溃疡性结肠炎大鼠肺肠同病的屏障共损伤机制及中药单体干预作用研究
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摘要
研究目的
本课题在肺与大肠相表里理论指导下,在溃疡性结肠炎(ulcerative colitis, UC)肠黏膜屏障功能热点研究环境下,创新性提出UC“毒损肠络”及UC肺损伤“毒损肠络,毒邪上攻损肺”病机学说,并通过实验观察UC模型大鼠肠黏膜紧密连接蛋白表达、通透性及肺组织紧密连接蛋白、炎性细胞因子、氧自由基表达的变化,探讨UC肺损伤病理机制,以期从微观上找到新的肺肠相关的物质支持,为病机假说提供实验依据。同时阐明中药单体苦参碱、黄芪多糖(APS)及二者合用对UC及UC肺损伤的作用途径及靶点,进一步论证与深化肺与大肠相表里理论,为临床解决UC及UC肺损伤这一医学难题提供新的治疗思路及有效药物。
研究方法
将120只健康雄性Wistar大鼠采用结肠黏膜组织致敏与三硝基苯磺酸-乙醇灌肠相结合的免疫复合法复制大鼠UC模型,另30只设为正常对照组。大鼠造模灌肠后第3d(Ow),随机选取正常组和模型组大鼠各10只,杀检取材,检验造模是否成功。剩余110只模型大鼠随机分为五组,即模型组、西药对照组、苦参碱治疗组、APS治疗组、单体混合组。治疗组于灌肠后第3d开始灌胃给药,均配成水溶液后按60kg体重成年人药量的8倍计算灌胃剂量,单体混合组将APS和苦参碱按照1：1比例混合配成溶液；正常组、模型组用等体积饮用水灌胃,每日1次。每日观察各组大鼠一般状态变化,于给药0w、2w、4w时称重,麻醉后腹主动脉取血处死,并取肺、肠组织进行相关指标检测。
研究结果
1.UC模型大鼠一般状态、体重的变化及中药单体的影响
UC模型大鼠一般生活状态差,0w、2w、4w时与同期正常组比较体重均明显降低(P<0.05或P<0.01),DAI评分升高(P<0.01),并有呼吸气急、喘促等肺部症状。各中药单体治疗组大鼠一般生活状态及肺部症状较模型组改善。2w时,苦参碱治疗组和单体混合组大鼠DAI评分与同期模型组比较降低(P<0.05),4w时单体混合组大鼠DAI评分显著低于模型组(P<0.05);APS治疗组及中药单体混合组大鼠体重增长较快,与同期正常组比较无显著性差异。
2.UC模型大鼠肺肠组织病理形态学变化及中药单体的影响
HE染色病理形态学观察结果：UC模型大鼠结肠黏膜有充血、水肿、糜烂、溃疡、坏死及血管炎表现,2w时未见明显改善,4w时较前有所改善,以慢性溃疡性炎症为主,有肉芽组织增生。肺间质炎性细胞浸润,间质充血、水肿、微血管炎可见于UC各个时期,4w时肺纤维化表现明显。中药单体能有效减轻UC肺肠组织病理形态学改变。
3.UC模型大鼠肠黏膜大体形态学损伤、肠黏膜通透性变化及中药单体的影响
肉眼观察行结肠黏膜大体形态学损伤评分(CMDI);ELISA方法检测大鼠血清ET水平;分光光度法检测大鼠血清DAO活性。结果：UC大鼠结肠短缩,与周围组织粘连严重,结肠袋消失,近端结肠扩张,肠壁变薄质脆,或肠壁增厚,肠腔变窄。结肠黏膜充血,糜烂、溃疡形成,基本结构消失,血管纹理模糊。2w和4w时CMDI评分均显著高于同期正常组(P<0.01)。0w、2w、4w模型组大鼠血清ET含量及DAO活性增高,与正常组比较差异显著(P<0.05或P<0.01)。苦参碱及单体混合组肠黏膜损伤程度减轻,CMDI评分与同期模型组比较差异显著(P<0.05);血清ET和DAO水平均明显降低(P<0.05或P<0.01),肠黏膜高通透性改善。
4.UC模型大鼠肠黏膜紧密连接相关蛋白ZO-1、Occludin表达的变化及中药单体的影响
Western-blot法测定ZO-1在UC大鼠肠黏膜中的表达,免疫组化法观察Occludin蛋白在肠黏膜中的分布与表达。结果：与正常组比较,UC模型组大鼠肠黏膜ZO-1和Occludin蛋白表达明显降低(P<0.05或P<0.01)。2w时,各治疗组大鼠肠黏膜ZO-1和Occludin蛋白表达均有所增加,但差异没有统计学意义;4w时与同期模型组比较,单体混合组ZO-1和Occludin蛋白表达显著高于同期模型组(P<0.05或P<0.01),APS(?)疗组Occludin蛋白表达亦明显升高(P<0.05)。
5.UC模型大鼠肺组织中紧密连接相关蛋白ZO-1、Occludin表达的变化及中药单体的影响
Western-blot去测定紧密连接蛋白ZO-1在UC大鼠肺组织中的表达,免疫组化法观察Occludin蛋白在肺组织中的分布与表达。结果：与正常组比较,UC模型组大鼠肺组织中ZO-1和Occludin蛋白表达明显降低(P<0.05或P<0.01)。2w和4w时,各治疗组肺组织中ZO-1蛋白表达均有所增加,2w时单体混合组ZO-1和Occludin蛋白表达显著高于同期模型组(P<0.05),4w时APS治疗组ZO-1表达OD值明显高于正常组和模型组,但各组间比较差异无统计学意义；APS治疗组及单体混合组大鼠肺组织Occludin蛋白表达与同期模型组比较显著上调(P<0.05)。
