胆碱能抗炎通路对内毒素复合油酸致大鼠急性肺损伤的影响

doi:10.3969/j.issn.1006-7795.2012.03.018

首都医科大学学报 ›› 2012, Vol. 33 ›› Issue (3): 371-376.doi: 10.3969/j.issn.1006-7795.2012.03.018

胆碱能抗炎通路对内毒素复合油酸致大鼠急性肺损伤的影响

郑晖¹, 许绍发², 贾鸿彦³, 古淑香³

1. 首都医科大学附属北京胸科医院麻醉科,北京 101149;2. 首都医科大学附属北京胸科医院胸外科,北京 101149;3. 首都医科大学附属北京胸科医院结核病分子生物学实验室,北京 101149

收稿日期:2012-03-15 修回日期:1900-01-01 出版日期:2012-06-21 发布日期:2012-06-21
通讯作者: 许绍发

Effect of the cholinergic anti-inflammatory pathway on acute lung injury induced by oleic acid and lipopolysaccharide in rats

ZHENG Hui¹, XU Shao-fa², JIA Hong-yan³, GU Shu-xiang³

1. Department of Anesthesiology, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China;2. Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China;3. Molecular Biology Laboratory of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China

Received:2012-03-15 Revised:1900-01-01 Online:2012-06-21 Published:2012-06-21

摘要/Abstract

摘要： 目的研究胆碱能抗炎通路(cholinergic anti-inflammatory pathway,CAP)对内毒素复合油酸2次打击致大鼠急性肺损伤(acute lung injury, ALI)的影响及其可能的作用机制。方法 24只雄性Wistar大鼠,体质量250±20g。按数字表法将大鼠随机分为4组,每组6只。1对照组(control group, C组):腹腔注射生理盐水10 mL·kg^-1;2急性肺损伤(ALI)组:腹腔注射1％内毒素(lipopolysaccharide, LPS) 10 mg·kg^-1,30 min后静脉注射油酸(oleic acid, OA)0.15 mL·kg^-1;3电刺激(stimulation, ST)组:右颈迷走神经干连接刺激电极,以5 V、2 ms、1 Hz强度持续刺激神经10 min,腹腔注射1％ LPS 10 mg·kg^-1,再持续刺激神经10 min,20 min后静脉注射OA 0.15 mL·kg^-1;4他克林(tetrahydroaminoacridine,THA)组:静脉注射胆碱酯酶抑制剂THA 1.5 mg·kg^-1,10 min后行急性肺损伤操作。各组动物均于130 min后从颈总动脉采血1 mL行血气分析,处死动物采集标本,分别检测肺组织Toll-样受体-2(Toll-like receptor-2, TLR₂)和TLR₄ mRNA、核转录因子κB(nuclear factor kappa-B, NF-κB)p⁶⁵、血清白介素-6(interleukin-6, IL-6)、肺组织髓过氧化物酶(mycloperoxidase,MPO)含量和肺组织湿质量-干质量比(wet weight/dry weight, W/D),HE染色观察左肺组织病理学改变。结果 ALI组与C组比较,pH和动脉氧分压(partial pressure of oxygen, PaO₂)均显著下降,二氧化碳分压(partial pressure of carbon dioxide, PaCO₂)显著升高;肺泡破坏严重,有大量组织液渗出;肺组织W/D及MPO活性均显著增高;肺组织NF-κB p⁶⁵蛋白表达明显增强;血清IL-6浓度显著升高;与C组相比,其余3个实验组肺组织TLR₂和TLR₄ mRNA表达均显著增加,组间比较差异无统计学意义;ST组和THA组与ALI组比较,pH和PaO₂均显著升高,PaCO₂显著下降;肺组织病理改变明显改善;肺组织W/D及MPO活性均显著降低;肺组织NF-κB p⁶⁵蛋白表达及血清IL-6浓度显著下降。结论电刺激迷走神经或者静脉注射他克林可通过激活CAP,减轻LPS复合油酸2次打击致大鼠ALI时的炎性反应;其可能的机制是抑制NF-κB途径活化,在转录前水平发挥抗炎作用,但是不影响ALI时TLR₂和TLR₄ mRNA的活化。

关键词: 胆碱能抗炎通路, 急性肺损伤, Toll-样受体

Abstract: Objective To investigate the effect of the cholinergic anti-inflammatory pathway(CAP) on the acute lung injury(ALI) induced by oleic acid and lipopolysaccharide in rats. Methods Twenty-four male Wistar rats were randomly divided into four groups(n=6). 1Control group: saline, 10 mL·kg^-1, intraperitoneally, 2ALI group: oleic acid was administrated with 0.15 mL·kg^-1intravenously 30 min afterintraperitoneal injection of lipopolysaccharide (LPS) with 10 mg·kg^-1, 3stimulation (ST) group: electrical stimulation(5V, 2 ms, 1Hz) of the right cervical vagus nerve for 10 min before and after LPS and OA administration, 4tetrahydroaminoacridine (THA) group: tetrahydroaminoacridine was given at 1.5 mg·kg^-1intravenously before LPS and OA administration. Blood and tissue samples were collected 130 minutes after the first drug injection in all groups. TLR₂ and TLR₄ mRNA, NF-κBp⁶⁵, MPO of lung tissue and IL-6 of serum were measured respectively. The blood gas analysis, wet weight to dry weight ratio (W/D) of right lung, and pathological changes were also observed. Results As compared with group C, the pH and PaO₂ decreased markedly in group ALI while the histopathologic changes of lung tissue showed alveolar hemorrhage, necrosis and proteinaceous alveolar edema. W/D ratio, the activity of MPO, NF-κB expression and the level of serum IL-6 significantly increased. As compared with group C, the expressions of the TLR₂ and TLR₄ mRNA were markedly increased in other three groups, but no significant change was found among these three groups. As compared with group ALI, pH and PaO₂ markedly increased in group ST and group THA as well as PaCO₂ decreased. The lung tissue showed slight pathological changes. W/D ratio and the activity of MPO were significantly reduced. The expression of NF-κB p⁶⁵ protein and the amount of serum IL-6 markedly decreased. Conclusions Electrical stimulation of the vagus nerve or administration of THA intravenously could protect the lung against ALI induced by LPS and OA via activating cholinergic anti-inflammatory pathway; the CAP can inhibit the activation of NF-κB and reduce the production of proinflammatory cytokine but had no effect on the expression of TLRs.

Key words: cholinergic anti-inflammatory pathway, acute lung injury, Toll-like receptors

中图分类号:

R 96

郑晖;许绍发;贾鸿彦;古淑香. 胆碱能抗炎通路对内毒素复合油酸致大鼠急性肺损伤的影响[J]. 首都医科大学学报, 2012, 33(3): 371-376.

ZHENG Hui;XU Shao-fa;JIA Hong-yan;GU Shu-xiang. Effect of the cholinergic anti-inflammatory pathway on acute lung injury induced by oleic acid and lipopolysaccharide in rats[J]. Journal of Capital Medical University, 2012, 33(3): 371-376.

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胆碱能抗炎通路对内毒素复合油酸致大鼠急性肺损伤的影响

Effect of the cholinergic anti-inflammatory pathway on acute lung injury induced by oleic acid and lipopolysaccharide in rats

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