摘要
背景：在机体的免疫系统中，肠道由于接触抗原的表面积最大并且免疫细胞数量较多，因而被认为是体内最大的免疫器官，全身约70%的免疫细胞存在于肠道，且肠道黏膜面积庞大，每时每刻都要接触大量的抗原，既能对正常的菌群和食物成分耐受，又能对肠道病原体产生有效的免疫应答，担负着重要的免疫功能，是机体免疫系统的第一道防线，其功能不仅作用于肠黏膜，还参与了全身免疫功能的调节。
在化疗药物治疗肿瘤的过程中，部分化疗药物的代谢产物对肠道黏膜造成了严重的破坏，损伤了肠道黏膜屏障，从而导致了腹泻等剂量限制性副反应的发生，在这些药物中最有代表性的为伊立替康（CPT-11）。伊立替康是喜树碱的半合成衍生物，能特异性地与拓扑异构酶I结合，使DNA双链结构破坏，导致细胞死亡，起到抗肿瘤的作用。CPT-11常用于标准方案化疗后复发的转移性大肠癌的治疗，此外,对肺癌、乳腺癌、胃癌、卵巢癌等也有一定的疗效。CPT-11常见的副作用有延迟性腹泻、中性粒细胞减少、恶心呕吐、急性胆碱能综合征及脱发、发热等，其中延迟性腹泻是CPT-11剂量限制性毒性的最主要原因。延迟性腹泻常发生于CPT-11给药后24小时，发生率约为60-87%，按照NCI的毒性标准，其中3/4级严重的腹泻约占20-39%。
针对伊立替康导致的延迟性腹泻的机理国内外学者做了广泛的研究，认为CPT-11的活性代谢产物SN-38的肠道累积是其主要原因。CPT-11在体内主要由羧酸酯酶（CE）催化并水解为活性代谢物SN-38，SN-38由肝内的UDP-葡萄糖醛酸转移酶1A1(UGT1A1)催化，生成无活性的代谢产物SN-38葡萄糖醛酸苷(SN-38G)。SN-38和SN-38G均可随胆汁排泄至十二指肠。肠道中的β-葡萄糖醛酸酶可将无活性的SN-38G重新转变成有活性的SN-38，造成了对肠道的损害，使肠绒毛变短或消失，肠上皮细胞坏死，导致促炎性细胞聚集并释放大量的促炎性细胞因子如TNF-α、IL-1β和IL-6等，这些促炎性因子的产生能够进一步导致巨噬细胞趋化并合成环氧化酶2（COX-2）和前列腺素E2(PGE2)，导致肠道炎症、溃疡及吸收能力的下降，发生腹泻。近年来，有研究者发现PGE2的表达能够诱导免疫抑制因子吲哚胺2，3-双加氧酶（IDO）的产生，IDO是一种含铁血红素单体蛋白，主要由胎盘滋养层细胞、外周血单核/巨噬细胞和树突状细胞分泌，能降解T细胞活化所必需的色氨酸，抑制T细胞增殖。有研究表明IDO可能是PGE2活化的下游，并且IDO和PGE2均与结肠癌的进展及预后差密切相关，其机制可能主要为IDO能降解T细胞活化所必需的色氨酸，阻断T细胞增殖，使活化的T细胞凋亡，并且通过减少IL-12等因子的产生，抑制抗肿瘤的Th1型免疫反应，同时还能增加调节性T细胞（Treg）的表达，促进Treg介导的免疫抑制，并促使抑制性细胞因子IL-10的产生，IL-10的产生能促使辅助性T细胞(Th)向Th2型偏移，驱动Th2型免疫，减弱Th1型抗肿瘤免疫，形成了抑制性免疫微环境，这种免疫抑制微环境的形成可能会降低宿主的抗肿瘤免疫，促进肿瘤免疫逃逸。因而如果不针对CPT-11代谢产物SN-38对肠道的损伤加以防护，可能会形成肠道免疫抑制微环境，进而破坏肠道免疫系统，减弱机体的抗肿瘤能力，促进肿瘤的复发转移，所以寻求防护肠道黏膜免受SN-38损伤，抑制促炎性因子及免疫抑制因子的产生，调节肠道免疫微环境，修复肠道免疫系统的破坏，对防止肿瘤的复发转移有着极其重要的意义。
小檗碱又称黄连素，是从中药黄连、黄柏中提取的一种抗菌性的异喹啉类生物碱，有清热解毒的作用。中医常用黄连、黄柏、三颗针等作为清热解毒的药物，其中主要有效成分即为小檗碱，此类药物性凉，能清除邪热或虚热、消除有害毒物，常用于治疗细菌性腹泻，肠道寄生虫感染及眼部沙眼感染等。有研究显示，小檗碱不仅具有抗炎的活性，抑制促炎性细胞因子如TNF-α、IL-1β和IL-6及免疫抑制因子PGE2的产生，同时还能抑制肠道中产生SN-38的β-葡萄糖醛酸酶,由此我们推测小檗碱可能通过上述机制，既减少了肠道损伤，降低了化疗所致的腹泻，又通过抑制Th2型免疫应答及免疫抑制微环境的形成，促进了Th1型免疫应答，增加了抗肿瘤的T细胞免疫，防止了肿瘤的复发转移。
目的：1.建立CPT-11延迟性腹泻模型，并检测其引起的肠道组织病理结构改变。
2.探讨CPT-11所致的肠道损伤对肠道免疫系统的影响，以及对继发全身免疫系统的作用。