6.UC模型大鼠肺组织中炎性细胞因子和氧自由基表达的变化及中药单体的影响
ELISA法测定UC大鼠肺组织中TNF-α、IL-1β含量,化学比色法测定大鼠肺组织匀浆中SOD、MDA及MPO活性。结果：2w和4w时,UC模型大鼠肺组织匀浆中TNF-α、IL-1β、MDA、MPO水平增高,SOD活力明显下降(P<0.05或P<0.01)。中药单体能够增强UC大鼠肺组织抗炎及清除氧自由基的能力,减轻脂质过氧化程度。
7.中药单体对UC大鼠肺肠组织中TFF3表达的影响
免疫组化法观察TFF3在UC大鼠肺肠组织中的分布与表达。结果：与正常组相比,2w和4w时UC模型组大鼠肠组织中TFF3表达均明显减少(P<0.05),单体混合组TFF3表达较同期模型组均显著升高(P<0.05);各时间点、各组大鼠肺组织TFF3表达比较没有统计学意义(P>0.05)。
结论
1.免疫复合法复制的大鼠UC模型,体现了肠黏膜屏障损害与免疫调节失衡这两个UC最主要的致病因素,是研究UC发病机制及药物治疗的理想模型。
2.“毒损肠络,毒邪上攻损肺”是UC肺损伤的根本病机,可能为UC迁延不愈、反复发作的重要原因。
3.UC大鼠肺肠组织病理改变说明UC湿热瘀毒上扰,肺气不利,肺肠同病。
4.UC大鼠肠黏膜ZO-1和Occludin表达下降,通透性增高,肠黏膜屏障损伤,是UC"毒损肠络”病机的生物学基础。
5.UC大鼠肺组织ZO-1和Occludin表达下降,屏障结构受损,是UC"毒损肠络,毒邪上攻损肺”病机的生物学基础。
6.UC大鼠肺组织中异常表达的炎性细胞因子和氧自由基是“肺与大肠相表里”的共同物质基础,是导致UC及UC肺损伤的内生之“毒’
7.中药单体苦参碱、APS及两单体混合能够改善UC大鼠生存状况,减轻肺肠组织病理形态学改变。
8.中药单体苦参碱、APS及两单体混合对UC肺损伤有保护作用,可能是通过增加肺肠组织ZO-1和Occludin表达,修复受损的肺肠屏障,增强肺组织抗炎及清除氧自由基能力,上调肺肠组织修复因子表达实现的。
Objects
Guided by the theory of the lung and the large intestine being interior-exteriorly related and under the hot environment of researching on the function of intestinal barrier, we put forward "toxin impairing intestine collateral" pathogenesis theory and deem that damp-heat blood stasis toxin accumulating long damage the intestine collateral and then upward attack the lung is the key cause for the relapses of UC and the lung injury. Afterwards, we establish the rat model of UC, study the injury mechanism of the intestinal mucosal barrier and reveal the inherent links between IMB and lung injury in UC, hope to find some new material foundation for the correlation between lung and intestine, provide strong experimental evidence for the pathogenesis theory, interpret the effects and mechanism of herb monomer including Matrine, astragalus polysaccharides (APS) and the two mixed when used to treat UC and lung injury in UC, deepen the theory of the lung and the large intestine being interior-exteriorly related and then present new ideas and methods also effective drug to solve this difficult medical problem.
