脓毒症小鼠肠道树突状细胞变化及其意义的研究
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摘要
脓毒症是外科危重症病人的常见并发症,由于其病理生理过程特别复杂牵涉全身各个器官,死亡率居高不下,是困扰外科和重症监护医师的一大难题。近年的研究提示,免疫功能紊乱是造成脓毒症治疗困难和高致死率的重要原因。而树突状细胞作为免疫系统重要组成部分,其变化对了解脓毒症机体免疫功能紊乱的发生和发展有重要意义。目前已有报道,脓毒症可以造成脾脏、血液等处的树突状细胞丢失。然而,树突状细胞作为一族群,由于所定居的组织器官不同,性质也不完全相同,因此,可以推测脓毒症过程中不同组织的树突状细胞的变化应该也是不尽相同的。
胃肠道是脓毒症的重要受累器官。研究显示在脓毒症过程中定植于胃肠道内的细菌及毒素极易发生易位,因此胃肠道又很有可能是脓毒症患者发生二次感染甚至多器官功能衰竭的重要源器官。树突状细胞在肠道广泛分布于肠粘膜固有层,Peyer’s结等多处,通过多种途径摄取肠腔内的抗原。其对肠道免疫系统实现防御病原体侵袭的同时又可以避免病理性炎症产生这一功能起了关键性的作用。但是目前对于脓毒症过程中肠道树突状细胞的改变的尚无研究。本研究观察脓毒症小鼠肠道树突状细胞的变化,并就可能的机制,及其对肠道炎症以及脓毒症治疗的影响和意义进行了研究。
肠道树突状细胞由于数目较少,分离检测较为困难。因此本研究第一部分我们在国外文献报道的基础上进行改良,分别运用EDTA+DTT和胶原酶Ⅳ消化小鼠肠道组织,制得小鼠肠粘膜固有层和PP结的单细胞悬液,在用CDllc等抗体的标记后,进行流式分析仪分析,建立了较为稳定的检测肠道树突状细胞的方法。本研究第二部分,我们用LPS腹腔注射的方法建立脓毒症小鼠模型,运用第一部分建立的检测方法,检测了小鼠各时相点肠道树突状细胞的数目、成熟度以及亚型。同时,对比了外周血树突状细胞的检测结果。此外还同时检测各时相点TNF-α和IL-10的水平,以综合评估各时相点炎症状态。本研究发现脓毒症小鼠肠道树突状细胞的变化特征与血液及文献报道的变化结果并不相同。LPS腹腔注射后,小鼠肠道树突状细胞数目在脓毒症早期明显增多,24小时后才开始下降。LPS注射90分钟后,肠道树突状细胞虽然增多,但成熟度的下降,CD86和MHCH表达下调。而CDS+树突状细胞比例大幅度上调。外周血树突状细胞数目的变化趋势与肠道树突状细胞的变化趋势相反。在脓毒症早期明显下降而24小时后出现回升,72小时后甚至超过正常小鼠。对此,我们推测可能存在脓毒症早期外周血树突状细胞向肠道的大量迁移。
为验证这一推测,第三部分我们分别检测LPS刺激后CX3CR1 - FKN和CCR6 - MP-3α这两对趋化因子及受体在肠道组织或骨髓源树突状细胞中表达的变化。结果发现LPS注射后肠道组织MIP-3α和FKN的表达上调。而体外实验中骨髓源树突状细胞在LPS刺激后CX3XR1和CCR6的表达更是成百倍的上调。业已证实,FKN-CX3XR1和CCR6-MIP3a这两对趋化因子及受体是介导树突状细胞迁移的重要趋化因子。因此,表明LPS刺激后树突状细胞的大量迁移是存在的。同时,为进一步了解迁移来的树突状细胞对于脓毒症肠道炎症反应的影响,本研究通过腹腔注射Flt3L,预处理小鼠,扩增树突状细胞的数目,进一步放大LPS注射后迁移入肠道的树突状细胞的数目,从而观察肠道的炎症反应的改变。通过与生理盐水预处理的小鼠比对,我们发现,Flt3L预处理小鼠注射LPS后,肠道炎症反应明显加重。这些小鼠的肠道组织TNF-α水平,肠道病理改变都显著严重于对照组。更为重要的是,实验中经Flt3L预处理小鼠在LPS注射后24小时全部死亡。此外还观察到,Flt3L预处理肠道树突状细胞数目虽然明显增多,但其抵御肠道细菌易位的能力并没有明显增强。