迷走神经和DVC在胆碱能抗炎通路中的作用及机制的研究
摘要
胆碱能抗炎通路(cholinergic anti-inflammatory pathway,CAP)是指当致病细菌入侵时,体内的迷走神经及其递质乙酰胆碱(Acetylcholine,Ach)与免疫系统相互作用参与抗炎。已有的研究表明,迷走传出神经及其递质Ach参与了胆碱能抗炎通路的调控过程。黄健等通过先夹伤迷走神经干中枢端,注射内毒素后,发现迷走神经传出纤维放电频率增加。Borovikova等直接电刺激内毒素血症大鼠的迷走神经传出纤维,可抑制肝脏和心脏肿瘤坏死因子-α(TNF-α)的生成,降低血清TNF-α的含量。Thomas等研究显示,电刺激迷走神经能够抑制缺血再灌注损伤所导致的全血TNF-α升高,缓解缺血再灌注引起的休克。石德光、胡森等切断迷走神经则使心肌的TNF-α水平显著升高,炎性损伤加重;电刺激切断的迷走神经远端能使内毒素(LPS)血症大鼠肺组织中TNF-α含量显著降低,炎性病理改变减轻。以上主要通过夹伤、电刺激或切断迷走神经的方法来研究迷走传出神经对炎症反应的影响,但在迷走传出神经正常的情况下,其在炎症反应中放电频率变化,无相关报道。
迷走传出神经及其递质Ach参与了抗炎反应,表明炎症反应中迷走传出神经位于迷走神经背核(DMV)内的节前神经元被激活,那么,炎症信息是如何传递至DMV的?通常认为周围免疫信息可通过两种途径传达到脑,一是血液中的细胞因子通过缺乏血脑屏障的最后区(AP)入脑,由AP直接传递至DMV,或由AP经孤束核(NTS)间接传递至DMV。二为细胞因子通过迷走传入神经将炎症信息传至NTS,由NTS传到DMV。胆碱能抗炎通路中炎症信号主要是通过缺乏血脑屏障的AP入脑还是通过迷走传入神经或两者兼之,还不明确。“延髓内脏带”(MVZ)含有儿茶酚胺(CA)类等多种神经活性物质。一系列研究表明MVZ内CA能神经元参与了心血管和胃肠道功能的调节,如脑出血急性期延髓内脏带内儿茶酚胺能神经元有Fos蛋白表达;大鼠在束缚浸水应激状态下DVC内Fos/TH表达增加。而内毒素炎症时,脑干NTS、DMV和AP内的儿茶酚胺能神经元是否参加了炎症信息的传递、分析和整合,有关该方面的研究至今尚未见报道。因此,本文拟采用辣椒素去神经化的方法观察内毒素炎症时对迷走神经传出纤维放电、血清TNF-α水平及DVC内c-Fos+TH表达的影响,以探讨迷走神经和DVC在胆碱能抗炎通路中的作用及其机制。
本研究分为三部分:
第一部分,观察内毒素(LPS)炎症时大鼠迷走神经放电、血压、血清TNF-α水平以及DVC内c-Fos表达情况。实验分两组:LPS组和对照(CON)组,LPS组静脉注射LPS;CON组静脉注射等容量的生理盐水。结果与结论:在LPS组,与LPS注射前相比迷走神经放电频率显著增加,血压降低但不显著;LPS组与CON组相比,神经放电频率和血清TNF-α水平显著升高,脑干NTS、DMV和AP的c-Fos表达均显著增强。提示迷走神经、AP和NTS参与了炎症反应。
第二部分,辣椒素去神经化后再给予LPS刺激致炎,观察大鼠迷走神经传出纤维放电、血压、血清TNF-α水平的变化以及脑干DVC内c-fos表达情况。实验分为两组:辣椒素+内毒素(CAS+LPS)组和LPS组,CAS+LPS组先以辣椒素去神经化后再静脉注射LPS刺激致炎;LPS组直接静脉注射等容量的LPS。结果与结论:在CAS+LPS组,与LPS注射前相比迷走神经传出纤维放电频率显著增加,血压升高但不明显;CAS+LPS组与LPS组相比,血清TNF-α浓度显著升高,脑干NTS、DMV和AP内c-fos表达均显著减弱。提示内毒素炎症时,迷走传出神经纤维兴奋增多,参入了抗炎症作用。外周炎症信息主要通过迷走传入神经传递至NTS,由NTS传到DMN,部分炎症信号可通过AP传至DMN。
第三部分,利用Fos蛋白与酪氨酸羟化酶(TH)免疫双标的方法,观察LPS炎症时对脑干NTS、DMV和AP内CA能神经元活动的影响。实验分为两组:LPS组和CON组,LPS组静脉注射LPS;CON组静脉注射生理盐水。结果与结论:LPS组与CON组相比,LPS炎症时,NTS、DMV和AP内TH阳性神经元和TH+Fos双标阳性神经元数目明显增多,表明儿茶酚胺能神经元参与了炎症反应。结果提示内毒素炎症时,脑干NTS、DMV和AP内的儿茶酚胺能神经元可能参与了胆碱能抗炎症通路炎症信息的传递和炎症反应的调节过程。
Some dataes have indicated that Acetylcholine (ACh), the principal neurotransm -itter of the vagus nerves, is a key mediator of the cholinergic anti-inflammatory pathway. Huang Jian have used a method of crushing the vagus nerve to record the frequency of cervical vagal efferent discharge and found the vagal efferent discharge significantly increased after LPS injection. Saddam studies revealed that surgical dissection of the efferent vagus nerve enhanced the production of proinflammatory cytokines and accelerated the development of septic shock. In addition, studies have revealed that electrical stimulation of efferent vagal nerve fibres inhibits inflammation and reduced lethality by suppressing the release of pro-inflammatory cytokines (Boro- vikova, Thomas, Shi Deguang and Hu Sen). The methods of crushing, electrical stimulation and vagotomy were used in the previous studies on the vagus nerves role in regulating inflammation. However, There is no study on the role of the intact vagus efferent nerve in systemic inflammatory response in endotoxemia rats.
