Zeng Si, Zhong Yinbo, Xiao Jie, Ji Jiafu, Xi Jin, Wei Xinchuan, Liu Renyu
Department of Anesthesiology, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Electronic Science and Technology University, Chengdu, China.
Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Transl Perioper Pain Med. 2020;7(3):225-233. doi: 10.31480/2330-4871/117. Epub 2020 Feb 20.
Respiratory failure significantly increases mortality in critically ill patients. While opioids are often used during the perioperative period and in critically ill situations, little is known about how opioids are involved in pulmonary immune function and the inflammatory response. There is currently no clear information on the role of the kappa opioid receptor (KOR) in pulmonary inflammation. Here we evaluate whether KORs are involved in the modulation of lung macrophages by the use of selective KOR agonists in lipopolysaccharide (LPS) activated alveolar macrophages.
The inflammatory response in rat NR8383 macrophages was induced by stimulation with LPS (100 ng/ml) at different time-points. The effects of the KOR agonists Salvinorin A (SA) and U50488 on inflammatory factors such as nitrite, TNF-α, IL-1β, iNOS and COX-2 were investigated. Nor-binaltorphimine, a selective KOR antagonist, was used to investigate the specific role of KOR.
Stimulation of NR8383 cells with LPS (100 ng/ml) significantly increased the level of TNF-α at 1h, 2h and 6h compared to un-stimulated cells. SA attenuated the inflammatory response by reducing the levels of TNF-α and IL-1β after LPS treatment. SA co-treatment reduced the elevated levels of NO induced by LPS and also alleviated the over-expression of iNOS and COX-2 within 2 hours after LPS activation, and such effects can be partially blocked by KOR antagonist, nor-binaltorphimine. Similar results from U50488 were observed.
Our results indicate that KORs may play a critical role in the modulation of the pulmonary inflammatory process by their activation in macrophages. Selective KOR agonists exert their anti-inflammatory effects acutely on lung macrophages, within 1-2 hours of LPS-stimulated inflammation .
呼吸衰竭显著增加重症患者的死亡率。虽然阿片类药物常在围手术期和重症情况下使用，但对于阿片类药物如何参与肺免疫功能和炎症反应知之甚少。目前关于κ阿片受体（KOR）在肺部炎症中的作用尚无明确信息。在此，我们通过在脂多糖（LPS）激活的肺泡巨噬细胞中使用选择性KOR激动剂来评估KOR是否参与肺巨噬细胞的调节。
在不同时间点用LPS（100 ng/ml）刺激大鼠NR8383巨噬细胞诱导炎症反应。研究KOR激动剂Salvinorin A（SA）和U50488对亚硝酸盐、TNF-α、IL-1β、诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）等炎症因子的影响。使用选择性KOR拮抗剂诺-纳洛酮来研究KOR的具体作用。
与未刺激的细胞相比，用LPS（100 ng/ml）刺激NR8383细胞在1小时、2小时和6小时时TNF-α水平显著升高。SA通过降低LPS处理后TNF-α和IL-1β的水平减轻炎症反应。SA联合处理降低了LPS诱导的NO升高水平，并在LPS激活后2小时内减轻了iNOS和COX-2的过度表达，且这种作用可被KOR拮抗剂诺-纳洛酮部分阻断。观察到U50488有类似结果。
我们的结果表明，KOR通过在巨噬细胞中的激活可能在肺部炎症过程的调节中起关键作用。选择性KOR激动剂在LPS刺激的炎症1-2小时内对肺巨噬细胞急性发挥抗炎作用。