这一结果证明,树突状细胞,尤其由外周血迁移而来的树突状细胞是脓毒症过程中肠道炎症发生、发展的关键因素,其对炎症反应起了促进作用。并且,这一结果为下一部分实验中脓毒症免疫治疗策略的制定提供了重要的依据。目前诸多研究表明,免疫功能的紊乱是造成脓毒症病人二次感染、多器官功能衰竭甚至死亡的重要原因。动物实验也发现给予免疫增强型的治疗可以取得了较好的效果。我们的研究结果显示,在脓毒症的病理生理过程中存在以过度的炎症反应为主要特点的阶段,如果在这一阶段或之前给予免疫增强治疗将会不利于炎症的控制和病人的预后。
因此,在本研究的第四部分,根据前面所发现的脓毒症小鼠肠道树突状细胞与炎症及免疫系统变化的规律,相对应的将相对应的给予如下的免疫治疗：在早期给予抑炎治疗,后期开始加用免疫增强剂治疗,并验证其作用效果。我们分别选择了树突状细胞数目达到高峰和开始出现丢失的拐点,即LPS注射后的3小时和24小时作为我们开始治疗的时间点。分别选择地塞米松和胸腺肽a1作为抑炎治疗和免疫增强治疗制剂。通过比较不同给药方式的小鼠,发现在LPS腹腔注射后3小时开始接受地塞米松注射,24小时开始加用胸腺肽α1的脓毒症小鼠,受到二次感染的打击后存活率仍达70%,并且这组小鼠抵御肠道细菌易位和二次感染的能力都强于其他给药方式治疗组。这一结果与树突状细胞数目的改变也直接相关。LPS注射12小时后,这组小鼠的肠道树突状细胞数目并没有明显增加,而后期也没有出现明显的丢失。表明这两种药物对脓毒症过程中树突状细胞调控作用是取得良好疗效的重要原因之一。
综上所述,我们的研究结果首次描述了脓毒症过程中肠道树突状细胞的变化规律,并揭示树突状细胞的迁移是其早期数目改变的重要机制。而针对脓毒症小鼠树突状细胞数目改变和机体炎症变化的时间动力学规律,运用地塞米松联合胸腺肽α1治疗脓毒症的免疫调控治疗也取得了良好的疗效。从而证实了树突状细胞作为脓毒症免疫调理治疗的指示剂和调控目标的可能性,为脓毒症治疗提供了一个新的可行的治疗方向。
Sepsis is a common and serious complication in general surgery patients. Because of its complex pathophysiology, the treatment of septic patients has troubled surgery and intensive care physicians for a long time. Recent studies indicate that immune dysfunction is a major cause of the high mortality rate of septic patients. Among the components of the immune system that may contribute to immune dysfunction in sepsis, dendritic cells (DC) play a key role. Several researchers have reported that profound depletion of DC occurs in both septic patients and septic mice. However, these researches mainly focused on the loss of DC in spleen or other lymph organ. Little insight was provided concerning the alterations of DC present in other organs during sepsis.
