本文選題：炎癥性腸病 + 腸炎��； 參考：《山東大學(xué)》2014年博士論文

【摘要】：背景 炎癥性腸病(inflammatory bowel disease, IBD)包括潰瘍性結(jié)腸炎和克羅恩病,是一種累及回腸、直腸和結(jié)腸粘膜的慢性非特異性腸道炎癥性疾病。IBD可發(fā)生于任何年齡,多見于20-49歲,亦可見于老年人或兒童。流行病學(xué)研究發(fā)現(xiàn)IBD發(fā)病率在世界范圍內(nèi)呈現(xiàn)逐漸增高的趨勢(shì)。我國(guó)缺乏大規(guī)模流行病學(xué)調(diào)查,但亦有證據(jù)表明其呈逐年上升趨勢(shì)。由于發(fā)病機(jī)制尚不明確,臨床上常表現(xiàn)為反復(fù)發(fā)作而治愈難度大。已有的研究證實(shí),遺傳易感因素、腸道菌群、粘膜免疫異常以及環(huán)境因素共同參與了該病的發(fā)生。目前,IBD的主要治療目的是抑制粘膜炎癥,常用藥物包括5-氨基水楊酸、糖皮質(zhì)激素、抗生素和一些免疫抑制劑。盡管這些治療方法在很多患者中均取得較好的治療效果,仍有許多患者不能臨床緩解,因此有待研究新的行之有效的治療方法。 結(jié)腸炎性巨噬細(xì)胞的浸潤(rùn)是IBD的一個(gè)重要特征,在IBD的發(fā)病中發(fā)揮著極為重要的作用。在IBD患者和實(shí)驗(yàn)性結(jié)腸炎模型中,外周血單核細(xì)胞可募集至結(jié)腸粘膜,分化成炎性巨噬細(xì)胞分泌包括TNFα、IL-1和IL-6在內(nèi)的促炎性細(xì)胞因子。NF-κB信號(hào)通路的活化被認(rèn)為是促炎性細(xì)胞因子表達(dá)和分泌的強(qiáng)效誘導(dǎo)者,且IBD患者結(jié)腸粘膜巨噬細(xì)胞中存在明顯的NF-κB信號(hào)通路活化。此外,巨噬細(xì)胞促炎性細(xì)胞因子的分泌是IBD的重要發(fā)病因素之一。因此,靶向粘膜炎性巨噬細(xì)胞的治療策略可能對(duì)研發(fā)新的治療藥物有重要的作用和價(jià)值。然而,由于缺乏有效的干預(yù)方法,針對(duì)于結(jié)腸粘膜巨噬細(xì)胞干預(yù)的研究極為有限。 氯化釓(gadolinium chloride,GdCl3)已被廣泛應(yīng)用于實(shí)驗(yàn)性研究。在實(shí)驗(yàn)性動(dòng)物中已經(jīng)發(fā)現(xiàn),氯化釓在肝臟中有清除巨噬細(xì)胞的作用,在肝損傷等疾病中有預(yù)防或治療的作用。此外,實(shí)驗(yàn)性動(dòng)物中發(fā)現(xiàn)氯化釓對(duì)巨噬細(xì)胞有選擇性抑制作用。已經(jīng)證實(shí),氯化釓對(duì)大鼠肺組織巨噬細(xì)胞沒有清除作用,但可以抑制LPS刺激后TNFα和IL-6的表達(dá)。然而,氯化釓對(duì)結(jié)腸粘膜巨噬細(xì)胞的作用知之甚少。 目的 1.研究應(yīng)用氯化釓后腸炎小鼠結(jié)腸粘膜炎癥程度和疾病嚴(yán)重程度。 2.探討氯化釓抑制腸炎小鼠粘膜炎癥的機(jī)制。 3.應(yīng)用RAW264.7細(xì)胞體外驗(yàn)證氯化釓對(duì)巨噬細(xì)胞活性的抑制作用。 方法 1.動(dòng)物處理 體重20-25g,周齡8-10周的雄性C57BL/6J小鼠被用于該研究。靜脈給予不同濃度的氯化釓,對(duì)照組給予PBS。流式細(xì)胞術(shù)檢測(cè)小鼠結(jié)腸粘膜巨噬細(xì)胞的比例。 2.