF erythroid 2-related factor 2 (Nrf2) gene expression, Nrf2 nuclear translocation in bronchial epithelial cells, and increased reduced glutathione/oxidized glutathione following Cl2 exposure whereas CysLTr1(-/-) mice did not. Furthermore, CysLTr1(-/-) mice demonstrated increased pulmonary E-cadherin expression and soluble E-cadherin shedding compared with WT mice. Loss of a functional cysLT1R results in aberrant antioxidant response and increased susceptibility to oxidative injury, apparently via a cysLT1R-dependent impairment of Nrf2 function.
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre and McGill University, Montreal, Quebec H4A 3J1, Canada;
authors.forename: Toby
authors.initials: T
authors.lastname: McGovern
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre and McGill University, Montreal, Quebec H4A 3J1, Canada;
authors.forename: Madison
authors.initials: M
authors.lastname: Goldberger
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre and McGill University, Montreal, Quebec H4A 3J1, Canada;
authors.forename: Michael
authors.initials: M
authors.lastname: Chen
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre and McGill University, Montreal, Quebec H4A 3J1, Canada;
authors.forename: Benoit
authors.identifier: 0000-0002-7093-5851
authors.initials: B
authors.lastname: Allard
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre and McGill University, Montreal, Quebec H4A 3J1, Canada;
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Hamamoto
authors.affiliation: Department of Allergy and Immunology, Brigham and Women's Hospital, Boston, MA 02130; and Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Kanaoka
authors.affiliation: Department of Allergy and Immunology, Brigham and Women's Hospital, Boston, MA 02130; and Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: K Frank
authors.initials: KF
authors.lastname: Austen
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre and McGill University, Montreal, Quebec H4A 3J1, Canada;
authors.forename: William S
authors.initials: WS
authors.lastname: Powell
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre and McGill University, Montreal, Quebec H4A 3J1, Canada; james.martin@mcgill.ca.
authors.forename: James G
authors.initials: JG
authors.lastname: Martin
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology*; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D002713:Chlorine / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007509:Irritants / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D018384:Oxidative Stress; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism*
chemical_list: D000485:Allergens; D015820:Cadherins; D007509:Irritants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D018077:Receptors, Leukotriene; D002713:Chlorine; C083169:leukotriene D4 receptor