Methods
120healthy male Wistar rats were made to UC models by immune complex method, while another30rats left in normal group. When the model were set up, randomly selected10rats in each group to check whether the model were set up successfully. Then the remaining UC model rats were randomly divided into5groups:normal group, model group, western medicine group, Matrine group, APS group and the two mixed group. Each medicine treatment group was given sulfasalazine enreric-coated tablets, Matrine, APS, and the two mixed separately. Normal and model group were fed with equivoluminal pure water. Observe the general condition of the rats everyday. At the end of0th,2nd,4th week, taking blood from the abdominal aorta and the lung and intestine to tested relevant indicators.
Results
1. The changes of general condition and weight in UC rats and the effects of the herb monomer.
Results:Rats in model group live in a poor life state and compared with the normal group, the weight were significantly loss (P<0.05or P<0.01) while the DAI scores rose (P <0.01), and companied with respiratory symptoms.2nd week, compared with the normal group, the DAI scores of rats in Matrine group and the two mixed group was significantly fallen (P<0.05).4th week, compared with the normal group, the DAI scores of rats in the two mixed group was significantly fallen (P<0.05), while the weight of the rats in APS group and the two mixed group was increased nearly to normal.
2. The pathomorphological changes in lung and intestinal tissue of UC rats and the effect of the herb monomer.
At the end of0th,2nd,4th week, killed the rats, paraffin embedded the lung and intestinal tissue, then sliced, HE stain and observed the morphological changes.
Results:Colonic mucosal hyperemia, edema, erosions, ulcers, necrosis and vasculitis.2nd week, there is no obvious change while at the end of4th week the pathomorphology change in some sort. The lung tissue demonstrated inflammatory cell infiltrate, hyperemia, edema and vasculitis all the time. At the end of4th week, pulmonary fibrosis was obviously. Lung injury is a common parenteral change of UC. Herb monomer can reduce the pathomorphological changes of lung and intestine effectively.
3. The damage degree of colonic mucosa and the change of intestinal permeability in UC model rats and the effect of the herb monomer.
At the end of0th,2nd,4th week, killed the rats, observed the damage degree of colonic mucosa and scoring. ELISA was used to detect the endotoxin (ET) level in serum, while spectrophotometric method was used to determine the enzyme activity for diamine oxidase, test the intestinal permeability whether changed.
Results:The colonic mucosa in the UC model rats showed hyperemia, erosion, ulcer, basic structure disappeared and the vascular texture fuzzy.2nd week, there is no obvious change while at the end of4th week the pathomorphology improved in some sort. Compared with normal group, the CDMI of the model group was significantly increased (P<0.01). At the end of0th,2nd,4th week, the level of ET and DAO in serum in model group was increased, indicating the colonic mucosa seriously damaged and the intestinal permeability increase. Using Matrine and APS mixed with Matrine could reduce the colonic mucosa injury and the colonic mucosal permeability insignificantly (P<0.05or P<0.01).
4. Expression of tight junction protein ZO-land Occludin in intestinal tissue of UC rats and the effect of the herb monomer.
Observed the expression of ZO-1in intestinal tissue of UC rats with the method of western blot while ovserved the distribution and expression of Occludin in the colonic mucosa epithelium tight junction regions by immunohistochemistry.
Results:Compared with normal group, the expression of tight junction protein ZO-land Occludin in colonic mucosa tissue of UC model group rats significantly decreased (P<0.05or P<0.01). At the end of2nd week, the expression of tight junction protein ZO-1and Occludin in all treatment group was increased, but there was no statistically significant difference between groups. At the end of4th week, compared with the model group, the expression of tight junction protein ZO-1and Occludin in Matrine and APS mixed group was significantly increased (P<0.05or P<0.01) and the expression of tight junction protein Occludin in APS group was also increased (P<0.05).