Today a large body of experimental data have documented that the gastrointestinal tract is not a passive organ for the patients who suffered from endotoxin shock (or sepsis). The ensuing translocation of bacteria and their products gained increasing acceptance as a major contributor to the development of secondary infection and MODS following septic shock. In gut, resident DC has been described in Peyer's patchs and lamina propria. Gut DC can pick up antigen that has been transported across the intestinal epithelium through various different routes. So, they are important for the immunologic and barrier functions of gut. Moreover, because of the needs of specialized immune system of the gut to respond appropriately to the large antigenic load normally present in the form of food antigens and commensal bacteria, gut DC have different properties and functions with those in spleen. Thus, in our present study we carefully characterize the alteration of gut DC during sepsis, and its effect for intestinal inflammation and the treatment of sepsis.
Due to its low number, the isolation and examination for gut DC is difficult. In this study, we make some improvements based on methods reported by Sun CM. We digest the intestine of mice with EDAT+DTT and Collagenase IV to get the single suspension of Peyer's patch(PP) or lamina propria(LP).Then the single cell suspension we got was stained with antibody such as CDllc for flow cytometry. The results indicate it is a stable method for the detection of intestinal DC.
In the second section, we induce the model of sepsis by intraperitoneal injection of LPS.Then we analyzed the population and MHCII and CD86 expression of DC that present in lamina propria (LP), Peyer's patches (PP), and blood. We also examined whether there was an increase or loss of a specific DC subpopulations. Additionally, according to the levels of TNF-a and IL-10, we assessed the inflammatory state at various time points. Interestingly, we found that the alteration of intestinal DC was different with splenetic DC's. Just after the injection of LPS, the number of intestinal DC significant increased rather than decreased. The loss of intestinal DC was observed until 24h after onset of sepsis. We also noted that the expression of CD86 and MHCII on intestinal DC were down-regulated by 90min in septic mice. Additionally, we found that the increase of LP and PP DC was mostly contributed to the expansion of CD4-CD8+DC. However, the changes of DC in circulating were opposite to gut DC's. Thus we speculated that the recruitment of DC precursors in blood into the intestine might be able to explain this.
In the third section, to verify our hypothesis, we examined the alteration of the gene expression of CX3CR1-FKN and CCC6-MIP-3a after LPS stimulation. And to evaluate the effect of the DC migrated from blood on intestinal inflammation induced with LPS, mice were pre-treated with Flt3L or normal saline, and then challenged with or without LPS. After that, occurrence of bacterial translocation to distant organ and inflammatory response were evaluated. Additionally, the population and maturity of DC in LP and circulating was analyzed by flow cytometry. We observed that pretreatment of Flt3L significantly expanded DC in LP and blood, but not induce alteration of their maturity. We also found LPS injection induced up-regulation of CX3CR1-FKN and CCC6-MIP-3a mRNA levels and drastic increase of DC in intestine. However, exacerbation of DC growth induced by Flt3L-pretreatment aggravated intestinal inflammation and increased the mortality of endotoxemic mice rather than enhance resistance to bacterial translocation. The data of this section proved that migration of DC from circulating into intestine was a major mechanism for the increase of gut DC after LPS injection. Moreover, it suggested that DC play a key role in the development of intestinal inflammation induced by LPS. And recent studies have addressed the effect of immune-enhance treatment such as Flt3L, IFN-y and Tal as an immunotherapeutic option to reverses sepsisi-related immunoparalysis. However, the data of the current study show that Flt3L-induced increase in numbers of DC caused serious consequences for the mice after challenged with LPS. Thus down-regulated DC numbers at the pro-inflammatory stage and up-regulated DC numbers when immune was suppressed may be able to help host survival in the campaign to endotoxin shock or sepsis.
Thus we verify our hypothesis in last section. Base on the results of above study, we choose 3 hour and 24 hour after LPS injection as the treatment time point. And dexamethasone (DXM) and thymosin alpha-1 (Tal, Zadaxin) that can be directly applied in the clinic were chosen as a means of anti-inflammation or immune-enhance treatment. Septic mice were randomly divided into five treatment groups.Then survival rates, levels of TNF-a and IL-10, the occurrence of bacterial translocation and the ability to clear secondary infections was observed. The behavior of DC over time was also evaluated. Among the five treatment groups, the combined treatment of dexamethasone and thymosin alpha-1 induced the highest survival rate, was associated with a decrease in bacterial translocation to extra-intestinal organs and enhanced the ability to eradicate secondary infections by reversing the change in DC numbers during sepsis. It provides evidence for a possible strategy to modulate numbers of DC to improve outcome of sepsis.
