Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury.
Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury.
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DOI：
10.4049/jimmunol.0901808
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发表时间：
2010-01-01
期刊：
影响因子：
--
通讯作者：
Malik AB
中科院分区：
文献类型：
--
作者：
Su X;Matthay MA;Malik AB
尽管α7烟碱乙酰胆碱受体（α7 nAChR）的激活调节对脓毒症的反应，但该途径在脓毒症诱导的急性肺损伤（ALI）的发展中的作用尚不清楚。在这项研究中，我们探讨了α7 nAChR在介导内毒素和活大肠杆菌诱导的小鼠ALI中的作用。由于我们发现小鼠支气管肺泡灌洗液和损伤肺中存在α7 nAChR+肺泡巨噬细胞和中性粒细胞，我们测试了肺迷走神经支配释放的乙酰胆碱是否刺激这些效应细胞，从而下调促炎性趋化因子/细胞因子的产生。给予α7 nAChR激动剂可减少支气管肺泡灌洗液MIP-2的产生和跨肺泡中性粒细胞迁移，并降低E.大肠杆菌肺炎小鼠，而迷走神经去神经增加MIP-2的生产和气道中性粒细胞的积累，并增加死亡率。此外，与α7 nAChR +/+小鼠相比，α7 nAChR −/−小鼠发生了严重的肺损伤，死亡率更高。肺泡巨噬细胞和中性粒细胞的免疫调节胆碱能α7 nAChR通路阻断LPS和E.通过减少趋化因子的产生和中性粒细胞的跨肺泡迁移，提示激活α7 nAChR可能是治疗脓毒症诱导的ALI的一种有前景的策略。
Although activation of the α7 nicotinic acetylcholine receptor (α7 nAChR) modulates the response to sepsis, the role of this pathway in the development of sepsis-induced acute lung injury (ALI) is not known. In this study, we addressed the contribution of α7 nAChR in mediating endotoxin- and live Escherichia coli–induced ALI in mice. Because we found that α7 nAChR+ alveolar macrophages and neutrophils were present in bronchoalveolar lavage and injured lungs of mice, we tested whether acetylcholine released by lung vagal innervation stimulated these effector cells and thereby down-regulated proinflammatory chemokine/cytokine generation. Administration of α7 nAChR agonists reduced bronchoalveolar lavage MIP-2 production and transalveolar neutrophil migration and reduced mortality in E. coli pneumonia mice, whereas vagal denervation increased MIP-2 production and airway neutrophil accumulation and increased mortality. In addition, α7 nAChR−/− mice developed severe lung injury and had higher mortality compared with α7 nAChR+/+ mice. The immunomodulatory cholinergic α7 nAChR pathway of alveolar macrophages and neutrophils blocked LPS- and E. coli–induced ALI by reducing chemokine production and transalveolar neutrophil migration, suggesting that activation of α7 nAChR may be a promising strategy for treatment of sepsis-induced ALI.
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