孤束核在内毒素致大鼠炎症中的作用及其机制研究
摘要
炎症是临床常见的一个病理过程，可以生于机体各部位的组织和各器官，例如毛囊炎、扁桃体炎、肺炎、肝炎、肾炎等。急性炎症平时具有红、肿、热、痛、机能掩藏等变化。这些变化实质上是机体与致炎因子进行抗争的结果。这种抗争始终存在在炎症过程。致炎因子，一方面引发组织细胞的损坏，使局部组织细胞变性、坏死；另一方面，诱导增加机体抗病机能，促进致炎因子的清除，修复受损的组织，从而使内环境和外环境之间以及机体的内环境达到新的均衡。但是，当炎症反应过于激烈的时候反而会对机体产生伤害。许多慢性病如类风湿性关节炎、克隆氏病等都与不当的炎症反应有关。
新近发现的胆碱能抗炎通路（cholinergic anti-inflammatory pathway）可以有效减少多种促炎因子的释放，对全身和局部炎症均具有明显的抑制作用。胆碱能抗炎症通路是当发生炎症反应时，在炎症部位的炎症信息会通过迷走神经及其递质乙酰胆碱（Acetylcholine,Ach）与免疫系统相互作用，从而完成抗炎作用。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，而迷走背核、孤束核和最后区这三个核团在解剖学中位置相邻,功能相关性较大,且之间具有密切的纤维联系,所以将它们合称为迷走复合体(DVC)。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[1]。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[2]。我们实验室前期工作发现内毒素炎症大鼠脑干DMV、AP和NTS的c-Fos表达均显著增强，表明AP和NTS参与了炎症反应。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传至NTS或两者兼之，还不明确。G. E. Hermann等大鼠注射LPS致炎后，右侧NTS、DMV的c-Fos表达要显著高于左侧。SimonsCT等的研究发现外周炎症信息主要通过左侧迷走神经传入NTS。这些结果提示神经系统对炎症的调节是否存在一侧优势，那么，左右两侧NTS对炎症反应是否存在着差异，相关研究尚未见报道。已有发现，NTS内观察到大量的pERK样免疫反应阳性神经元，ERK1/2通路在内脏感觉、运动的信号转导过程中都发挥了重要作用，但对孤束核内ERK1/2通路在炎症反应中是否活化而影响炎症反应还未见报道。因此，本文采用内毒素炎症模型，分别利用电生理技术和免疫组化方法记录迷走神经放电和DMV、AP神经元的c-Fos表达，探讨NTS在在炎症反应中的作用及DMV、NTS和AP在炎症反应的相关性，以进一步探究DMV、NTS和AP在胆碱能抗炎通路中所起的作用。
本研究分为三部分：
第一部分，损毁双侧NTS后观察内毒素炎症模型中，大鼠肿瘤坏死因子（TNF-α）水平、白细胞数目、迷走神经放电，动脉血压以及DMV和AP内c-Fos的表达情况。实验分为三组：假损毁双侧NTS+LPS组、损毁双侧NTS+LPS组以及损毁双侧NTS+生理盐水组。结果与讨论：损毁双侧+LPS组和损毁双侧+生理盐水组相比，TNF-α水平显著升高，AP和DMV的c-Fos表达均增强，但差异不显著，说明注射LPS引起了大鼠的炎症反应；损毁双侧+LPS组和假损毁双侧+LPS组相比，TNF-α水平显著升高，AP和DMV的c-Fos表达量减少，但差异不显著，说明NTS参与了抗炎症反应。
第二部分，分别损毁左、右两侧NTS后，再注射LPS致炎，观察大鼠肿瘤坏死因子（TNF-α）水平、白细胞个数、迷走神经放电、动脉血压以及DMV和AP内C-Fos的表达情况。实验分为四组：损毁左侧+LPS组、假损毁左侧+LPS组、损毁右侧+LPS组以及假损毁右侧+LPS组。结果与讨论：损毁左侧+LPS组和假损毁左侧+LPS组相比，TNF-α水平显著升高，差异极显著，DMV的c-Fos表达量显著降低。损毁右侧+LPS组和假损毁右侧+LPS组相比，TNF-α水平无明显变化，DMV的c-Fos表达量显著升高，说明左、右侧NTS在抗炎症反应中作用不同。左侧NTS参与抗炎症反应，而右侧NTS可能对炎症反应作用较小。
第三部分，观察PD98059对LPS致大鼠炎症AP和DMV内c-Fos表达的影响。实验分为两组：注射PD98059+LPS组和注射生理盐水+LPS组。结果与讨论：注射PD98059以后，DMV的c-Fos表达量显著减少，这说明了NTS内ERK1/2通路参与了炎症反应，也进一步表明NTS参与了将炎症信息传至DMV的过程。
Inflammation is a common clinical pathophysiological process that can occurs inthe body parts of the tissues and organs. such as folliculitis, tonsillitis, pneumonia,hepatitis, nephritis and so on. The classic signs of acute inflammation are redness,calor heat, swelling, pain and loss of function. inflammation is one of the initialresponses to the presence of an invader and focuses the immune system at the site ofinfection. inflammation is the first-alert mechanism that calls into action the cellsresponsible for surveillance and protection, heralding them to go to work and limit thedamage. In this instance, inflammation is a beneficial process . However,inflammation can cause considerable damage to host tissues, which can be part of themicrobial pathogenesis of a disease process. The magnitude of the inflammatoryresponse is crucial: insufficient responses result in immunodeficiency, which can leadto infection and cancer; excessive responses cause morbidity and mortalityin diseasessuch as rheumatoid arthritis, Crohn’s disease,atherosclerosis. Homeostasis and healthare restored when inflammation is limited by anti-inflammatory responses that areredundant, rapid, reversible, localized, adaptive to changes in input and integrated bythe nervous system.
