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 CysLTrl(-/-) 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 trans location 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.