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车叶草苷减轻溃疡性结肠炎大鼠结肠黏膜损伤及炎症反应的机制
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| 篇名： | 车叶草苷减轻溃疡性结肠炎大鼠结肠黏膜损伤及炎症反应的机制 |
| TITLE： | Mechanism of the alleviation of colonic mucosal injury and inflammatory response in rats with ulcerative colitis by asperuloside |
| 摘要： | 目的 基于干扰素基因刺激因子（STING）/TANK结合激酶1（TBK1）/干扰素调节因子3（IRF3）信号通路，探究车叶草苷（ASP）对溃疡性结肠炎（UC）大鼠结肠组织病理损伤及炎症反应的影响机制。方法以肠腔内注射三硝基苯磺酸和乙醇构建UC大鼠模型，并将造模成功的大鼠分为模型组、ASP低剂量组（17.5mg/kg）、ASP高剂量组（35mg/kg）、ASP高剂量+STING激活剂组（35mg/kgASP+20mg/kgADU-S100），每组16只；另取16只健康大鼠，肠腔内注射生理盐水，作为对照组。各组大鼠灌胃或/和腹腔注射相应药液或生理盐水，每天1次，连续14d。末次给药后24h，使用疾病活动指数（DAI）和结肠黏膜损伤指数（CMDI）分别评估各组大鼠的UC严重程度和结肠黏膜损伤程度，观察其结肠组织病理改变并进行组织病理学评分，检测其结肠组织细胞凋亡情况、炎症因子[肿瘤坏死因子α（TNF-α）、β干扰素（IFN-β）、白细胞介素4（IL-4）、IL-10]水平和通路相关蛋白表达情况[STING、TBK1、IRF3、核因子κBp65（NF-κBp65）]。结果与对照组比较，模型组大鼠结肠组织黏膜及腺体结构严重受损，黏膜上皮磨损，隐窝缺失，可见明显的炎症细胞浸润；DAI、CMDI、结肠组织病理学评分，细胞凋亡率，TNF-α、IFN-β水平，以及STING蛋白的表达水平和TBK1、IRF3、NF-κBp65蛋白的磷酸化水平均显著升高；IL-4、IL-10水平均显著降低（P＜0.05）。与模型组比较，ASP低、高剂量组大鼠结肠组织黏膜结构相对完整，腺体排列有序，充血和水肿减轻，炎症细胞浸润及溃疡明显减少；上述各定量指标均显著改善，且高剂量组的改善较低剂量组明显（P＜0.05）。与ASP高剂量组比较，ASP高剂量+STING激活剂组大鼠的上述指标均被显著逆转（P＜0.05）。结论ASP可能通过抑制STING/TBK1/IRF3信号通路来减轻UC大鼠的结肠组织病理损伤及炎症反应。 |
| ABSTRACT： | OBJECTIVE To explore the effects and potential mechanism of asperuloside （ASP） on colonic pathological injury and inflammatory response in rats with ulcerative colitis （UC） based on the stimulator of interferon genes （STING）/TANK binding kinase 1 （TBK1）/interferon regulatory factor 3 （IRF3） signaling pathway. METHODS A UC rat model was established by intrarectal injection of trinitrobenzenesulfonic acid and ethanol. The successfully modeled rats were allocated to model group， low- dose ASP group （17.5 mg/kg）， high-dose ASP group （35 mg/kg）， and high-dose ASP+STING activator ADU-S100 group （35 mg/kg ASP+20 mg/kg ADU-S100）， with 16 rats in each group. Another 16 healthy rats were selected as control group， by intrarectally injecting with normal saline. The rats in each group were given the corresponding drug solutions or normal saline by gavage or/and intraperitoneal injection once a day for 14 consecutive days. Twenty-four hours after the last administration， the disease activity index （DAI） and colonic mucosal damage index （CMDI） were employed to assess the severity of UC and colonic mucosal damage in each group. Colonic tissue pathological changes were observed， and histopathological scores were recorded. Apoptosis in colonic tissue， levels of inflammatory cytokines [tumor necrosis factor-α （TNF-α）， interferon-β （IFN-β）， interleukin-4 （IL-4）， IL-10]， and expressions of pathway-related proteins [STING， TBK1， IRF3， nuclear factor-κB p65 （NF-κB p65）] were detected. RESULTS Compared with the control group， the model group showed severe destruction of colonic mucosa and glandular structure， mucosal epithelial erosion， crypt loss， marked inflammatory cell infiltration； it also demonstrated significant increase in DAI score， CMDI score， colonic histopathological score， apoptosis rate， the levels of TNF-α and IFN-β， and protein expression of STING and phosphorylation levels of TBK1， IRF3 and NF-κB p65， while the levels of IL-4 and IL-10 were significantly decreased （P＜0.05）. Compared with the model group， the low- and high-dose ASP groups showed relatively intact colonic mucosal structure， orderly glandular arrangement， reduced congestion and edema， and markedly reduced inflammatory cell infiltration and ulcers； all quantitative indicators were significantly improved， with the high-dose group showing more pronounced improvements than the low-dose group （P＜0.05）. Compared with the high-dose ASP group， the above indicators of rats in the high-dose ASP+STING activator group were significantly reversed （P＜0.05）. CONCLUSIONS ASP may alleviate colonic pathological injury and inflammatory response in UC rats by inhibiting the STING/TBK1/IRF3 signaling pathway. |
| 期刊： | 2024年第35卷第22期 |
| 作者： | 张霞；李秀芬；赵汉清；贾慧宇；董利平 |
| AUTHORS： | ZHANG Xia，LI Xiufen，ZHAO Hanqing，JIA Huiyu，DONG Liping |
| 关键字： | 车叶草苷；溃疡性结肠炎；结肠组织病理损伤；炎症反应；STING/TBK1/IRF3信号通路 |
| KEYWORDS： | asperuloside； ulcerative colitis； colonic pathological injury； inflammatory response； STING/TBK1/IRF3 signaling |
| 阅读数： | 7 次 |
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