Recent studies have uncovered a mechanism by which the inflammatory processcan be regulated by activity of the parasympathetic nervous system. Efferent (motor)signals carried by the vagus nerve via the neurotransmitter acetylcholine (ACh), canmodulate the activity of resident macrophages and attenuate local and systemicinflammation. This regulatory activity has been termed "the cholinergicanti-inflammatory pathway". The vagus efferent nerve and neurotransmitter Achinvolved in the antiinflammatory response, which showed that inflammatory responsehave activated vagus preganglionic neurons in the DMV.The adjacent DMV, NTS and AP have complicated neuronal contact and close correlation in function, so that theyconstitute the dorsal vagal complex (DVC) .However, how was the inflammatoryinformation relayed to the DMV? The immune information can signal the brainthrough two pathways:The first, cytokines of the bloodstream passed through the lackof blood-brain barrier of the AP into the brain, then directly transmit to the DMV orindirectly transmit to the DMV by the NTS; The second, cytokine release in theperiphery is sensed by receptors located on the vagus nerve. This information istransmitted to the NTS in the brain stem and subsequently to the DMN. It remainsunclear whether inflammatory information was transmitted to the brain stem mainlythrough the lack of blood-brain barrier of the AP or vagus afferent nerve, or both incholinergic anti-inflammatory pathway. Studies by Gaykema et al. G. E. Hermannshowed that the right side of each brain stem contained somewhat morec-Fos-activated NST cells than the corresponding left side after systemicadministration of LPS. Gaykema et al. have already shown that hepatic afferentswhich ascend predominantly within the left cervical vagal trunk to terminate withinthe left NST were the principal pathway by which systemic exposure to endotoxinprovoked c-Fos activation of brain stem neurons. we propose the followinghypotheses that if brain lateralization is involved in the regulation of the inflammatoryprocess and Two sides of NTS are differently involved in the modulation ofinflammatory responses. The previous work demonstrated that pERK-IR cells areexpressed in the nucleus tractus solitarii (NTS) after capsaicin injection into thewhisker pad. However, It remains unclear the role of the ERK1/2 signaling pathwaywithin the NTS in LPS-induced inflammation responses. Therefore, This presentstudy was designed to examine the discharge of vagal nerve fibers, levels of TNF-αinthe serum and c-Fos expression of DVC in LPS-induced inflammation to furtherexplore the function and the mechanism of DVC in the cholinergic anti-inflammatorypathway.