3.验证小檗碱是否能够缓解CPT-11所致的肠道及免疫系统的损伤并探讨其相应的分子机制。
方法：1.皮下种植瘤小鼠CPT-11延迟性腹泻模型的建立：
（1）小鼠皮下移植瘤模型的建立：每日监测肿瘤大小，并绘制肿瘤生长曲线。
（2）建立BALB/c小鼠CPT-11延迟性腹泻模型，并通过腹泻评分及HE染色评估模型及肠道损伤情况。
2.CPT-11所致的肠道黏膜损伤对免疫系统的影响：
（1）CPT-11所致的肠道损伤对肠道免疫的影响：①ELISA检测肠道促炎性因子TNF-α，IL-6，IL-1β的表达②ELISA检测肠道免疫抑制因子PGE2，Western检测免疫抑制因子IDO的表达③ELISA检测肠道Th1型细胞因子IL-12及Th2型细胞因子IL-10的表达④流式检测肠集合淋巴结中Treg的比例。
（2）CPT-11所致的肠道损伤对全身免疫的影响：①ELISA检测血中Th1型细胞因子IL-12及Th2型细胞因子IL-10的表达②流式检测血中Treg的比例。
3.小檗碱缓解CPT-11所致的肠道黏膜免疫系统损伤的机制研究：
（1）小檗碱缓解CPT-11所致的腹泻及肠道损伤：①腹泻评分②HE染色
（2）小檗碱修复CPT-11对肠道免疫的破坏：①ELISA检测肠道促炎性因子TNF-α，IL-6，IL-1β的表达②ELISA检测肠道免疫抑制因子PGE2，Western检测免疫抑制因子IDO的表达③ELISA检测肠道Th1型细胞因子IL-12及Th2型细胞因子IL-10的表达④流式检测肠集合淋巴结中Treg的比例。
（3）小檗碱增加全身抗肿瘤免疫：①ELISA检测血中Th1型细胞因子IL-12及Th2型细胞因子IL-10的表达②流式检测血中Treg的比例。
结果：1.CPT-11诱导延迟性腹泻的最佳剂量是100mg/kg/day，连续给药3天，延迟性腹泻发生率为72%，致死率为40%，并且检测到严重的肠道黏膜损伤。HE染色示：肠绒毛变短或消失，肠上皮细胞核固缩、核碎裂、核溶解，呈坏死表现，肠腺体严重受损，炎细胞大量浸润。
2.（1）CPT-11所致的肠道损伤对肠道免疫的影响：①CPT-11给药组肠道促炎性细胞因子如TNF-α，IL-6和IL-1β表达增加，CPT-11组中TNF-α的表达由对照组中的0.86±0.32增加到了7.90±1.14，P<0.01。IL-1β的表达也由对照组中的5.84±0.70增加到了21.08±1.80，P<0.01。对照组中IL-6的表达为8.06±1.14，而CPT-11组中的表达为23.12±5.42，显著增加，差异有统计学意义（P<0.01）。②CPT-11给药组诱导了免疫抑制因子PGE2及IDO的表达。CPT-11组的PGE2为79.00±6.12显著高于对照组中的21.92±2.254，P<0.01。同样，与对照组相比，CPT-11组中IDO的蛋白表达也显著上调（P<0.01）。③CPT-11给药组抑制了肠道抗肿瘤Th1型细胞因子IL-12的产生，促进了Th2型细胞因子IL-10的产生，使Th细胞由Th1型向Th2型偏移，CPT-11组中，抗肿瘤免疫的Th1型细胞所产生的IL-12由对照组的4.76±0.97降至2.18±0.62，P<0.01。而抑制Th1型免疫应答的Th2型细胞因子IL-10在CPT-11组中为23.82±4.66显著高于对照组中的4.62±0.99，P<0.01。④CPT-11给药组中肠集合淋巴结中Treg/CD4+T细胞比率显著升高，由（1.53±0.42）%增至（5.50±0.90）%，P<0.01。
（2）CPT-11所致的肠道损伤对全身免疫的影响：CPT-11降低了血中抗肿瘤的Th1型细胞因子IL-12的表达，同时促进了Th2型细胞因子IL-10的产生，使Th细胞由Th1型向Th2型偏移，并且血中Treg/CD4+T细胞比率升高。Treg/CD4+T细胞在CPT-11组中的比率由（4.95±0.44）%增至（7.90±0.48）%，P<0.01。CPT-11所致的腹泻组中，抗肿瘤免疫的Th1型细胞所产生的IL-12下调，由对照组的131.60±16.06降至107.80±12.95，差异有统计学意义（P<0.05）。而抑制Th1型免疫应答的Th2型细胞因子IL-10在CPT-11组中为70.26±6.41显著高于对照组中的43.86±7.22，P<0.01。