5. Expression of tight junction protein ZO-land Occludin in lung tissue of UC rats and the effect of the herb monomer.
Observed the expression of ZO-1in lung of UC rats with the method of western blot while ovserved the distribution and expression of Occludin in the rat alveolar epithelium tight junction regions by immunohistochemistry.
Results:Compared with normal group, the expression of tight junction protein ZO-1and Occludin in lung tissue of UC model group rats significantly decreased (P<0.05or P<0.01) At the end of2nd,4th week, the expression of tight junction protein ZO-1in lung tissue in all treatment group was increased. At the end of2nd week, the expression of tight junction protein ZO-1in lung tissue in the two mixed group was significantly increased (P<0.05). At the end of4th week, the OD values of tight junction protein ZO-1in lung tissue in APS group was obviously higher than normal group and model group, but there was no statistically significant difference among all groups. The expression of tight junction protein Occludin in lung tissue in APS group and the two mixed group was increased significantly (P<0.05).
6. The changes of inflammatory cytokine and oxygen free radical in lung of UC rats and the effect of the herb monomer.
The content of TNF-α and IL-1β in lung was determined by ELISA while the activity of SOD, MDA and MPO was evaluated with colorimetry.
Results:At the end of2nd,4th week, compared with normal group, the level of TNF-a, IL-1β, MDA, MPO in lung in UC rats was increased significantly while the activity of SOD was decreased significantly (P<0.05or P<0.01). The herb monomer could relieve lung injury of UC rats by promoting the capacity of the lung to resist inflammation and eliminate oxygen free radical, reducing lipid peroxidation.
7Effect of the herb monomer on the expression of TFF3in lung and intestinal tissue of UC rats.
Obvserved the distribution and expression of TFF3in lung and intestinal tissue by immunohistochemistry.
Results:At the end of2nd,4th week, compared with normal group, the expression of TFF3in intestinal tissue was decreased significantly (P<0.05) while the expression of TFF3in intestinal tissue in the two mixed group was increased significantly (P<0.05). At the end of2nd,4th week, the expression of TFF3in lung tissue had no statistically significant difference among all groups (P>0.05).
Conclusions
1. Setting up the rat UC model by allergizing with colonic mucosal of rabbit added TNBS-50%alcohol coloclysis could produce the symptoms similar to human clinical manifestation of UC and reflect intestinal barrier dysfunction and immune imbalance the both two contributing factors of UC. It is an ideal model for studying the pathogenesis of UC.
2. The pathomorphological observation of colonic mucosal and lung tissue of UC rats showed massive infiltration of inflammatory cells, hyperemia, dropsy, vasculitis and intestinal fibrosis in later stages, providing pathological evidence for the theory of "toxin impairing intestine collateral and then upward attack the lung"
3. The expression of tight junction protein in colonic mucosal tissue was decreased, indicated the structure of colonic mucosa epithelium tight junction injury, causing the colonic mucosal permeability insignificantly increased, having colonic mucosal barrier dysfunction. It is maybe the foundation of "toxin impairing intestine collateral" pathogenesis theory.
4. The expression of tight junction protein in lung tissue of UC rats was decreased and this was considered closely related to the lung injury of UC rats. It maybe the foundation of the theory of "toxin impairing intestine collateral and then upward attack the lung" and also maybe the key cause for the persistent unhealed and relapses of UC.
5. The abnormal expression of inflammatory cytokine and oxygen free radical in lung of UC rats may be the common material basis between lung and large intestine in UC, also could be seen as the "endogenous toxin" causing UC and lung injury of UC.
6. The herb monomer Matrine, APS and the two mixed can improve the general life station of UC rats, relieve the pathomorphological changes of colonic mucosal and lung effectively. APS has advantage in putting on weight of UC rats, while Matrine and Matrine mixed with APS can reduce the disease activity of UC rats.
7. The herb monomer Matrine, APS and the two mixed is able to reduce inflammation in lung and colonic mucosal, improve local microcirculation and thus repair damaged lung and intestine tissue by increasing the expression of tight junction proteins, repairing damaged lung and intestine barrier, decreasing the lung and intestinal permeability, resisting to inflammation and oxygen free radical and upregulating the expression of repair factor in lung and intestine.