This research was divided into three parts:
The first part recorded the vagus nerve discharge, blood pressure, levels ofTNF-αin the serum and the c-fos expression in DMV and AP after LPS injection. The experiment was divided into three groups: sham lesioned bilateral NTS+ LPS group,lesioned bilateral NTS + LPS group and lesioned bilateral + physiological salinegroup. Results and discussion: Compared with sham lesioned bilateral + physiologicalsaline group, level of TNF-αof lesioned bilateral NTS + LPS group was increasedsignificantly and c-Fos expression in AP and DMV were increased but not significant.These results illustrates that LPS injection cause the inflammatory response andNTS participated in the Inflammation process
The second part observed levels of TNF-α, leukocyte count, arterial bloodpressure and c-Fos expression in DMV and AP after lesion of the left of the NTSor right . The experiment was divided into four groups: left NTS lesioned +LPSgroup, sham left NTS lesioned +LPS group, right NTS lesioned +LPS group andsham right NTS lesioned +LPS group. Results and discussion: Compare with shamlesioned NTS+LPS, level of TNF–αin the left NTS lesioned +LPS group ,but no inthe right NTS lesioned ,was increased significantly. Compare with sham lesionedNTS+LPS ,the c-Fos expression in DMV of the left NTS lesioned +LPS groupdecreased significantly. The left NTS lesioned have no significant impacts on thec-Fos expression in DMV. The results revealed that the left side of NTS played amajor role in the anti-inflammatory response.,
The third part,observed the impact of PD98059 on the AP and DMV c-Fosexpression in LPS-induced inflammation. Experiment was divided into two groups:injection PD98059 + LPS group and injected saline + LPS group. Results anddiscussion: After the injection of PD98059, compare with the control group, the c-Fosexpression in DMV was significantly reduced after injection PD98059, This indicatesthat ERK1/2 pathway in NTS involved in the inflammatory response, and that someinflammatory signals can be transmitted through the NTS to DMV..
新近发现的胆碱能抗炎通路（cholinergic anti-inflammatory pathway）可以有效减少多种促炎因子的释放，对全身和局部炎症均具有明显的抑制作用。胆碱能抗炎症通路是当发生炎症反应时，在炎症部位的炎症信息会通过迷走神经及其递质乙酰胆碱（Acetylcholine,Ach）与免疫系统相互作用，从而完成抗炎作用。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，而迷走背核、孤束核和最后区这三个核团在解剖学中位置相邻,功能相关性较大,且之间具有密切的纤维联系,所以将它们合称为迷走复合体(DVC)。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[1]。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[2]。