BACKGROUND Cystic fibrosis (CF) lung disease is characterized by severe bacterial infections, excessive neutrophilic inflammation and oxidative stress. The neutrophil enzyme myeloperoxidase (MPO), which produces hypochlorous acid, is associated with worse disease outcomes. Therefore, pharmacological inhibition of MPO in the airways has therapeutic potential. We investigated whether treating mice with an MPO inhibitor during pulmonary infection decreases oxidative stress and improves infection outcomes in mice with CF-like lung inflammation without impacting on bacterial clearance. METHODS Transgenic β-epithelial sodium channel (βENaC)-overexpressing mice (n = 10) were infected with Burkholderia multivorans and treated twice daily with the MPO inhibitor AZM198 (125 μmol/kg) or vehicle administered by oral gavage for two days. Bodyweight was recorded daily. MPO activity, markers of oxidative stress, inflammatory cytokines and leukocytes numbers were measured in bronchoalveolar lavage fluid (BALF). Bacterial burden was determined in lung tissue homogenates. RESULTS During the course of infection, mice treated with AZM198 lost less weight than vehicle-treated mice (p < 0.01). MPO activity and glutathione sulfonamide, a hypochlorous acid-specific glutathione oxidation product, were significantly lower in BALF from AZM198-treated mice (p < 0.05). The inflammatory cytokines CXCL1 and TNF-α in BALF and bacterial burden in the lung were not significantly different between treated and control mice. CONCLUSIONS Orally administered AZM198 inhibits MPO activity in epithelial lining fluid. Blocking hypochlorous acid production in epithelial lining fluid during pulmonary infections through inhibition of MPO improves morbidity in mice with CF-like lung inflammation without interfering with clearance of bacteria. Pharmacological inhibition of MPO is an approach to limit destructive oxidative stress in cystic fibrosis lung disease in humans.

中文翻译：

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抑制髓过氧化物酶可降低患有囊性纤维化样肺炎的小鼠的发病率和氧化应激。

背景技术囊性纤维化（CF）肺病的特征在于严重的细菌感染，过度的嗜中性粒细胞炎症和氧化应激。产生次氯酸的嗜中性粒细胞髓过氧化物酶（MPO）与疾病恶化相关。因此，气道中MPO的药理抑制作用具有治疗潜力。我们调查了在肺部感染期间用MPO抑制剂治疗小鼠是否能降低氧化应激并改善CF型肺部炎症小鼠的感染结果而不会影响细菌清除。方法用过表达伯克霍尔德氏菌感染过表达β-上皮钠通道（βENaC）的转基因小鼠（n = 10），每天两次用MPO抑制剂AZM198（125μmol/ kg）或媒介物经口管饲法处理两天。每天记录体重。在支气管肺泡灌洗液（BALF）中测量MPO活性，氧化应激指标，炎性细胞因子和白细胞数量。确定肺组织匀浆中的细菌负担。结果在感染过程中，用AZM198治疗的小鼠体重减轻的幅度小于溶媒治疗的小鼠（p <0.01）。在AZM198处理的小鼠的BALF中，MPO活性和次氯酸特异性谷胱甘肽氧化产物谷胱甘肽磺酰胺显着降低（p <0.05）。在治疗小鼠和对照小鼠中，BALF中的炎性细胞因子CXCL1和TNF-α以及肺中的细菌负荷没有显着差异。结论口服AZM198可抑制上皮内衬液中的MPO活性。通过抑制MPO阻止肺部感染期间上皮内衬液中次氯酸的产生，可改善CF型肺部炎症小鼠的发病率，而不会干扰细菌的清除。MPO的药理抑制作用是一种限制人类囊性纤维化肺病中破坏性氧化应激的方法。