胃肠道是脓毒症的重要受累器官。研究显示在脓毒症过程中定植于胃肠道内的细菌及毒素极易发生易位,因此胃肠道又很有可能是脓毒症患者发生二次感染甚至多器官功能衰竭的重要源器官。树突状细胞在肠道广泛分布于肠粘膜固有层,Peyer’s结等多处,通过多种途径摄取肠腔内的抗原。其对肠道免疫系统实现防御病原体侵袭的同时又可以避免病理性炎症产生这一功能起了关键性的作用。但是目前对于脓毒症过程中肠道树突状细胞的改变的尚无研究。本研究观察脓毒症小鼠肠道树突状细胞的变化,并就可能的机制,及其对肠道炎症以及脓毒症治疗的影响和意义进行了研究。
肠道树突状细胞由于数目较少,分离检测较为困难。因此本研究第一部分我们在国外文献报道的基础上进行改良,分别运用EDTA+DTT和胶原酶Ⅳ消化小鼠肠道组织,制得小鼠肠粘膜固有层和PP结的单细胞悬液,在用CDllc等抗体的标记后,进行流式分析仪分析,建立了较为稳定的检测肠道树突状细胞的方法。本研究第二部分,我们用LPS腹腔注射的方法建立脓毒症小鼠模型,运用第一部分建立的检测方法,检测了小鼠各时相点肠道树突状细胞的数目、成熟度以及亚型。同时,对比了外周血树突状细胞的检测结果。此外还同时检测各时相点TNF-α和IL-10的水平,以综合评估各时相点炎症状态。本研究发现脓毒症小鼠肠道树突状细胞的变化特征与血液及文献报道的变化结果并不相同。LPS腹腔注射后,小鼠肠道树突状细胞数目在脓毒症早期明显增多,24小时后才开始下降。LPS注射90分钟后,肠道树突状细胞虽然增多,但成熟度的下降,CD86和MHCH表达下调。而CDS+树突状细胞比例大幅度上调。外周血树突状细胞数目的变化趋势与肠道树突状细胞的变化趋势相反。在脓毒症早期明显下降而24小时后出现回升,72小时后甚至超过正常小鼠。对此,我们推测可能存在脓毒症早期外周血树突状细胞向肠道的大量迁移。
为验证这一推测,第三部分我们分别检测LPS刺激后CX3CR1 - FKN和CCR6 - MP-3α这两对趋化因子及受体在肠道组织或骨髓源树突状细胞中表达的变化。结果发现LPS注射后肠道组织MIP-3α和FKN的表达上调。而体外实验中骨髓源树突状细胞在LPS刺激后CX3XR1和CCR6的表达更是成百倍的上调。业已证实,FKN-CX3XR1和CCR6-MIP3a这两对趋化因子及受体是介导树突状细胞迁移的重要趋化因子。因此,表明LPS刺激后树突状细胞的大量迁移是存在的。同时,为进一步了解迁移来的树突状细胞对于脓毒症肠道炎症反应的影响,本研究通过腹腔注射Flt3L,预处理小鼠,扩增树突状细胞的数目,进一步放大LPS注射后迁移入肠道的树突状细胞的数目,从而观察肠道的炎症反应的改变。通过与生理盐水预处理的小鼠比对,我们发现,Flt3L预处理小鼠注射LPS后,肠道炎症反应明显加重。这些小鼠的肠道组织TNF-α水平,肠道病理改变都显著严重于对照组。更为重要的是,实验中经Flt3L预处理小鼠在LPS注射后24小时全部死亡。此外还观察到,Flt3L预处理肠道树突状细胞数目虽然明显增多,但其抵御肠道细菌易位的能力并没有明显增强。这一结果证明,树突状细胞,尤其由外周血迁移而来的树突状细胞是脓毒症过程中肠道炎症发生、发展的关键因素,其对炎症反应起了促进作用。并且,这一结果为下一部分实验中脓毒症免疫治疗策略的制定提供了重要的依据。目前诸多研究表明,免疫功能的紊乱是造成脓毒症病人二次感染、多器官功能衰竭甚至死亡的重要原因。动物实验也发现给予免疫增强型的治疗可以取得了较好的效果。我们的研究结果显示,在脓毒症的病理生理过程中存在以过度的炎症反应为主要特点的阶段,如果在这一阶段或之前给予免疫增强治疗将会不利于炎症的控制和病人的预后。
因此,在本研究的第四部分,根据前面所发现的脓毒症小鼠肠道树突状细胞与炎症及免疫系统变化的规律,相对应的将相对应的给予如下的免疫治疗：在早期给予抑炎治疗,后期开始加用免疫增强剂治疗,并验证其作用效果。我们分别选择了树突状细胞数目达到高峰和开始出现丢失的拐点,即LPS注射后的3小时和24小时作为我们开始治疗的时间点。分别选择地塞米松和胸腺肽a1作为抑炎治疗和免疫增强治疗制剂。通过比较不同给药方式的小鼠,发现在LPS腹腔注射后3小时开始接受地塞米松注射,24小时开始加用胸腺肽α1的脓毒症小鼠,受到二次感染的打击后存活率仍达70%,并且这组小鼠抵御肠道细菌易位和二次感染的能力都强于其他给药方式治疗组。这一结果与树突状细胞数目的改变也直接相关。LPS注射12小时后,这组小鼠的肠道树突状细胞数目并没有明显增加,而后期也没有出现明显的丢失。表明这两种药物对脓毒症过程中树突状细胞调控作用是取得良好疗效的重要原因之一。
