Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, Center for Comparative Respiratory Biology and Medicine, University of California, Davis, CA, USA.
Free Radic Res. 2011 Feb;45(2):165-76. doi: 10.3109/10715762.2010.521154. Epub 2010 Oct 18.
Neutrophil-dependent reactions catalysed by myeloperoxidase (MPO) are thought to play important roles in the pulmonary pathobiology of cystic fibrosis (CF). Aerosolized thiol antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC) are currently being utilized as therapeutics to modify CF respiratory tract oxidative processes. This study hypothesized that MPO in CF airway lining fluids may be a target of such therapeutics. MPO activity in sputum from 21 adult CF patients was found to be inversely associated with lung function (FEV(1)). In contrast, systemic inflammation (assessed by plasma C-reactive protein) was not correlated with lung function. Ex vivo studies revealed that GSH and NAC effectively scavenged N-chloramines in sputum and inhibited sputum MPO activity with potency exquisitely dependent upon MPO activity levels. Detailed kinetic analyses revealed that NAC and GSH inhibit MPO by distinct mechanisms. Activation of the key pro-inflammatory transcription factor NF-κB in cultured HBE1 cells was inhibited by GSH. The findings reveal that MPO activity and its reactive products represent useful predictors of the doses of inhaled thiol antioxidants required to ameliorate airway oxidative stress and inflammation in CF patients and provide mechanistic insight into the antioxidative/anti-inflammatory mechanisms of action of GSH and NAC when administered into the CF lung.
髓过氧化物酶（MPO）催化的中性粒细胞依赖反应被认为在囊性纤维化（CF）的肺部病理生物学中发挥重要作用。雾化硫醇抗氧化剂，如谷胱甘肽（GSH）和 N-乙酰半胱氨酸（NAC），目前被用作治疗剂来修饰 CF 呼吸道的氧化过程。本研究假设 CF 气道衬液中的 MPO 可能是此类治疗剂的作用靶点。研究发现，21 名成年 CF 患者的痰中 MPO 活性与肺功能（FEV1）呈负相关。相比之下，全身炎症（通过血浆 C-反应蛋白评估）与肺功能无关。离体研究表明，GSH 和 NAC 可有效清除痰中的 N-氯胺，并抑制痰 MPO 活性，其效力高度依赖于 MPO 活性水平。详细的动力学分析表明，NAC 和 GSH 通过不同的机制抑制 MPO。GSH 抑制培养的 HBE1 细胞中关键促炎转录因子 NF-κB 的激活。这些发现表明 MPO 活性及其反应产物是预测 CF 患者吸入硫醇抗氧化剂所需剂量以改善气道氧化应激和炎症的有用指标，并为 GSH 和 NAC 给药进入 CF 肺部时的抗氧化/抗炎作用机制提供了机制见解。