我们实验室前期工作发现内毒素炎症大鼠脑干DMV、AP和NTS的c-Fos表达均显著增强，表明AP和NTS参与了炎症反应。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传至NTS或两者兼之，还不明确。G. E. Hermann等大鼠注射LPS致炎后，右侧NTS、DMV的c-Fos表达要显著高于左侧。SimonsCT等的研究发现外周炎症信息主要通过左侧迷走神经传入NTS。这些结果提示神经系统对炎症的调节是否存在一侧优势，那么，左右两侧NTS对炎症反应是否存在着差异，相关研究尚未见报道。已有发现，NTS内观察到大量的pERK样免疫反应阳性神经元，ERK1/2通路在内脏感觉、运动的信号转导过程中都发挥了重要作用，但对孤束核内ERK1/2通路在炎症反应中是否活化而影响炎症反应还未见报道。因此，本文采用内毒素炎症模型，分别利用电生理技术和免疫组化方法记录迷走神经放电和DMV、AP神经元的c-Fos表达，探讨NTS在在炎症反应中的作用及DMV、NTS和AP在炎症反应的相关性，以进一步探究DMV、NTS和AP在胆碱能抗炎通路中所起的作用。
本研究分为三部分：
第一部分，损毁双侧NTS后观察内毒素炎症模型中，大鼠肿瘤坏死因子（TNF-α）水平、白细胞数目、迷走神经放电，动脉血压以及DMV和AP内c-Fos的表达情况。实验分为三组：假损毁双侧NTS+LPS组、损毁双侧NTS+LPS组以及损毁双侧NTS+生理盐水组。结果与讨论：损毁双侧+LPS组和损毁双侧+生理盐水组相比，TNF-α水平显著升高，AP和DMV的c-Fos表达均增强，但差异不显著，说明注射LPS引起了大鼠的炎症反应；损毁双侧+LPS组和假损毁双侧+LPS组相比，TNF-α水平显著升高，AP和DMV的c-Fos表达量减少，但差异不显著，说明NTS参与了抗炎症反应。
第二部分，分别损毁左、右两侧NTS后，再注射LPS致炎，观察大鼠肿瘤坏死因子（TNF-α）水平、白细胞个数、迷走神经放电、动脉血压以及DMV和AP内C-Fos的表达情况。实验分为四组：损毁左侧+LPS组、假损毁左侧+LPS组、损毁右侧+LPS组以及假损毁右侧+LPS组。结果与讨论：损毁左侧+LPS组和假损毁左侧+LPS组相比，TNF-α水平显著升高，差异极显著，DMV的c-Fos表达量显著降低。损毁右侧+LPS组和假损毁右侧+LPS组相比，TNF-α水平无明显变化，DMV的c-Fos表达量显著升高，说明左、右侧NTS在抗炎症反应中作用不同。左侧NTS参与抗炎症反应，而右侧NTS可能对炎症反应作用较小。
第三部分，观察PD98059对LPS致大鼠炎症AP和DMV内c-Fos表达的影响。实验分为两组：注射PD98059+LPS组和注射生理盐水+LPS组。结果与讨论：注射PD98059以后，DMV的c-Fos表达量显著减少，这说明了NTS内ERK1/2通路参与了炎症反应，也进一步表明NTS参与了将炎症信息传至DMV的过程。
Inflammation is a common clinical pathophysiological process that can occurs inthe body parts of the tissues and organs. such as folliculitis, tonsillitis, pneumonia,hepatitis, nephritis and so on. The classic signs of acute inflammation are redness,calor heat, swelling, pain and loss of function. inflammation is one of the initialresponses to the presence of an invader and focuses the immune system at the site ofinfection. inflammation is the first-alert mechanism that calls into action the cellsresponsible for surveillance and protection, heralding them to go to work and limit thedamage. In this instance, inflammation is a beneficial process . However,inflammation can cause considerable damage to host tissues, which can be part of themicrobial pathogenesis of a disease process. The magnitude of the inflammatoryresponse is crucial: insufficient responses result in immunodeficiency, which can leadto infection and cancer; excessive responses cause morbidity and mortalityin diseasessuch as rheumatoid arthritis, Crohn’s disease,atherosclerosis. Homeostasis and healthare restored when inflammation is limited by anti-inflammatory responses that areredundant, rapid, reversible, localized, adaptive to changes in input and integrated bythe nervous system.
