Eosinophils generate brominating oxidants in allergen-induced asthma

Eosinophils promote tissue injury and contribute to the pathogenesis of all ergen-triggered diseases like asthma, but the chemical basis of damage to e osinophil targets is unknown. We now demonstrate that eosinophil activation in vivo results in oxidative damage of proteins through bromination of tyr osine residues, a heretofore unrecognized pathway for covalent modification of biologic targets in human tissues. Mass spectrometric studies demonstra ted that 3-bromotyrosine serves as a specific "molecular fingerprint" for p roteins modified through the eosinophil peroxidase-H2O2 system in the prese nce 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 segmen ts 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 allergi c asthmatic individuals were modestly but not statistically significantly e levated over those in control subjects. After exposure to segmental allerge n 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 i dentify 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.