综上所述,我们的研究结果首次描述了脓毒症过程中肠道树突状细胞的变化规律,并揭示树突状细胞的迁移是其早期数目改变的重要机制。而针对脓毒症小鼠树突状细胞数目改变和机体炎症变化的时间动力学规律,运用地塞米松联合胸腺肽α1治疗脓毒症的免疫调控治疗也取得了良好的疗效。从而证实了树突状细胞作为脓毒症免疫调理治疗的指示剂和调控目标的可能性,为脓毒症治疗提供了一个新的可行的治疗方向。
Sepsis is a common and serious complication in general surgery patients. Because of its complex pathophysiology, the treatment of septic patients has troubled surgery and intensive care physicians for a long time. Recent studies indicate that immune dysfunction is a major cause of the high mortality rate of septic patients. Among the components of the immune system that may contribute to immune dysfunction in sepsis, dendritic cells (DC) play a key role. Several researchers have reported that profound depletion of DC occurs in both septic patients and septic mice. However, these researches mainly focused on the loss of DC in spleen or other lymph organ. Little insight was provided concerning the alterations of DC present in other organs during sepsis.
Today a large body of experimental data have documented that the gastrointestinal tract is not a passive organ for the patients who suffered from endotoxin shock (or sepsis). The ensuing translocation of bacteria and their products gained increasing acceptance as a major contributor to the development of secondary infection and MODS following septic shock. In gut, resident DC has been described in Peyer's patchs and lamina propria. Gut DC can pick up antigen that has been transported across the intestinal epithelium through various different routes. So, they are important for the immunologic and barrier functions of gut. Moreover, because of the needs of specialized immune system of the gut to respond appropriately to the large antigenic load normally present in the form of food antigens and commensal bacteria, gut DC have different properties and functions with those in spleen. Thus, in our present study we carefully characterize the alteration of gut DC during sepsis, and its effect for intestinal inflammation and the treatment of sepsis.