The vagus efferent nerve and neurotransmitter Ach involved in the anti-inflam- matory response, and this results showed that inflammatory response have activated vagus preganglionic neurons in the DMV. Howerver, how was the inflammatory information relayed to the DMV? the immune information can signal the brain through two pathways:The first, cytokines of the bloodstream passed through the lack of blood-brain barrier of the AP into the brain, then directly transmit to the DMV or indirectly transmit to the DMV by the NTS; The second, cytokine release in the periphery is sensed by receptors located on the vagus nerve. This information is transmitted to the NTS in the brain stem and subsequently to the DMN. It remains unclear whether inflammatory information was transmitted to the brain stem mainly through the lack of blood-brain barrier of the AP or vagus afferent nerve, or both in cholinergic anti-inflammatory pathway.The medulla oblongata internal organs belt contains many different types of active materials such as the catecholamines. A series of research indicated that CA neurons within the MVZ participated in the regulation of the cardiovascular and gastrointestinal function. Fos expression of CA neurons in the MVZ significantly increased during the acute stage of cerebral hemorrhage. The Fos/TH expression in DVC increased under water immersion and restraint stress however, whether CA neurons in NTS, DMV and AP participate in the transmission, analysis and conformity of inflammatory information has not been reported Therefore, This present study was designed to examine the discharge of vagal efferent fibers, levels of TNF-αin the serum and c-Fos/TH expression of DVC in endotoxin-induced inflammation to further explore the function and the mechanism of vagus nerve and DVC in the cholinergic anti-inflammatory pathway.
This study was divided into three parts:
The first part recorded the vagus nerve discharge, blood pressure, levels of TNF-αin the serum and the c-fos expression of DVC after LPS injection. The experiment was divided into two groups: the LPS group treated with LPS and the CON group treated with saline. Results and conclusions: discharge frequency of the vagal nerve was significantly increased after LPS injected, but there was no significant different on blood pressure before or after LPS injection;compared with the control group, discharge frequency of the vagal nerve, levels of serum TNF-αand c-Fos expression in the NTS, DMV and AP were significantly increased after LPS injected. This experiment showed the vagus nerve, AP and NTS participated in Inflammation.
The second part recorded the vagus nerve discharge, blood pressure, level of serum TNF-αand c-fos expression of DVC in LPS-induced inflammation after capsaicin denervation. The experiment was divided into two groups: the CAS group which LPS was intravenous injected after denervation with capsaicin and the LPS group which LPS was intravenous injected. Results and conclusions: discharge frequency of vagal efferent fibers in CAS was significantly increased after LPS injected in CAS group, but not blood pressure; compared with the LPS group, the serum TNF-αlevel was obviously increased in CAS, but c-fos expression in DVC was significantly reduced. The results revealed that the excitability of vagus efferent nerve fibers increased during the endotoxin inflammation, so that the efferent vagus nerve fibers involved in anti-inflammatory response. Peripheral inflammatory information is mainly passed through the vagus afferent nerve to NTS, then transmit to the DMV, and some inflammatory signals can be transmitted through the AP to DMV.