本课题在肺与大肠相表里理论指导下,在溃疡性结肠炎(ulcerative colitis, UC)肠黏膜屏障功能热点研究环境下,创新性提出UC“毒损肠络”及UC肺损伤“毒损肠络,毒邪上攻损肺”病机学说,并通过实验观察UC模型大鼠肠黏膜紧密连接蛋白表达、通透性及肺组织紧密连接蛋白、炎性细胞因子、氧自由基表达的变化,探讨UC肺损伤病理机制,以期从微观上找到新的肺肠相关的物质支持,为病机假说提供实验依据。同时阐明中药单体苦参碱、黄芪多糖(APS)及二者合用对UC及UC肺损伤的作用途径及靶点,进一步论证与深化肺与大肠相表里理论,为临床解决UC及UC肺损伤这一医学难题提供新的治疗思路及有效药物。
研究方法
将120只健康雄性Wistar大鼠采用结肠黏膜组织致敏与三硝基苯磺酸-乙醇灌肠相结合的免疫复合法复制大鼠UC模型,另30只设为正常对照组。大鼠造模灌肠后第3d(Ow),随机选取正常组和模型组大鼠各10只,杀检取材,检验造模是否成功。剩余110只模型大鼠随机分为五组,即模型组、西药对照组、苦参碱治疗组、APS治疗组、单体混合组。治疗组于灌肠后第3d开始灌胃给药,均配成水溶液后按60kg体重成年人药量的8倍计算灌胃剂量,单体混合组将APS和苦参碱按照1：1比例混合配成溶液；正常组、模型组用等体积饮用水灌胃,每日1次。每日观察各组大鼠一般状态变化,于给药0w、2w、4w时称重,麻醉后腹主动脉取血处死,并取肺、肠组织进行相关指标检测。
研究结果
1.UC模型大鼠一般状态、体重的变化及中药单体的影响
UC模型大鼠一般生活状态差,0w、2w、4w时与同期正常组比较体重均明显降低(P<0.05或P<0.01),DAI评分升高(P<0.01),并有呼吸气急、喘促等肺部症状。各中药单体治疗组大鼠一般生活状态及肺部症状较模型组改善。2w时,苦参碱治疗组和单体混合组大鼠DAI评分与同期模型组比较降低(P<0.05),4w时单体混合组大鼠DAI评分显著低于模型组(P<0.05);APS治疗组及中药单体混合组大鼠体重增长较快,与同期正常组比较无显著性差异。
2.UC模型大鼠肺肠组织病理形态学变化及中药单体的影响
HE染色病理形态学观察结果：UC模型大鼠结肠黏膜有充血、水肿、糜烂、溃疡、坏死及血管炎表现,2w时未见明显改善,4w时较前有所改善,以慢性溃疡性炎症为主,有肉芽组织增生。肺间质炎性细胞浸润,间质充血、水肿、微血管炎可见于UC各个时期,4w时肺纤维化表现明显。中药单体能有效减轻UC肺肠组织病理形态学改变。
3.UC模型大鼠肠黏膜大体形态学损伤、肠黏膜通透性变化及中药单体的影响
肉眼观察行结肠黏膜大体形态学损伤评分(CMDI);ELISA方法检测大鼠血清ET水平;分光光度法检测大鼠血清DAO活性。结果：UC大鼠结肠短缩,与周围组织粘连严重,结肠袋消失,近端结肠扩张,肠壁变薄质脆,或肠壁增厚,肠腔变窄。结肠黏膜充血,糜烂、溃疡形成,基本结构消失,血管纹理模糊。2w和4w时CMDI评分均显著高于同期正常组(P<0.01)。0w、2w、4w模型组大鼠血清ET含量及DAO活性增高,与正常组比较差异显著(P<0.05或P<0.01)。苦参碱及单体混合组肠黏膜损伤程度减轻,CMDI评分与同期模型组比较差异显著(P<0.05);血清ET和DAO水平均明显降低(P<0.05或P<0.01),肠黏膜高通透性改善。
4.UC模型大鼠肠黏膜紧密连接相关蛋白ZO-1、Occludin表达的变化及中药单体的影响
Western-blot法测定ZO-1在UC大鼠肠黏膜中的表达,免疫组化法观察Occludin蛋白在肠黏膜中的分布与表达。结果：与正常组比较,UC模型组大鼠肠黏膜ZO-1和Occludin蛋白表达明显降低(P<0.05或P<0.01)。2w时,各治疗组大鼠肠黏膜ZO-1和Occludin蛋白表达均有所增加,但差异没有统计学意义;4w时与同期模型组比较,单体混合组ZO-1和Occludin蛋白表达显著高于同期模型组(P<0.05或P<0.01),APS(?)疗组Occludin蛋白表达亦明显升高(P<0.05)。
5.UC模型大鼠肺组织中紧密连接相关蛋白ZO-1、Occludin表达的变化及中药单体的影响
Western-blot去测定紧密连接蛋白ZO-1在UC大鼠肺组织中的表达,免疫组化法观察Occludin蛋白在肺组织中的分布与表达。结果：与正常组比较,UC模型组大鼠肺组织中ZO-1和Occludin蛋白表达明显降低(P<0.05或P<0.01)。2w和4w时,各治疗组肺组织中ZO-1蛋白表达均有所增加,2w时单体混合组ZO-1和Occludin蛋白表达显著高于同期模型组(P<0.05),4w时APS治疗组ZO-1表达OD值明显高于正常组和模型组,但各组间比较差异无统计学意义；APS治疗组及单体混合组大鼠肺组织Occludin蛋白表达与同期模型组比较显著上调(P<0.05)。
