Dickerhof Nina, Huang Jie, Min Elysia, Michaëlsson Erik, Lindstedt Eva-Lotte, Pearson John F, Kettle Anthony J, Day Brian J
Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand.
Department of Medicine, National Jewish Health, Denver, CO, USA.
Free Radic Biol Med. 2020 May 20;152:91-99. doi: 10.1016/j.freeradbiomed.2020.03.001. Epub 2020 Mar 4.
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.
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.
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.
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.
囊性纤维化（CF）肺部疾病的特征是严重的细菌感染、过度的中性粒细胞炎症和氧化应激。产生次氯酸的中性粒细胞酶髓过氧化物酶（MPO）与更差的疾病结局相关。因此，气道中MPO的药理学抑制具有治疗潜力。我们研究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具有CF样肺部炎症的小鼠的感染结局，同时不影响细菌清除。
将过表达β-上皮钠通道（βENaC）的转基因小鼠（n = 10）感染多食伯克霍尔德菌，并通过口服灌胃每天两次用MPO抑制剂AZM198（125 μmol/kg）或赋形剂治疗两天。每天记录体重。在支气管肺泡灌洗液（BALF）中测量MPO活性、氧化应激标志物、炎性细胞因子和白细胞数量。在肺组织匀浆中测定细菌载量。
在感染过程中，用AZM198治疗的小鼠体重减轻比用赋形剂治疗的小鼠少（p < 0.01）。来自用AZM198治疗的小鼠的BALF中的MPO活性和谷胱甘肽磺酰胺（一种次氯酸特异性谷胱甘肽氧化产物）显著更低（p < 0.05）。治疗组和对照组小鼠的BALF中的炎性细胞因子CXCL1和TNF-α以及肺部细菌载量没有显著差异。
口服AZM198可抑制上皮衬液中的MPO活性。通过抑制MPO在肺部感染期间阻断上皮衬液中的次氯酸产生可改善具有CF样肺部炎症的小鼠的发病率，而不干扰细菌清除。MPO的药理学抑制是限制人类囊性纤维化肺部疾病中破坏性氧化应激的一种方法。
