Kim Suil, Nadel Jay A
Cardiovascular Research Institute, Cancer Center, and Department of Medicine, University of California San Francisco,94143-0130, USA.
Treat Respir Med. 2004;3(3):147-59. doi: 10.2165/00151829-200403030-00003.
Airway mucus hypersecretion is a serious and presently untreatable symptom of COPD. Over the past several years, emerging evidence has implicated epidermal growth factor receptor (EGFR) expression and activation in mucin production by airway epithelial (goblet) cells. Activated neutrophils recruited to the airways (and their secreted products) play several key roles in EGFR-dependent mucus hypersecretion: (i) activated neutrophils secrete tumor necrosis factor (TNF)-alpha, which induces EGFR expression in airway epithelial cells; (ii) activated neutrophils release reactive oxygen species, which activate EGFR; (iii) neutrophil elastase cleaves the EGFR proligand, pro-transforming growth factor (TGF)-alpha, releasing mature TGF alpha which activates EGFR in a ligand-dependent fashion; and (iv) neutrophil elastase causes potent goblet cell degranulation. The secretion of active products by neutrophils appears carefully regulated. The local release of neutrophil elastase requires close contact between the neutrophil and another cell, mediated by surface adhesion molecules, thus limiting proteolysis to the immediate pericellular environment. In the airway lumen, neutrophils undergo apoptosis and are cleared by macrophages without releasing their intracellular contents. In contrast, neutrophils that die by necrosis disgorge proteases and reactive oxygen species into the lumen. In COPD, conditions within the airway lumen promote neutrophil necrosis. It is concluded that neutrophil death via necrosis leads to the high concentrations of free neutrophil elastase and reactive oxygen species in the sputum of patients with airway neutrophilia and mucus hypersecretion. Inflammatory cells (neutrophils), molecules (neutrophil elastase and reactive oxygen species), signaling pathways (EGFR), and cellular processes (neutrophil necrosis) contribute to mucus hypersecretion in COPD, and are potential targets for therapy. Interventions that target EGFR, neutrophil elastase, and reactive oxygen species exist and can be evaluated as treatments for neutrophil-dependent mucus hypersecretion.
气道黏液高分泌是慢性阻塞性肺疾病（COPD）的一种严重且目前无法治疗的症状。在过去几年中，新出现的证据表明表皮生长因子受体（EGFR）的表达和激活与气道上皮（杯状）细胞黏蛋白的产生有关。募集到气道的活化中性粒细胞（及其分泌产物）在EGFR依赖性黏液高分泌中发挥几个关键作用：（i）活化的中性粒细胞分泌肿瘤坏死因子（TNF）-α，其诱导气道上皮细胞中EGFR的表达；（ii）活化的中性粒细胞释放活性氧，其激活EGFR；（iii）中性粒细胞弹性蛋白酶切割EGFR前配体、前转化生长因子（TGF）-α，释放成熟的TGF-α，其以配体依赖性方式激活EGFR；以及（iv）中性粒细胞弹性蛋白酶导致强力杯状细胞脱颗粒。中性粒细胞活性产物的分泌似乎受到严格调控。中性粒细胞弹性蛋白酶的局部释放需要中性粒细胞与另一个细胞之间通过表面黏附分子介导的紧密接触，从而将蛋白水解限制在紧邻细胞周围的环境中。在气道腔内，中性粒细胞发生凋亡并被巨噬细胞清除，而不释放其细胞内内容物。相反，因坏死而死亡的中性粒细胞会将蛋白酶和活性氧释放到腔内。在COPD中，气道腔内的条件促进中性粒细胞坏死。得出的结论是，通过坏死导致的中性粒细胞死亡会导致气道嗜中性粒细胞增多和黏液高分泌患者痰液中游离中性粒细胞弹性蛋白酶和活性氧的高浓度。炎症细胞（中性粒细胞）、分子（中性粒细胞弹性蛋白酶和活性氧）、信号通路（EGFR）和细胞过程（中性粒细胞坏死）促成了COPD中的黏液高分泌，并且是潜在的治疗靶点。针对EGFR、中性粒细胞弹性蛋白酶和活性氧的干预措施已经存在，可以作为治疗中性粒细胞依赖性黏液高分泌的方法进行评估。