6.UC模型大鼠肺组织中炎性细胞因子和氧自由基表达的变化及中药单体的影响
ELISA法测定UC大鼠肺组织中TNF-α、IL-1β含量,化学比色法测定大鼠肺组织匀浆中SOD、MDA及MPO活性。结果：2w和4w时,UC模型大鼠肺组织匀浆中TNF-α、IL-1β、MDA、MPO水平增高,SOD活力明显下降(P<0.05或P<0.01)。中药单体能够增强UC大鼠肺组织抗炎及清除氧自由基的能力,减轻脂质过氧化程度。
7.中药单体对UC大鼠肺肠组织中TFF3表达的影响
免疫组化法观察TFF3在UC大鼠肺肠组织中的分布与表达。结果：与正常组相比,2w和4w时UC模型组大鼠肠组织中TFF3表达均明显减少(P<0.05),单体混合组TFF3表达较同期模型组均显著升高(P<0.05);各时间点、各组大鼠肺组织TFF3表达比较没有统计学意义(P>0.05)。
结论
1.免疫复合法复制的大鼠UC模型,体现了肠黏膜屏障损害与免疫调节失衡这两个UC最主要的致病因素,是研究UC发病机制及药物治疗的理想模型。
2.“毒损肠络,毒邪上攻损肺”是UC肺损伤的根本病机,可能为UC迁延不愈、反复发作的重要原因。
3.UC大鼠肺肠组织病理改变说明UC湿热瘀毒上扰,肺气不利,肺肠同病。
4.UC大鼠肠黏膜ZO-1和Occludin表达下降,通透性增高,肠黏膜屏障损伤,是UC"毒损肠络”病机的生物学基础。
5.UC大鼠肺组织ZO-1和Occludin表达下降,屏障结构受损,是UC"毒损肠络,毒邪上攻损肺”病机的生物学基础。
6.UC大鼠肺组织中异常表达的炎性细胞因子和氧自由基是“肺与大肠相表里”的共同物质基础,是导致UC及UC肺损伤的内生之“毒’
7.中药单体苦参碱、APS及两单体混合能够改善UC大鼠生存状况,减轻肺肠组织病理形态学改变。
8.中药单体苦参碱、APS及两单体混合对UC肺损伤有保护作用,可能是通过增加肺肠组织ZO-1和Occludin表达,修复受损的肺肠屏障,增强肺组织抗炎及清除氧自由基能力,上调肺肠组织修复因子表达实现的。
Objects
Guided by the theory of the lung and the large intestine being interior-exteriorly related and under the hot environment of researching on the function of intestinal barrier, we put forward "toxin impairing intestine collateral" pathogenesis theory and deem that damp-heat blood stasis toxin accumulating long damage the intestine collateral and then upward attack the lung is the key cause for the relapses of UC and the lung injury. Afterwards, we establish the rat model of UC, study the injury mechanism of the intestinal mucosal barrier and reveal the inherent links between IMB and lung injury in UC, hope to find some new material foundation for the correlation between lung and intestine, provide strong experimental evidence for the pathogenesis theory, interpret the effects and mechanism of herb monomer including Matrine, astragalus polysaccharides (APS) and the two mixed when used to treat UC and lung injury in UC, deepen the theory of the lung and the large intestine being interior-exteriorly related and then present new ideas and methods also effective drug to solve this difficult medical problem.
