黄芪建中丸对TNBS诱导的大鼠结肠炎结肠粘膜损伤的修复作用及其机理
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摘要
目的：探索黄芪建中丸对TNBS诱导的结肠炎大鼠结肠粘膜损伤的修复作用及其机制。
方法：采用三硝基苯磺酸(2,4,6-trinitrobenzene sulfonic acid, TNBS)复制大鼠溃疡性结肠炎结肠粘膜损伤模型,并用黄芪建中丸(Huang Qi Jian Zhong Pellet(?), HQJZ)干预治疗14天。黄芪建中丸的疗效主要是通过肉眼下观察和组织学检测来进行评价,结肠微循环状态及结肠局部血流量分别通过倒置显微镜及激光多普勒图像仪进行检测。结肠组织匀浆中三磷酸腺苷(adenosine triphosphate,ATP)、二磷酸腺苷(adenosine diphosphate, ADP)、一磷酸腺苷(adenosine monophosphate AMP)、髓过氧化物酶(myeloperoxidase, MPO)、白介素-6(interleukin-6, IL-6)、白介素-10(interleukin-10, IL-10)分别采用酶联免疫吸试验(enzyme linked immunosorbent assay, ELISA)进行检测,同时采用免疫组织化学的方法检测MPO在结肠粘膜的表达。外周血粘附分子CD11b和结肠组织匀浆中肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)分别采用流式细胞数进行分析。F-actin和Occludin在结肠组织中的表达主要采用免疫荧光染色并在荧光研究下进行观察。AMPK活化激酶(AMP-activated protein kinase-α, AMPK-α)磷酸化-AMPK-α(phospho-AMPK-α,p-AMPK-α).ATP5D,RhoA,Rho激酶(Rho kinase-ⅠI, ROCK-Ⅰ),磷酸化肌球蛋白轻链(phospho-myosin light chain,p-MLC),occludin,Rac-1,p21活化激酶(p21-activated kinase-1,PAK-1)均采用蛋白印迹法进行检测分析。
结果：经过14天的治疗之后,和未经治疗的TNBS诱导的结肠炎大鼠相比较,黄芪建中丸有效地降低结肠重量、结肠重量指数、结肠肉眼下损伤评分和组织学病理损伤评分,恢复结肠长度,较好地改善了结肠微循环障碍,表现在升高了结肠血流量和毛细血管密度,抑制了结肠粘膜层和浆膜层的白蛋白渗出白细胞滚动和粘附,而且修复了受损结肠粘膜。黄芪建中丸显著升高了AMPK-α,phospho-AMPK-α和ATP5D活性,其结果导致ATP水平升高,下调了ADP/ATP,AMP/ATP的比值恢复了F-actin的聚合作用。而且黄芪建中丸有效地抑制了TNBS诱导的结肠炎大鼠结肠粘膜损伤区域的RhoA和ROCK-Ⅰ的活性升高,Rac-1和PAK-1低表达,抑制了MLC的磷酸化,进而上调了Occludin的表达,下调了CD11b,MPO, TNF一α和IL-6的表达,增强了IL-10的表达。
结论：
结论一：黄芪建中丸可有效缓解TNBS诱导的大鼠结肠炎结肠粘膜损伤。
结论二：黄芪建中丸有效缓解结肠粘膜损伤主要是通过活化AMPK,调节能量状况和Rho/Rac间平衡,改善结肠微循环障碍,维持结肠上皮完整性来实现的。
Objective:The purpose of the present study was to explore the repair mechanism of Huang Qi Jian Zhong Pellet(?)(HQJZ) against2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colonic mucosal injury in rats.