3.（1）小檗碱缓解CPT-11所致的腹泻及肠道损伤：小檗碱100mg/kg（每天一次，连3天），显著减少了CPT-11所致的腹泻的严重程度和肠道黏膜损伤。腹泻评分显著降低（P＜0.05），CPT-11组中肠道黏膜损伤严重，肠绒毛变短或消失，肠上皮细胞坏死，正常肠腺体破坏，炎细胞浸润。小檗碱+CPT-11组中，肠道黏膜破坏显著减轻，肠上皮细胞坏死较少，肠腺体正常。
（2）小檗碱修复CPT-11对肠道免疫的破坏：①小檗碱抑制肠道促炎性因子及免疫抑制因子的增加。促炎性因子TNF-α的表达在小檗碱+CPT-11组中为5.02±1.43，显著低于CPT-11组中的7.90±1.14（P<0.01）。小檗碱+CPT-11组中的IL-1β为13.08±4.13，明显低于CPT-11组中的21.08±1.80（P<0.01）。IL-6在小檗碱+CPT-11组中为11.80±2.90，低于CPT-11组中的23.12±5.43（P<0.01）。小檗碱+CPT-11组中PGE2为44.00±4.12，与CPT-11组中的79.00±6.12相比，显著降低（P<0.01），且小檗碱组与对照组无差异（P>0.05）。小檗碱+CPT-11组中IDO的蛋白表达水平也显著低于CPT-11组（P<0.05）。②小檗碱抑制免疫抑制微环境的形成，同时降低Treg/CD4+T细胞比率。小檗碱+CPT-11组中，抗肿瘤免疫的Th1型细胞所产生的IL-12上调，由CPT-11组中的2.18±0.62增加至3.36±0.48，P<0.05。而抑制Th1型免疫应答的Th2型细胞因子IL-10在小檗碱+CPT-11组中为10.94±2.83显著低于对照组中的23.82±4.66，P<0.01。与CPT-11相比，小檗碱+CPT-11组中Treg/CD4+T细胞比率降低，由CPT-11组的（5.50±0.90）%降至（4.20±0.50）%，P<0.05。
（3）小檗碱增加全身抗肿瘤免疫：小檗碱+CPT-11组中，抗肿瘤免疫的Th1型细胞所产生的IL-12上调，由CPT-11组中的107.80±12.95增加至128.80±9.34，P<0.05。而抑制Th1型免疫应答的Th2型细胞因子IL-10在小檗碱+CPT-11组中为51.32±5.53显著低于CPT-11组中为70.26±6.41，P<0.01。与CPT-11相比，小檗碱+CPT-11组中Treg/CD4+T细胞比率也降低，由CPT-11组的（7.90±0.48）%降至（5.68±1.83）%，P<0.05。
结论：1. CPT-11所致的肠道损伤，增加了肠道促炎性因子及免疫抑制因子的产生，改变了肠道免疫格局，形成了抑制性免疫微环境。
2.肠道免疫抑制微环境的形成能够减弱宿主的抗肿瘤免疫，促进肿瘤免疫逃逸，增加肿瘤复发转移的机会。
3.小檗碱通过减少了肠道损伤，缓解了腹泻，同时还能阻断肠道免疫抑制微环境的形成，增加了抗肿瘤免疫的Th1型细胞因子的表达，增强机体的抗肿瘤活性，减少肿瘤复发转移的机率。
Background: In the immune system, intestinal is believed to be the biggest immuneorgan because it has a large number of immune cells and the largest surface contactedwith antigen. The area of intestinal mucosa is large and constantly facing a high load ofantigens. And approximately70%of the immunocyte are present in the gut and arecontinuously discriminating between harmless and pathogenic antigens. They are thefirst line of defense pathogenic and the function of them is not only in the intestinalmucosa, but also involved in the systemic immunity.