The third part, the method of double-target immunological of Fos protein and tyrosine hydroxylase (TH) was used to research the CA neurons activities in the brain stem NTS,DVC and AP during the endotoxin inflammation. The experiment was divided into two groups: the LPS group treated with LPS and the CON group treated with saline.Results and conclusions: compared with the CON group, the majority of the Fos protein activated neuron were CA neuron during the endotoxin inflammation.The results indicated that CA neuron which consisted in NTS,DMV and AP in brainstem involved in the inflammation information of the transfer, analysis and integration in the cholinergic anti-inflammatory pathway during the endotoxin inflammation.
迷走传出神经及其递质Ach参与了抗炎反应,表明炎症反应中迷走传出神经位于迷走神经背核(DMV)内的节前神经元被激活,那么,炎症信息是如何传递至DMV的?通常认为周围免疫信息可通过两种途径传达到脑,一是血液中的细胞因子通过缺乏血脑屏障的最后区(AP)入脑,由AP直接传递至DMV,或由AP经孤束核(NTS)间接传递至DMV。二为细胞因子通过迷走传入神经将炎症信息传至NTS,由NTS传到DMV。胆碱能抗炎通路中炎症信号主要是通过缺乏血脑屏障的AP入脑还是通过迷走传入神经或两者兼之,还不明确。“延髓内脏带”(MVZ)含有儿茶酚胺(CA)类等多种神经活性物质。一系列研究表明MVZ内CA能神经元参与了心血管和胃肠道功能的调节,如脑出血急性期延髓内脏带内儿茶酚胺能神经元有Fos蛋白表达;大鼠在束缚浸水应激状态下DVC内Fos/TH表达增加。而内毒素炎症时,脑干NTS、DMV和AP内的儿茶酚胺能神经元是否参加了炎症信息的传递、分析和整合,有关该方面的研究至今尚未见报道。因此,本文拟采用辣椒素去神经化的方法观察内毒素炎症时对迷走神经传出纤维放电、血清TNF-α水平及DVC内c-Fos+TH表达的影响,以探讨迷走神经和DVC在胆碱能抗炎通路中的作用及其机制。
本研究分为三部分:
第一部分,观察内毒素(LPS)炎症时大鼠迷走神经放电、血压、血清TNF-α水平以及DVC内c-Fos表达情况。实验分两组:LPS组和对照(CON)组,LPS组静脉注射LPS;CON组静脉注射等容量的生理盐水。结果与结论:在LPS组,与LPS注射前相比迷走神经放电频率显著增加,血压降低但不显著;LPS组与CON组相比,神经放电频率和血清TNF-α水平显著升高,脑干NTS、DMV和AP的c-Fos表达均显著增强。提示迷走神经、AP和NTS参与了炎症反应。
第二部分,辣椒素去神经化后再给予LPS刺激致炎,观察大鼠迷走神经传出纤维放电、血压、血清TNF-α水平的变化以及脑干DVC内c-fos表达情况。实验分为两组:辣椒素+内毒素(CAS+LPS)组和LPS组,CAS+LPS组先以辣椒素去神经化后再静脉注射LPS刺激致炎;LPS组直接静脉注射等容量的LPS。结果与结论:在CAS+LPS组,与LPS注射前相比迷走神经传出纤维放电频率显著增加,血压升高但不明显;CAS+LPS组与LPS组相比,血清TNF-α浓度显著升高,脑干NTS、DMV和AP内c-fos表达均显著减弱。提示内毒素炎症时,迷走传出神经纤维兴奋增多,参入了抗炎症作用。外周炎症信息主要通过迷走传入神经传递至NTS,由NTS传到DMN,部分炎症信号可通过AP传至DMN。
第三部分,利用Fos蛋白与酪氨酸羟化酶(TH)免疫双标的方法,观察LPS炎症时对脑干NTS、DMV和AP内CA能神经元活动的影响。实验分为两组:LPS组和CON组,LPS组静脉注射LPS;CON组静脉注射生理盐水。结果与结论:LPS组与CON组相比,LPS炎症时,NTS、DMV和AP内TH阳性神经元和TH+Fos双标阳性神经元数目明显增多,表明儿茶酚胺能神经元参与了炎症反应。结果提示内毒素炎症时,脑干NTS、DMV和AP内的儿茶酚胺能神经元可能参与了胆碱能抗炎症通路炎症信息的传递和炎症反应的调节过程。
Some dataes have indicated that Acetylcholine (ACh), the principal neurotransm -itter of the vagus nerves, is a key mediator of the cholinergic anti-inflammatory pathway. Huang Jian have used a method of crushing the vagus nerve to record the frequency of cervical vagal efferent discharge and found the vagal efferent discharge significantly increased after LPS injection. Saddam studies revealed that surgical dissection of the efferent vagus nerve enhanced the production of proinflammatory cytokines and accelerated the development of septic shock. In addition, studies have revealed that electrical stimulation of efferent vagal nerve fibres inhibits inflammation and reduced lethality by suppressing the release of pro-inflammatory cytokines (Boro- vikova, Thomas, Shi Deguang and Hu Sen). The methods of crushing, electrical stimulation and vagotomy were used in the previous studies on the vagus nerves role in regulating inflammation. However, There is no study on the role of the intact vagus efferent nerve in systemic inflammatory response in endotoxemia rats.
