Eosinophils generate brominating oxidants in allergen-induced asthma
Eosinophils generate brominating oxidants in allergen-induced asthma
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DOI：
10.1172/jci9702
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发表时间：
2000-05-01
影响因子：
15.9
通讯作者：
Hazen, SL
中科院分区：
文献类型：
--
作者：
Wu, WJ;Samoszuk, MK;Hazen, SL
嗜酸性粒细胞促进组织损伤，并参与哮喘等过敏原引发疾病的发病机制，但对嗜酸性粒细胞靶点损伤的化学基础尚不清楚。我们现在证明，体内嗜酸性粒细胞的激活通过酪氨酸残基的溴化导致蛋白质的氧化损伤，这是迄今为止未被识别的人体组织中生物靶标的共价修饰途径。质谱研究表明，在存在血浆卤化物水平的情况下，3-溴酪氨酸可作为通过嗜酸性过氧化物酶- h2o2系统修饰的蛋白质的特定“分子指纹”。我们应用局部过敏原挑战来模拟嗜酸性粒细胞和溴化氧化剂在人肺损伤中的作用。哮喘患者（而非健康对照）的支气管内活检标本显示嗜酸性粒细胞和嗜酸性过氧化物酶显著富集，轻度过敏性哮喘患者支气管肺泡灌洗（BAL）蛋白中3-溴酪氨酸的基线水平与对照组相比略有升高，但没有统计学意义上的显著升高。暴露于节段性过敏原攻击后，哮喘患者的肺节段BAL 3-溴酪氨酸含量增加了约10倍，但3-氯酪氨酸含量仅增加了2至3倍，3-氯酪氨酸是中性粒细胞和单核细胞衍生的髓过氧化物酶形成的一种特异性氧化产物。这些结果表明，由嗜酸性粒细胞产生的活性溴化物质是体内形成的一类独特的氧化剂。他们还揭示了嗜酸性过氧化物酶作为人类过敏原引发的炎症组织损伤的潜在治疗靶点。
Eosinophils promote tissue injury and contribute to the pathogenesis of allergen-triggered diseases like asthma, but the chemical basis of damage to eosinophil targets is unknown. We now demonstrate that eosinophil activation in vivo results in oxidative damage of proteins through bromination of tyrosine residues, a heretofore unrecognized pathway for covalent modification of biologic targets in human tissues. Mass spectrometric studies demonstrated that 3-bromotyrosine serves as a specific "molecular fingerprint" for proteins modified through the eosinophil peroxidase-H2O2 system in the presence of plasma levels of halides. We applied a localized allergen challenge to model the effects of eosinophils and brominating oxidants in human lung injury. Endobronchial biopsy specimens from allergen-challenged lung segments of asthmatic, but not healthy control, subjects demonstrated significant enrichments in eosinophils and eosinophil peroxidase, Baseline levels of 3-bromotyrosine in bronchoalveolar lavage (BAL) proteins from mildly allergic asthmatic individuals were modestly but not statistically significantly elevated over those in control subjects. After exposure to segmental allergen challenge, lung segments of asthmatics, but not healthy control subjects, exhibited a >10-fold increase in BAL 3-bromotyrosine content, but only two- to threefold increases in 3-chlorotyrosine, a specific oxidation product formed by neutrophil- and monocyte-derived myeloperoxidase. These results identify reactive brominating species produced by eosinophils as a distinct class of oxidants formed in vivo. They also reveal eosinophil peroxidase as a potential therapeutic target for allergen-triggered inflammatory tissue injury in humans.