In an effort to control cancer and sustain remission, adjuvant chemotherapy havebeen used to eliminate microscopic tumor and extend life expectancy in patients.However, parts of the chemotherapy agents caused serious damage to the intestinalmucosa leading to the diarrhea which is the dose limiting toxicity of the agents, and oneof the most representative drug among them is irinotecan (CPT-11). Irinotecan (CPT-11)is a semi synthetic derivative of camptothecin. CPT-11can bind to thetopoisomeraseⅠ-DNA complex which prevent relegation of the DNA strand. This leadsto double-strand DNA breakage and cell death that is the primary mechanism ofantitumour activity of CPT-11. CPT-11is one of the most commonly usedchemotherapy agents in metastatic colorectal cancer and also has certain effect on lungcancer, breast cancer, gastric cancer, ovarian cancer and so on. The common side effects of CPT-11are late diarrhea, neutropenia, acute cholinergic syndrome, nausea andvomiting and others: such as hair loss, fever and so on. Among them the late diarrhea isthe main reason of dose limiting toxicity of CPT-11. The late diarrhea often occurs in24hours after CPT-11administration, the incidence is about60-87%. According to thetoxicity of NCI standard, the severe diarrhea of grade3/4account for about20-39%.
However, the mechanism of irinotecan induced diarrhea is still unclear, manyscholars believed that irinotecan is to coverted by hepatic or gastrointestinalcarboxylesterases to its active metabolite7-ethyl-10-hydroxycamptothecin (SN-38).SN-38is further processed by glucuronyltransferase to become SN-38glucuronide(SN-38G), a less toxic form of SN-38. However, SN-38G is transported to the intestineduring bile excretion, and is able to be hydrolysed by β-glucuronide to return to thetoxic form, SN-38. SN-38is responsible for the damage to the intestinal mucosa,characterized by stubby and bare of villi, necrosis of intestinal epithelial cell,destruction of normal mucosal architecture and also inflammatory cellular infiltrationwere noted which caused chemotactic of macrophage and synthesis of cyclooxygenase2(COX-2) and prostaglandin E2(PGE2). These caused the inflammation and ulcer inintestinal, leading to the decrease of absorption in intestine and diarrhea. In addition, thePGE2drived by COX-2also can induce the expression of indoleamine2,3-dioxygenase(IDO). IDO is a heme monomer protein, mainly secreted by the placental trophoblastcells, peripheral blood monocytes/macrophages and dendritic cells. Some reasearchershave showed that IDO is the downstream of PGE2, and both IDO and PGE2are relatedto the progress and poor prognosis of colorectal cancer. The mechanism is that IDO candegrade the lubricious ammonia acid which is required for the T cells activated andsuppress the proliferation of T cells, including apoptosis of them and reduce the produceof IL-12. These inhibit the Th1type of anti-tumor immune response and increased theexpression of regulatory T cells (Treg) and suppressive cytokines of IL-10. Theproduction of IL-10can promote the Th cells shift to Th2, driving Th2type immunityand weakened Th1type of anti-tumor immunity which formed the immunosuppressivemicroenvironment. The antitumor immunity is suppressed in this immunosuppressive microenvironment, which leads to the immunologic escape of tumor. So if the injury ofintestine induced by SN-38is not protected, the immunosuppressive microenvironmentis formed and destroy the intestinal immune system which weaken the ability ofanti-tumor, promoting the metastasis and recurrence of tumor. Thus, to seek methods ofprotecting intestinal mucosa from the damage of SN-38, inhibiting the proinflammatoryand immunosuppressive cytokines, regulating the immunity microenvironment andrepairing the intestinal immune system is vital to prevent metastasis and recurrence oftumor.
