Department of Pathology and UBC James Hogg Research Centre, Institute for Heart and Lung Health, University of British Columbia, Vancouver, British Columbia, Canada.
Am J Respir Crit Care Med. 2012 Jan 1;185(1):34-43. doi: 10.1164/rccm.201103-0468OC.
Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation.
To determine the role of MPO in COPD.
We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure.
At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-κB binding.
We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.
炎症和氧化应激与香烟烟雾产生慢性阻塞性肺疾病（COPD）的有害作用有关。髓过氧化物酶（MPO）是一种中性粒细胞和巨噬细胞产物，在杀菌中很重要，但也会引发炎症反应和组织氧化。
确定 MPO 在 COPD 中的作用。
我们用 2-硫代黄嘌呤 MPO 抑制剂 AZ1 处理豚鼠，建立 6 个月香烟烟雾暴露模型，一组在吸烟第 1 天开始接受化合物治疗，另一组在烟雾暴露 3 个月后接受治疗。
在 6 个月时，两种治疗方法均消除了烟雾引起的灌洗液炎症细胞增加，在很大程度上改善了生理变化，并阻止或停止了形态学肺气肿和小气道重塑的进展。香烟烟雾引起髓过氧化物酶生成的蛋白质氧化标志物二酪氨酸的免疫组织化学染色显著增加，这一效应在两种治疗组中都明显降低。血清 8-异前列腺素，另一种氧化应激标志物，也显示出类似的趋势。两种治疗方法还防止了小肺内动脉的肌化，但仅部分改善了烟雾引起的肺动脉高压。急性 AZ1 可防止烟雾引起的细胞因子介质和核因子-κB 结合表达增加。
我们得出结论，MPO 抑制剂能够阻止肺气肿和小气道重塑的进展，并在长期吸烟暴露过程中相对较晚开始治疗时，部分预防肺动脉高压，这表明 MPO 抑制可能是一种新的、有用的 COPD 治疗方法。保护作用似乎与抑制氧化损伤和下调烟雾引起的炎症反应有关。
