Cell Biology, Erasmus MC, Rotterdam, Netherlands.
Pediatric Pulmonology, Erasmus MC, Rotterdam, Netherlands.
Mediators Inflamm. 2018 Jan 9;2018:1067134. doi: 10.1155/2018/1067134. eCollection 2018.
Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) share molecular mechanisms that cause the pathological symptoms they have in common. Here, we review evidence suggesting that hyperactivity of the EGFR/ADAM17 axis plays a role in the development of chronic lung disease in both CF and COPD. The ubiquitous transmembrane protease A disintegrin and metalloprotease 17 (ADAM17) forms a functional unit with the EGF receptor (EGFR), in a feedback loop interaction labeled the ADAM17/EGFR axis. In airway epithelial cells, ADAM17 sheds multiple soluble signaling proteins by proteolysis, including EGFR ligands such as amphiregulin (AREG), and proinflammatory mediators such as the interleukin 6 coreceptor (IL-6R). This activity can be enhanced by injury, toxins, and receptor-mediated external triggers. In addition to intracellular kinases, the extracellular glutathione-dependent redox potential controls ADAM17 shedding. Thus, the epithelial ADAM17/EGFR axis serves as a receptor of incoming luminal stress signals, relaying these to neighboring and underlying cells, which plays an important role in the resolution of lung injury and inflammation. We review evidence that congenital CFTR deficiency in CF and reduced CFTR activity in chronic COPD may cause enhanced ADAM17/EGFR signaling through a defect in glutathione secretion. In future studies, these complex interactions and the options for pharmaceutical interventions will be further investigated.
慢性阻塞性肺疾病（COPD）和囊性纤维化（CF）具有共同的分子机制，导致它们具有共同的病理症状。在这里，我们回顾了一些证据，表明表皮生长因子受体/解整合素金属蛋白酶 17（EGFR/ADAM17）轴的过度活跃在 CF 和 COPD 中慢性肺部疾病的发展中起作用。广泛存在的跨膜蛋白酶 A 解整合素和金属蛋白酶 17（ADAM17）与表皮生长因子受体（EGFR）形成一个功能单元，在一个被标记为 ADAM17/EGFR 轴的反馈环相互作用中。在气道上皮细胞中，ADAM17 通过蛋白水解作用释放多种可溶性信号蛋白，包括表皮生长因子受体配体如双调蛋白（AREG）和促炎介质如白细胞介素 6 核心受体（IL-6R）。这种活性可以通过损伤、毒素和受体介导的外部触发来增强。除了细胞内激酶外，细胞外谷胱甘肽依赖的氧化还原电位还控制 ADAM17 的脱落。因此，上皮细胞 ADAM17/EGFR 轴作为传入腔内应激信号的受体，将这些信号传递给相邻和下方的细胞，在肺损伤和炎症的消退中发挥重要作用。我们回顾了一些证据，即 CF 中的先天性 CFTR 缺乏和慢性 COPD 中 CFTR 活性降低可能通过谷胱甘肽分泌缺陷导致 ADAM17/EGFR 信号的增强。在未来的研究中，这些复杂的相互作用和药物干预的选择将进一步研究。