Recent studies have uncovered a mechanism by which the inflammatory processcan be regulated by activity of the parasympathetic nervous system. Efferent (motor)signals carried by the vagus nerve via the neurotransmitter acetylcholine (ACh), canmodulate the activity of resident macrophages and attenuate local and systemicinflammation. This regulatory activity has been termed "the cholinergicanti-inflammatory pathway". The vagus efferent nerve and neurotransmitter Achinvolved in the antiinflammatory response, which showed that inflammatory responsehave activated vagus preganglionic neurons in the DMV.The adjacent DMV, NTS and AP have complicated neuronal contact and close correlation in function, so that theyconstitute the dorsal vagal complex (DVC) .However, how was the inflammatoryinformation relayed to the DMV? The immune information can signal the brainthrough two pathways:The first, cytokines of the bloodstream passed through the lackof blood-brain barrier of the AP into the brain, then directly transmit to the DMV orindirectly transmit to the DMV by the NTS; The second, cytokine release in theperiphery is sensed by receptors located on the vagus nerve. This information istransmitted to the NTS in the brain stem and subsequently to the DMN. It remainsunclear whether inflammatory information was transmitted to the brain stem mainlythrough the lack of blood-brain barrier of the AP or vagus afferent nerve, or both incholinergic anti-inflammatory pathway. Studies by Gaykema et al. G. E. Hermannshowed that the right side of each brain stem contained somewhat morec-Fos-activated NST cells than the corresponding left side after systemicadministration of LPS. Gaykema et al. have already shown that hepatic afferentswhich ascend predominantly within the left cervical vagal trunk to terminate withinthe left NST were the principal pathway by which systemic exposure to endotoxinprovoked c-Fos activation of brain stem neurons. we propose the followinghypotheses that if brain lateralization is involved in the regulation of the inflammatoryprocess and Two sides of NTS are differently involved in the modulation ofinflammatory responses. The previous work demonstrated that pERK-IR cells areexpressed in the nucleus tractus solitarii (NTS) after capsaicin injection into thewhisker pad. However, It remains unclear the role of the ERK1/2 signaling pathwaywithin the NTS in LPS-induced inflammation responses. Therefore, This presentstudy was designed to examine the discharge of vagal nerve fibers, levels of TNF-αinthe serum and c-Fos expression of DVC in LPS-induced inflammation to furtherexplore the function and the mechanism of DVC in the cholinergic anti-inflammatorypathway.
This research was divided into three parts:
The first part recorded the vagus nerve discharge, blood pressure, levels ofTNF-αin the serum and the c-fos expression in DMV and AP after LPS injection. The experiment was divided into three groups: sham lesioned bilateral NTS+ LPS group,lesioned bilateral NTS + LPS group and lesioned bilateral + physiological salinegroup. Results and discussion: Compared with sham lesioned bilateral + physiologicalsaline group, level of TNF-αof lesioned bilateral NTS + LPS group was increasedsignificantly and c-Fos expression in AP and DMV were increased but not significant.These results illustrates that LPS injection cause the inflammatory response andNTS participated in the Inflammation process
The second part observed levels of TNF-α, leukocyte count, arterial bloodpressure and c-Fos expression in DMV and AP after lesion of the left of the NTSor right . The experiment was divided into four groups: left NTS lesioned +LPSgroup, sham left NTS lesioned +LPS group, right NTS lesioned +LPS group andsham right NTS lesioned +LPS group. Results and discussion: Compare with shamlesioned NTS+LPS, level of TNF–αin the left NTS lesioned +LPS group ,but no inthe right NTS lesioned ,was increased significantly. Compare with sham lesionedNTS+LPS ,the c-Fos expression in DMV of the left NTS lesioned +LPS groupdecreased significantly. The left NTS lesioned have no significant impacts on thec-Fos expression in DMV. The results revealed that the left side of NTS played amajor role in the anti-inflammatory response.,
The third part,observed the impact of PD98059 on the AP and DMV c-Fosexpression in LPS-induced inflammation. Experiment was divided into two groups:injection PD98059 + LPS group and injected saline + LPS group. Results anddiscussion: After the injection of PD98059, compare with the control group, the c-Fosexpression in DMV was significantly reduced after injection PD98059, This indicatesthat ERK1/2 pathway in NTS involved in the inflammatory response, and that someinflammatory signals can be transmitted through the NTS to DMV..
引文
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