Methods
120healthy male Wistar rats were made to UC models by immune complex method, while another30rats left in normal group. When the model were set up, randomly selected10rats in each group to check whether the model were set up successfully. Then the remaining UC model rats were randomly divided into5groups:normal group, model group, western medicine group, Matrine group, APS group and the two mixed group. Each medicine treatment group was given sulfasalazine enreric-coated tablets, Matrine, APS, and the two mixed separately. Normal and model group were fed with equivoluminal pure water. Observe the general condition of the rats everyday. At the end of0th,2nd,4th week, taking blood from the abdominal aorta and the lung and intestine to tested relevant indicators.
Results
1. The changes of general condition and weight in UC rats and the effects of the herb monomer.
Results:Rats in model group live in a poor life state and compared with the normal group, the weight were significantly loss (P<0.05or P<0.01) while the DAI scores rose (P <0.01), and companied with respiratory symptoms.2nd week, compared with the normal group, the DAI scores of rats in Matrine group and the two mixed group was significantly fallen (P<0.05).4th week, compared with the normal group, the DAI scores of rats in the two mixed group was significantly fallen (P<0.05), while the weight of the rats in APS group and the two mixed group was increased nearly to normal.
2. The pathomorphological changes in lung and intestinal tissue of UC rats and the effect of the herb monomer.
At the end of0th,2nd,4th week, killed the rats, paraffin embedded the lung and intestinal tissue, then sliced, HE stain and observed the morphological changes.
Results:Colonic mucosal hyperemia, edema, erosions, ulcers, necrosis and vasculitis.2nd week, there is no obvious change while at the end of4th week the pathomorphology change in some sort. The lung tissue demonstrated inflammatory cell infiltrate, hyperemia, edema and vasculitis all the time. At the end of4th week, pulmonary fibrosis was obviously. Lung injury is a common parenteral change of UC. Herb monomer can reduce the pathomorphological changes of lung and intestine effectively.
3. The damage degree of colonic mucosa and the change of intestinal permeability in UC model rats and the effect of the herb monomer.
At the end of0th,2nd,4th week, killed the rats, observed the damage degree of colonic mucosa and scoring. ELISA was used to detect the endotoxin (ET) level in serum, while spectrophotometric method was used to determine the enzyme activity for diamine oxidase, test the intestinal permeability whether changed.
Results:The colonic mucosa in the UC model rats showed hyperemia, erosion, ulcer, basic structure disappeared and the vascular texture fuzzy.2nd week, there is no obvious change while at the end of4th week the pathomorphology improved in some sort. Compared with normal group, the CDMI of the model group was significantly increased (P<0.01). At the end of0th,2nd,4th week, the level of ET and DAO in serum in model group was increased, indicating the colonic mucosa seriously damaged and the intestinal permeability increase. Using Matrine and APS mixed with Matrine could reduce the colonic mucosa injury and the colonic mucosal permeability insignificantly (P<0.05or P<0.01).
4. Expression of tight junction protein ZO-land Occludin in intestinal tissue of UC rats and the effect of the herb monomer.
Observed the expression of ZO-1in intestinal tissue of UC rats with the method of western blot while ovserved the distribution and expression of Occludin in the colonic mucosa epithelium tight junction regions by immunohistochemistry.
Results:Compared with normal group, the expression of tight junction protein ZO-land Occludin in colonic mucosa tissue of UC model group rats significantly decreased (P<0.05or P<0.01). At the end of2nd week, the expression of tight junction protein ZO-1and Occludin in all treatment group was increased, but there was no statistically significant difference between groups. At the end of4th week, compared with the model group, the expression of tight junction protein ZO-1and Occludin in Matrine and APS mixed group was significantly increased (P<0.05or P<0.01) and the expression of tight junction protein Occludin in APS group was also increased (P<0.05).