Due to its low number, the isolation and examination for gut DC is difficult. In this study, we make some improvements based on methods reported by Sun CM. We digest the intestine of mice with EDAT+DTT and Collagenase IV to get the single suspension of Peyer's patch(PP) or lamina propria(LP).Then the single cell suspension we got was stained with antibody such as CDllc for flow cytometry. The results indicate it is a stable method for the detection of intestinal DC.
In the second section, we induce the model of sepsis by intraperitoneal injection of LPS.Then we analyzed the population and MHCII and CD86 expression of DC that present in lamina propria (LP), Peyer's patches (PP), and blood. We also examined whether there was an increase or loss of a specific DC subpopulations. Additionally, according to the levels of TNF-a and IL-10, we assessed the inflammatory state at various time points. Interestingly, we found that the alteration of intestinal DC was different with splenetic DC's. Just after the injection of LPS, the number of intestinal DC significant increased rather than decreased. The loss of intestinal DC was observed until 24h after onset of sepsis. We also noted that the expression of CD86 and MHCII on intestinal DC were down-regulated by 90min in septic mice. Additionally, we found that the increase of LP and PP DC was mostly contributed to the expansion of CD4-CD8+DC. However, the changes of DC in circulating were opposite to gut DC's. Thus we speculated that the recruitment of DC precursors in blood into the intestine might be able to explain this.
In the third section, to verify our hypothesis, we examined the alteration of the gene expression of CX3CR1-FKN and CCC6-MIP-3a after LPS stimulation. And to evaluate the effect of the DC migrated from blood on intestinal inflammation induced with LPS, mice were pre-treated with Flt3L or normal saline, and then challenged with or without LPS. After that, occurrence of bacterial translocation to distant organ and inflammatory response were evaluated. Additionally, the population and maturity of DC in LP and circulating was analyzed by flow cytometry. We observed that pretreatment of Flt3L significantly expanded DC in LP and blood, but not induce alteration of their maturity. We also found LPS injection induced up-regulation of CX3CR1-FKN and CCC6-MIP-3a mRNA levels and drastic increase of DC in intestine. However, exacerbation of DC growth induced by Flt3L-pretreatment aggravated intestinal inflammation and increased the mortality of endotoxemic mice rather than enhance resistance to bacterial translocation. The data of this section proved that migration of DC from circulating into intestine was a major mechanism for the increase of gut DC after LPS injection. Moreover, it suggested that DC play a key role in the development of intestinal inflammation induced by LPS. And recent studies have addressed the effect of immune-enhance treatment such as Flt3L, IFN-y and Tal as an immunotherapeutic option to reverses sepsisi-related immunoparalysis. However, the data of the current study show that Flt3L-induced increase in numbers of DC caused serious consequences for the mice after challenged with LPS. Thus down-regulated DC numbers at the pro-inflammatory stage and up-regulated DC numbers when immune was suppressed may be able to help host survival in the campaign to endotoxin shock or sepsis.
Thus we verify our hypothesis in last section. Base on the results of above study, we choose 3 hour and 24 hour after LPS injection as the treatment time point. And dexamethasone (DXM) and thymosin alpha-1 (Tal, Zadaxin) that can be directly applied in the clinic were chosen as a means of anti-inflammation or immune-enhance treatment. Septic mice were randomly divided into five treatment groups.Then survival rates, levels of TNF-a and IL-10, the occurrence of bacterial translocation and the ability to clear secondary infections was observed. The behavior of DC over time was also evaluated. Among the five treatment groups, the combined treatment of dexamethasone and thymosin alpha-1 induced the highest survival rate, was associated with a decrease in bacterial translocation to extra-intestinal organs and enhanced the ability to eradicate secondary infections by reversing the change in DC numbers during sepsis. It provides evidence for a possible strategy to modulate numbers of DC to improve outcome of sepsis.
引文
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