The Cholinergic Pathways in Inflammation: A Potential Pharmacotherapeutic Target for COPD
The Cholinergic Pathways in Inflammation: A Potential Pharmacotherapeutic Target for COPD
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DOI：
10.3389/fphar.2018.01426
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发表时间：
2018-12
影响因子：
5.6
通讯作者：
M. Yamada;M. Ichinose
中科院分区：
文献类型：
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作者：
M. Yamada;M. Ichinose
在COPD中，胆碱能系统的活性增加，这是由气道平滑肌收缩引起的气流限制的原因之一。因此，用抗胆碱能药物阻断收缩作用是减少气流限制的有用治疗干预。除了支气管收缩和粘液分泌的作用外，来自COPD动物模型的越来越多的证据表明乙酰胆碱在炎症中起作用。使用毒蕈碱M3受体缺陷小鼠或M3选择性拮抗剂的实验显示，实质细胞上的M3受体，而不是造血细胞上的M3受体，参与乙酰胆碱的促炎作用。最近，长效β2肾上腺素能激动剂（LABA）和长效毒蕈碱拮抗剂（LAMA）的组合已可用于COPD治疗。这些双重长效支气管扩张剂可能具有协同抗炎作用，因为刺激β2肾上腺素能受体可通过与拮抗M3受体不同的信号通路诱导炎症细胞抑制作用，尽管这些抗炎作用尚未在COPD患者中得到明确证实。与ACh通过毒蕈碱受体的促炎作用相反，已经证明，涉及副交感神经系统的胆碱能抗炎途径调节过度的炎症反应以在组织损伤和感染期间保护器官。通过α7烟碱乙酰胆碱受体（α7nAChR）刺激乙酰胆碱对白细胞（包括巨噬细胞和2型先天性淋巴细胞）产生抑制作用。尽管尚不清楚乙酰胆碱通过炎症细胞中的α7nAChR的抑制作用是否可以调节COPD的炎症，但包括胆碱能抗炎通路在内的神经免疫相互作用可能是潜在的治疗靶点。
In COPD, the activity of the cholinergic system is increased, which is one of the reasons for the airflow limitation caused by the contraction of airway smooth muscles. Therefore, blocking the contractive actions with anticholinergics is a useful therapeutic intervention to reduce the airflow limitation. In addition to the effects of bronchoconstriction and mucus secretion, accumulating evidence from animal models of COPD suggest acetylcholine has a role in inflammation. Experiments using muscarinic M3-receptor deficient mice or M3 selective antagonists revealed that M3-receptors on parenchymal cells, but not on hematopoietic cells, are involved in the pro-inflammatory effect of acetylcholine. Recently, combinations of long-acting β2 adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) have become available for COPD treatment. These dual long-acting bronchodilators may have synergistic anti-inflammatory effects because stimulation of β2 adrenergic receptors induces inhibitory effects in inflammatory cells via a different signaling pathway from that by antagonizing M3-receptor, though these anti-inflammatory effects have not been clearly demonstrated in COPD patients. In contrast to the pro-inflammatory effects by ACh via muscarinic receptors, it has been demonstrated that the cholinergic anti-inflammatory pathway, which involves the parasympathetic nervous systems, regulates excessive inflammatory responses to protect organs during tissue injury and infection. Stimulation of acetylcholine via the α7 nicotinic acetylcholine receptor (α7nAChR) exerts inhibitory effects on leukocytes including macrophages and type 2 innate lymphoid cells. Although it remains unclear whether the inhibitory effects of acetylcholine via α7nAChR in inflammatory cells can regulate inflammation in COPD, neuroimmune interactions including the cholinergic anti-inflammatory pathway might serve as potential therapeutic targets.