Berberine an isoquinoline alkaloid, which is extract from rhizoma coptis is presentin several plants, such as Hydrastis canadensis (goldenseal), Berberis aquifolium(Oregon grape), and berberis vulgaris (barberry). The berberine is one of the mostcommonly used herbal medicines for the treatment of bacteria-associated diarrhea,intestinal parasitic infections and ocular trachoma infections for several decades.Several studies revealed that berberine had anti-inflammatory activity and inhibited theproduce of proinflammatory and immunosuppressive cytokines, such as TNF-α, IL-1β,IL-6and PGE2. At the same time, the berberine also inhibited the β-glucuronide whichproduce SN-38in intestine. Thus based on the mechanism above, we deduced berberinemay not only reduce the diarrhea and the injury of intestine induced by CPT-11, but alsoinhibit the Th2type immunity and the formation of immunosuppressivemicroenvironment, promoting the Th1type anti-tumor immunity and improving theanti-tumor immune of T cells which prevent the recurrence and metastasis of tumor.
Objective:1. To establish the diarrhea model induced by CPT-11and detect thechanges of pathology in intestinal.
2. To investigate whether the intestinal immune system is damaged bythe injury of intestinal induced by CPT-11and then affect the systemic immunity,leading to the recurrence and metastasis of tumor.
3. To verification whether berberine alleviate the injury of intestinal immunity induced by CPT-11and explore it’s molecular mechanism
Methods:1. We establish the diarrhea model induced by CPT-11of subcutaneousimplanted tumor mice and assess the injury of intestinal by score of diarrhea and HEstaining.
2. The effect on immune system by the injury of intestinal induced byCPT-11:①Enzyme-linked immunosorbent assay(ELISA) was used to deteced theexpression of TNF-α, IL-1β, IL-6, PGE2and IL-10in the tissue extracts and blood.②Western blot was used to deteced the expression of IDO in intestine.③Flow cytometrywas used to deteced Treg in Peyer’s Patches and blood.
3. Berberine alleviate the injury of intestinal immunity induced byCPT-11:①Assess the injury of intestinal by score of diarrhea and HE staining.②Enzyme-linked immunosorbent assay(ELISA) was used to deteced the expression ofTNF-α, IL-1β, IL-6, PGE2and IL-10in the tissue extracts and blood.③Western blotwas used to deteced the expression of IDO in intestine.④Flow cytometry was used todeteced Treg in Peyer’s Patches and blood.
Results:1. The optimal dose of CPT-11induced diarrhea was100mg/kg/day, for3consecutive days, the incidence of onset diarrhea was72%, mortality was40%, andcompared to the control group, the CPT-11treatment group caused severe damage ofmucosal surface in intestine, characterized by stubby and bare of villi, necrosis ofepithelial cells in intestine, destruction of normal mucosal architecture andinflammatory cellular infiltration.
2. The expression of proinflammatory cytokines such as TNF-α, IL-6, IL-1βof CPT-11treatment group were increased and Th1type anti-tumor immune cytokineIL-12was decreased. The expression of immunosuppression cytokines including PGE2,IL-10and IDO of CPT-11treatment group were all increased. In the CPT-11treatmentgroup, Treg was increased in the Peyer’s Patches and blood.
3. Compared to the CPT-11treatment group, the berberine+CPT-11treatment group showed less damage of epithelial cells and intestinal glands. Theinflammatory cellular infiltration of berberine+CPT-11treatment group was alsodecreased and diarrhea was alleviated. In berberine+CPT-11treatment group, theexpression of TNF-α, IL-6, IL-1β were decreased and along with the IL-12increased,the immunosuppression cytokines PGE2, IL-10and IDO were all decreased. The Tregwas decreased in the Peyer’s Patches and blood of the berberine+CPT-11treatmentgroup.
Conclusions：1. The injury of intestinal induced by CPT-11increased the intestinalinflammatory cytokines and immunosuppressive cytokines, forming theimmunosuppressive microenvironment.
2. The immunosuppressive microenvironment may reduce theantitumor immunity and then affect the systemic immunity, leading to the recurrenceand metastasis of tumor.
3. Berberine alleviate the injury of intestinal immunity induced byCPT-11and inhibit the formation of immunosuppressive microenvironment, increasingthe antitumor immunity. Berberine is not only reduced the toxicity of chemotherapydrug in intestine, but also prevented the recurrence and metastasis of tumor.
引文
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