5. Expression of tight junction protein ZO-land Occludin in lung tissue of UC rats and the effect of the herb monomer.
Observed the expression of ZO-1in lung of UC rats with the method of western blot while ovserved the distribution and expression of Occludin in the rat alveolar epithelium tight junction regions by immunohistochemistry.
Results:Compared with normal group, the expression of tight junction protein ZO-1and Occludin in lung tissue of UC model group rats significantly decreased (P<0.05or P<0.01) At the end of2nd,4th week, the expression of tight junction protein ZO-1in lung tissue in all treatment group was increased. At the end of2nd week, the expression of tight junction protein ZO-1in lung tissue in the two mixed group was significantly increased (P<0.05). At the end of4th week, the OD values of tight junction protein ZO-1in lung tissue in APS group was obviously higher than normal group and model group, but there was no statistically significant difference among all groups. The expression of tight junction protein Occludin in lung tissue in APS group and the two mixed group was increased significantly (P<0.05).
6. The changes of inflammatory cytokine and oxygen free radical in lung of UC rats and the effect of the herb monomer.
The content of TNF-α and IL-1β in lung was determined by ELISA while the activity of SOD, MDA and MPO was evaluated with colorimetry.
Results:At the end of2nd,4th week, compared with normal group, the level of TNF-a, IL-1β, MDA, MPO in lung in UC rats was increased significantly while the activity of SOD was decreased significantly (P<0.05or P<0.01). The herb monomer could relieve lung injury of UC rats by promoting the capacity of the lung to resist inflammation and eliminate oxygen free radical, reducing lipid peroxidation.
7Effect of the herb monomer on the expression of TFF3in lung and intestinal tissue of UC rats.
Obvserved the distribution and expression of TFF3in lung and intestinal tissue by immunohistochemistry.
Results:At the end of2nd,4th week, compared with normal group, the expression of TFF3in intestinal tissue was decreased significantly (P<0.05) while the expression of TFF3in intestinal tissue in the two mixed group was increased significantly (P<0.05). At the end of2nd,4th week, the expression of TFF3in lung tissue had no statistically significant difference among all groups (P>0.05).
Conclusions
1. Setting up the rat UC model by allergizing with colonic mucosal of rabbit added TNBS-50%alcohol coloclysis could produce the symptoms similar to human clinical manifestation of UC and reflect intestinal barrier dysfunction and immune imbalance the both two contributing factors of UC. It is an ideal model for studying the pathogenesis of UC.
2. The pathomorphological observation of colonic mucosal and lung tissue of UC rats showed massive infiltration of inflammatory cells, hyperemia, dropsy, vasculitis and intestinal fibrosis in later stages, providing pathological evidence for the theory of "toxin impairing intestine collateral and then upward attack the lung"
3. The expression of tight junction protein in colonic mucosal tissue was decreased, indicated the structure of colonic mucosa epithelium tight junction injury, causing the colonic mucosal permeability insignificantly increased, having colonic mucosal barrier dysfunction. It is maybe the foundation of "toxin impairing intestine collateral" pathogenesis theory.
4. The expression of tight junction protein in lung tissue of UC rats was decreased and this was considered closely related to the lung injury of UC rats. It maybe the foundation of the theory of "toxin impairing intestine collateral and then upward attack the lung" and also maybe the key cause for the persistent unhealed and relapses of UC.
5. The abnormal expression of inflammatory cytokine and oxygen free radical in lung of UC rats may be the common material basis between lung and large intestine in UC, also could be seen as the "endogenous toxin" causing UC and lung injury of UC.
6. The herb monomer Matrine, APS and the two mixed can improve the general life station of UC rats, relieve the pathomorphological changes of colonic mucosal and lung effectively. APS has advantage in putting on weight of UC rats, while Matrine and Matrine mixed with APS can reduce the disease activity of UC rats.
7. The herb monomer Matrine, APS and the two mixed is able to reduce inflammation in lung and colonic mucosal, improve local microcirculation and thus repair damaged lung and intestine tissue by increasing the expression of tight junction proteins, repairing damaged lung and intestine barrier, decreasing the lung and intestinal permeability, resisting to inflammation and oxygen free radical and upregulating the expression of repair factor in lung and intestine.
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