CysLT1 Receptor Is Protective against Oxidative Stress in a Model of Irritant-Induced Asthma

The bronchoconstrictive and proinflammatory properties of cysteinyl leukotrienes (cysLTs) in allergic asthma mediate their effects predominantly through the cysLT 1 receptor (cysLT 1 R). However, the role of cysLTs and cysLT 1 R in innate immune-triggered asthma is largely unexplored. We explored the synthesis of cysLTs and cysLT 1 R as determinants of airway responses in an oxidative stress–induced model of irritant asthma. Wild-type (WT) mice exposed to 100 ppm Cl 2 for 5 min had airway neutrophilia, increased cysLT production, and pulmonary expression of cysLT-related biosynthetic genes. CysLT 1 R-deficient ( CysLTr1 −/− ) mice that were exposed to Cl 2 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 Cl 2 . 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 Cl 2 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 cysLT 1 R results in aberrant antioxidant response and increased susceptibility to oxidative injury, apparently via a cysLT 1 R-dependent impairment of Nrf2 function.