Glutathione reaction products with a chemical allergen, methylene-diphenyl diisocyanate, stimulate alternative macrophage activation and eosinophilic airway inflammation.
Glutathione reaction products with a chemical allergen, methylene-diphenyl diisocyanate, stimulate alternative macrophage activation and eosinophilic airway inflammation.
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DOI：
10.1021/tx5005002
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发表时间：
2015-04-20
影响因子：
4.1
通讯作者：
Colangelo CM
中科院分区：
文献类型：
--
作者：
Wisnewski AV;Liu J;Colangelo CM
自从60多年前人们首次认识到异氰酸酯可用于生成聚氨酯以来，异氰酸酯一直是职业性哮喘的主要化学原因，但异氰酸酯哮喘的发病机制尚不清楚。本研究提供了体内证据，证明GSH介导的途径是呼吸道异氰酸酯暴露的哮喘样嗜酸性炎症反应的基础。在幼稚小鼠中，谷胱甘肽反应产物与化学变应原亚甲基二苯基二异氰酸酯的混合物可诱导先天性免疫反应，其特征是呼吸道几丁质酶Ym-1和IL-12/IL-23β(但不是α)亚单位水平显著增加。然而，在通过先前皮肤暴露对MDI免疫致敏的小鼠中，相同剂量的GSH-MDI可诱导显著更大的炎症反应，包括显著增加呼吸道嗜酸性粒细胞数量和粘液产生，以及IL-12/IL-23β、几丁质酶和其他替代巨噬细胞激活的指标。小鼠气道液中的“自身”蛋白白蛋白被GSH-MDI修饰在第414k位，这是MDI与人白蛋白反应的首选位置。414K-MDI结合似乎通过GSH的NH2末端将GSH共价交联到白蛋白上，这是一种独特的构象，可能是环化的单(GSH)-MDI或不对称(S，N‘-连接)双(GSH)-MDI的产物。总之，这些数据支持一种可能的硫醇介导的转氨甲酰化机制，将MDI暴露与致病性嗜酸性炎症反应联系起来。
Isocyanates have been a leading chemical cause of occupational asthma since their utility for generating polyurethane was first recognized over 60 years ago, yet the mechanisms of isocyanate asthma pathogenesis remain unclear. The present study provides in vivo evidence that a GSH mediated pathway underlies asthma-like eosinophilic inflammatory responses to respiratory tract isocyanate exposure. In naïve mice, a mixture of GSH reaction products with the chemical allergen, methylene-diphenyl diisocyanate (MDI), induced innate immune responses, characterized by significantly increased airway levels of Chitinase YM-1 and IL-12/IL-23β (but not α) subunit. However, in mice immunologically sensitized to MDI via prior skin exposure, identical GSH–MDI doses induced substantially greater inflammatory responses, including significantly increased airway eosinophil numbers and mucus production, along with IL-12/IL-23β, chitinases, and other indicators of alternative macrophage activation. The “self”-protein albumin in mouse airway fluid was uniquely modified by GSH–MDI at position 414K, a preferred site of MDI reactivity on human albumin. The 414K–MDI conjugation appears to covalently cross-link GSH to albumin via GSH's NH2-terminus, a unique conformation possibly resulting from cyclized mono(GSH)–MDI or asymmetric (S,N′-linked) bis(GSH)–MDI conjugates. Together, the data support a possible thiol mediated transcarbamoylating mechanism linking MDI exposure to pathogenic eosinophilic inflammatory responses.