Methods:Colonic mucosal injury was induced by TNBS in Sprague-Dawley rats followed by treatment with HQJZ for14days. The therapeutic effects of HQJZ were evaluated by macroscopic observation and histological examination, the status of colonic microcirculation and blood flow were observed by inverted intravital microscopy and Laser-Doppler perfusion imager, respectively. The level of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and productions of myeloperoxidase (MPO), interleukin-6(IL-6) and interleukin-10(IL-10) were measured by enzyme linked immunosorbent assay (ELISA), while MPO expression in colonic mucosa tissues was stained by immunohistochemistry. Expression of CD11b in blood and tumor necrosis factor-a (TNF-a) in colonic mucosa were assessed by flow cytometry analysis. The immunofluorescence staining of F-actin and Occludin in colon tissues were observed by confocal microscopy. The expression of AMP-activated protein kinase-α (AMPK-α), phospho-AMPK-α (p-AMPK-α), ATP5D, RhoA, Rho kinase-Ⅰ (ROCK-Ⅰ), phospho-myosin light chain (p-MLC), Claudin-5, Occludin, Rac-1, p21-activated kinase-1(PAK-1) proteins were analyzed by Western blotting.
Results:After treatment for14days, compared with TNBS-induced rats without treatment, HQJZ effectively decreased colonic weight, colonic weight index, macroscopic and histological scores, shortened colonic length, and finely improved colonic microcirculation disturbances, as well as increased colonic blood flow and functional capillary density, inhibited albumin leakage, leukocyte rolling on and adhesion to chorion and mucous layer. Moreover, to restore damaged colonic mucosa, HQJZ remarkably enhanced activity of AMPK-α, phospho-AMPK-α and ATP5D which resulted in increase the level of ATP and decrease of the ratio of ADP/ATP and AMP/ATP, and restored F-actin polymerization in TNBS-induced rats treated by HQJZ. Meanwhile HQJZ effectively inhibited increased activity of RhoA and ROCK-I, decreased expession of Rac-1and PAK-1in damaged colonic mucosa of rats induced by TNBS, and restrained MLC phosphorylation, enhanced expression of Occludin, and decreased productions of CD11b, MPO, TNF-a and IL-6, heighted expression of IL-10.
Conclusions:The present study demonstrated that HQJZ effectively enhanced ATP level and improved energy status to restore damaged colonic mucosa induced by TNBS, which was attributed to activation of AMPK resulted in balance of Rho/Rac and improvement of colonic microcirculatory disturbances.
方法：采用三硝基苯磺酸(2,4,6-trinitrobenzene sulfonic acid, TNBS)复制大鼠溃疡性结肠炎结肠粘膜损伤模型,并用黄芪建中丸(Huang Qi Jian Zhong Pellet(?), HQJZ)干预治疗14天。黄芪建中丸的疗效主要是通过肉眼下观察和组织学检测来进行评价,结肠微循环状态及结肠局部血流量分别通过倒置显微镜及激光多普勒图像仪进行检测。结肠组织匀浆中三磷酸腺苷(adenosine triphosphate,ATP)、二磷酸腺苷(adenosine diphosphate, ADP)、一磷酸腺苷(adenosine monophosphate AMP)、髓过氧化物酶(myeloperoxidase, MPO)、白介素-6(interleukin-6, IL-6)、白介素-10(interleukin-10, IL-10)分别采用酶联免疫吸试验(enzyme linked immunosorbent assay, ELISA)进行检测,同时采用免疫组织化学的方法检测MPO在结肠粘膜的表达。外周血粘附分子CD11b和结肠组织匀浆中肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)分别采用流式细胞数进行分析。F-actin和Occludin在结肠组织中的表达主要采用免疫荧光染色并在荧光研究下进行观察。AMPK活化激酶(AMP-activated protein kinase-α, AMPK-α)磷酸化-AMPK-α(phospho-AMPK-α,p-AMPK-α).ATP5D,RhoA,Rho激酶(Rho kinase-ⅠI, ROCK-Ⅰ),磷酸化肌球蛋白轻链(phospho-myosin light chain,p-MLC),occludin,Rac-1,p21活化激酶(p21-activated kinase-1,PAK-1)均采用蛋白印迹法进行检测分析。