The vagus efferent nerve and neurotransmitter Ach involved in the anti-inflam- matory response, and this results showed that inflammatory response have activated vagus preganglionic neurons in the DMV. Howerver, how was the inflammatory information relayed to the DMV? the immune information can signal the brain through two pathways:The first, cytokines of the bloodstream passed through the lack of blood-brain barrier of the AP into the brain, then directly transmit to the DMV or indirectly transmit to the DMV by the NTS; The second, cytokine release in the periphery is sensed by receptors located on the vagus nerve. This information is transmitted to the NTS in the brain stem and subsequently to the DMN. It remains unclear whether inflammatory information was transmitted to the brain stem mainly through the lack of blood-brain barrier of the AP or vagus afferent nerve, or both in cholinergic anti-inflammatory pathway.The medulla oblongata internal organs belt contains many different types of active materials such as the catecholamines. A series of research indicated that CA neurons within the MVZ participated in the regulation of the cardiovascular and gastrointestinal function. Fos expression of CA neurons in the MVZ significantly increased during the acute stage of cerebral hemorrhage. The Fos/TH expression in DVC increased under water immersion and restraint stress however, whether CA neurons in NTS, DMV and AP participate in the transmission, analysis and conformity of inflammatory information has not been reported Therefore, This present study was designed to examine the discharge of vagal efferent fibers, levels of TNF-αin the serum and c-Fos/TH expression of DVC in endotoxin-induced inflammation to further explore the function and the mechanism of vagus nerve and DVC in the cholinergic anti-inflammatory pathway.
This study was divided into three parts:
The first part recorded the vagus nerve discharge, blood pressure, levels of TNF-αin the serum and the c-fos expression of DVC after LPS injection. The experiment was divided into two groups: the LPS group treated with LPS and the CON group treated with saline. Results and conclusions: discharge frequency of the vagal nerve was significantly increased after LPS injected, but there was no significant different on blood pressure before or after LPS injection;compared with the control group, discharge frequency of the vagal nerve, levels of serum TNF-αand c-Fos expression in the NTS, DMV and AP were significantly increased after LPS injected. This experiment showed the vagus nerve, AP and NTS participated in Inflammation.
The second part recorded the vagus nerve discharge, blood pressure, level of serum TNF-αand c-fos expression of DVC in LPS-induced inflammation after capsaicin denervation. The experiment was divided into two groups: the CAS group which LPS was intravenous injected after denervation with capsaicin and the LPS group which LPS was intravenous injected. Results and conclusions: discharge frequency of vagal efferent fibers in CAS was significantly increased after LPS injected in CAS group, but not blood pressure; compared with the LPS group, the serum TNF-αlevel was obviously increased in CAS, but c-fos expression in DVC was significantly reduced. The results revealed that the excitability of vagus efferent nerve fibers increased during the endotoxin inflammation, so that the efferent vagus nerve fibers involved in anti-inflammatory response. Peripheral inflammatory information is mainly passed through the vagus afferent nerve to NTS, then transmit to the DMV, and some inflammatory signals can be transmitted through the AP to DMV.
The third part, the method of double-target immunological of Fos protein and tyrosine hydroxylase (TH) was used to research the CA neurons activities in the brain stem NTS,DVC and AP during the endotoxin inflammation. The experiment was divided into two groups: the LPS group treated with LPS and the CON group treated with saline.Results and conclusions: compared with the CON group, the majority of the Fos protein activated neuron were CA neuron during the endotoxin inflammation.The results indicated that CA neuron which consisted in NTS,DMV and AP in brainstem involved in the inflammation information of the transfer, analysis and integration in the cholinergic anti-inflammatory pathway during the endotoxin inflammation.
引文
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