Abstract：
Chronic obstructive pulmonary disease (COPD) is an important public health challenge worldwide, and is usually caused by significant exposure to noxious agents, particularly cigarette smoke. Recent studies have revealed that excessive production of neutrophil extracellular traps (NETs) in the airways is associated with disease severity in COPD patients. NETs are extracellular neutrophil-derived structures composed of chromatin fibers decorated with histones and granule proteases including neutrophil elastase (NE). However, the effective prevention of NET formation in COPD remains elusive. Here, we demonstrated that treatment with GW311616A, a potent and selective inhibitor of NE, prevented cigarette smoke extract (CSE)-induced NET formation in human neutrophils by blocking NE nuclear translocation and subsequent chromatin decondensation. Inhibition of NE also abrogated CSE-induced ROS production and migration impairment of neutrophils. Administration of GW311616A in vivo substantially reduced pulmonary generation of NETs while attenuating the key pathological changes in COPD, including airway leukocyte infiltration, mucus-secreting goblet cell hyperplasia, and emphysema-like alveolar destruction in a mouse model of COPD induced by chronic cigarette smoke exposure. Mice treated with GW311616A also showed significant attenuation of neutrophil numbers and percentages and the levels of neutrophil chemotactic factors (LTB4, KC, and CXCL5) and proinflammatory cytokines (IL-1β, and TNF-α) in bronchoalveolar lavage fluid compared to mice treated with cigarette smoke exposure only. Furthermore, GW311616A treatment considerably improved lung function in the COPD mouse model, including preventing the decline of FEV100/FVC and delta PEF as well as inhibiting the increase in FRC, TLC, and FRC/TLC. Overall, our study suggests that NE plays a critical role in cigarette smoke-induced NET formation by neutrophils and that inhibition of NE is a promising strategy to suppress NET-mediated pathophysiological changes in COPD.
摘要：
慢性阻塞性肺疾病(COPD)是世界范围内一个重要的公共卫生挑战。通常是由大量接触有毒物质引起的，尤其是香烟烟雾。最近的研究表明，气道中中性粒细胞胞外陷阱（NETs）的过度产生与COPD患者的疾病严重程度有关。NET是细胞外中性粒细胞衍生的结构，由用组蛋白和颗粒蛋白酶（包括中性粒细胞弹性蛋白酶（NE））装饰的染色质纤维组成。然而,有效预防COPD中NET的形成仍然难以捉摸。这里,我们证明了用GW311616A治疗，一种有效和选择性的NE抑制剂，通过阻断NE核易位和随后的染色质缩合，防止了香烟烟雾提取物（CSE）诱导的人中性粒细胞中的NET形成。NE的抑制还消除了CSE诱导的ROS产生和嗜中性粒细胞的迁移损害。GW311616A的体内给药显著减少了NETs的肺生成，同时减弱了COPD的关键病理变化，包括气道白细胞浸润，分泌粘液的杯状细胞增生，慢性香烟烟雾暴露诱导的COPD小鼠模型中的肺气肿样肺泡破坏。用GW311616A处理的小鼠还显示中性粒细胞数量和百分比以及中性粒细胞趋化因子水平的显着减弱（LTB4，KC，和CXCL5）和促炎细胞因子（IL-1β，与仅暴露于香烟烟雾的小鼠相比，支气管肺泡灌洗液中的TNF-α）。此外，GW311616A治疗显著改善COPD小鼠模型的肺功能,包括防止FEV100/FVC和ΔPEF的下降以及抑制FRC的增加，TLC,和FRC/TLC。总的来说,我们的研究表明,NE在香烟烟雾诱导的中性粒细胞形成NET中起关键作用,抑制NE是抑制NET介导的COPD病理生理变化的有前景的策略.