结果：经过14天的治疗之后,和未经治疗的TNBS诱导的结肠炎大鼠相比较,黄芪建中丸有效地降低结肠重量、结肠重量指数、结肠肉眼下损伤评分和组织学病理损伤评分,恢复结肠长度,较好地改善了结肠微循环障碍,表现在升高了结肠血流量和毛细血管密度,抑制了结肠粘膜层和浆膜层的白蛋白渗出白细胞滚动和粘附,而且修复了受损结肠粘膜。黄芪建中丸显著升高了AMPK-α,phospho-AMPK-α和ATP5D活性,其结果导致ATP水平升高,下调了ADP/ATP,AMP/ATP的比值恢复了F-actin的聚合作用。而且黄芪建中丸有效地抑制了TNBS诱导的结肠炎大鼠结肠粘膜损伤区域的RhoA和ROCK-Ⅰ的活性升高,Rac-1和PAK-1低表达,抑制了MLC的磷酸化,进而上调了Occludin的表达,下调了CD11b,MPO, TNF一α和IL-6的表达,增强了IL-10的表达。
结论：
结论一：黄芪建中丸可有效缓解TNBS诱导的大鼠结肠炎结肠粘膜损伤。
结论二：黄芪建中丸有效缓解结肠粘膜损伤主要是通过活化AMPK,调节能量状况和Rho/Rac间平衡,改善结肠微循环障碍,维持结肠上皮完整性来实现的。
Objective:The purpose of the present study was to explore the repair mechanism of Huang Qi Jian Zhong Pellet(?)(HQJZ) against2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colonic mucosal injury in rats.
Methods:Colonic mucosal injury was induced by TNBS in Sprague-Dawley rats followed by treatment with HQJZ for14days. The therapeutic effects of HQJZ were evaluated by macroscopic observation and histological examination, the status of colonic microcirculation and blood flow were observed by inverted intravital microscopy and Laser-Doppler perfusion imager, respectively. The level of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and productions of myeloperoxidase (MPO), interleukin-6(IL-6) and interleukin-10(IL-10) were measured by enzyme linked immunosorbent assay (ELISA), while MPO expression in colonic mucosa tissues was stained by immunohistochemistry. Expression of CD11b in blood and tumor necrosis factor-a (TNF-a) in colonic mucosa were assessed by flow cytometry analysis. The immunofluorescence staining of F-actin and Occludin in colon tissues were observed by confocal microscopy. The expression of AMP-activated protein kinase-α (AMPK-α), phospho-AMPK-α (p-AMPK-α), ATP5D, RhoA, Rho kinase-Ⅰ (ROCK-Ⅰ), phospho-myosin light chain (p-MLC), Claudin-5, Occludin, Rac-1, p21-activated kinase-1(PAK-1) proteins were analyzed by Western blotting.
Results:After treatment for14days, compared with TNBS-induced rats without treatment, HQJZ effectively decreased colonic weight, colonic weight index, macroscopic and histological scores, shortened colonic length, and finely improved colonic microcirculation disturbances, as well as increased colonic blood flow and functional capillary density, inhibited albumin leakage, leukocyte rolling on and adhesion to chorion and mucous layer. Moreover, to restore damaged colonic mucosa, HQJZ remarkably enhanced activity of AMPK-α, phospho-AMPK-α and ATP5D which resulted in increase the level of ATP and decrease of the ratio of ADP/ATP and AMP/ATP, and restored F-actin polymerization in TNBS-induced rats treated by HQJZ. Meanwhile HQJZ effectively inhibited increased activity of RhoA and ROCK-I, decreased expession of Rac-1and PAK-1in damaged colonic mucosa of rats induced by TNBS, and restrained MLC phosphorylation, enhanced expression of Occludin, and decreased productions of CD11b, MPO, TNF-a and IL-6, heighted expression of IL-10.
Conclusions:The present study demonstrated that HQJZ effectively enhanced ATP level and improved energy status to restore damaged colonic mucosa induced by TNBS, which was attributed to activation of AMPK resulted in balance of Rho/Rac and improvement of colonic microcirculatory disturbances.
引文
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