腸炎的誘導(dǎo) (1)TNBS灌腸造腸炎模型 將2mg的TNBS溶解于50%的乙醇溶液中,終體積為O.1ml。用注射器(0.1m1)吸取配置好的TNBS溶液,隨后與一聚乙烯塑料管(內(nèi)徑為1.2mm)相連,用石蠟油充分潤(rùn)滑導(dǎo)管末端后灌腸,導(dǎo)管末端距小鼠的肛門約2-3cm,將注射器內(nèi)的TNBS緩慢推入結(jié)腸。對(duì)照組小鼠給予同等劑量的生理鹽水。 TNBS灌腸后第3天至第7天,用注射器(0.1m1)吸取配置好的氯化釓(10mg/kg體重)溶液灌腸。對(duì)照組給予等量的PBS灌腸。在TNBS灌腸后第7天或第14天,處死小鼠。 TNBS灌腸后第3天至第7天,用注射器(O.1m1)吸取配置好的氯化釓(10mg/kg體重)溶液,行尾靜脈注射。對(duì)照組給予等量的PBS灌腸。在TNBS灌腸后第7天或第14天,處死小鼠。 (2)DSS誘導(dǎo)腸炎 將DSS (40,000MW)溶于飲用水中,使其終濃度為3%(w/v),給予小鼠連續(xù)飲用7天,對(duì)照組給予正常的飲用水飲用。 飲用DSS第3天,用注射器(O.1m1)吸取配置好的氯化釓(10mg/kg體重)溶液,隨后與一聚乙烯塑料管(內(nèi)徑為1.2mmm)相連,用石蠟油充分潤(rùn)滑導(dǎo)管末端灌腸,導(dǎo)管末端距小鼠的肛門約2-3cm,將注射器內(nèi)的氯化釓緩慢推入結(jié)腸。對(duì)照組給予等量的PBS灌腸。在DSS誘導(dǎo)腸炎后第7天或第14天,處死小鼠。 飲用DSS誘導(dǎo)腸炎第3天,用注射器(O.1m1)吸取配置好的氯化釓(10mg/kg體重)溶液,行尾靜脈注射。對(duì)照組給予等量的PBS灌腸。在DSS誘導(dǎo)腸炎后第7天或第14天,處死小鼠。 3.腸炎嚴(yán)重程度評(píng)估 每日監(jiān)測(cè)小鼠體重,腸炎程度通過疾病活動(dòng)指數(shù)(DAI)進(jìn)行評(píng)估。疾病活動(dòng)指數(shù)評(píng)分主要評(píng)估體重減輕程度、血便情況和糞便硬度。對(duì)每組的每只老鼠進(jìn)行評(píng)估,每一項(xiàng)的評(píng)分為0-4分,共計(jì)12分。小鼠與誘導(dǎo)炎癥后第7天或第14天處死,取結(jié)腸標(biāo)本甲醛固定,對(duì)實(shí)驗(yàn)設(shè)計(jì)和操作全盲的醫(yī)師進(jìn)行組織學(xué)炎癥程度評(píng)分。 4.流式檢測(cè)結(jié)腸粘膜巨噬細(xì)胞比例 提取結(jié)腸粘膜細(xì)胞,孵育F4/80抗體,流式檢測(cè)結(jié)腸粘膜巨噬細(xì)胞比例。 5.血清和結(jié)腸粘膜細(xì)胞因子水平檢測(cè) 收集小鼠外周血血清,提取結(jié)腸粘膜蛋白,ELISA檢測(cè)TNFα、IL-1β和IL-6水平。 6.細(xì)胞處理 RAW264.7培養(yǎng)于DMEM+10%FBS的培養(yǎng)基中,將RAW264.7種在96孔板中,培養(yǎng)12h后,給予不同濃度的氯化釓分別處理不同時(shí)間點(diǎn)。 7.氯化釓處理后細(xì)胞活性和凋亡的檢測(cè) 上述RAW264.7細(xì)胞經(jīng)氯化釓處理后,加入MTT檢測(cè)細(xì)胞活性。此外,RAW264.7經(jīng)氯化釓處理24h后,流式檢測(cè)其凋亡水平。 8.LPS刺激細(xì)胞檢測(cè)細(xì)胞因子分泌 將RAW264.7種在24孔板中,LPS刺激后,ELISA檢測(cè)TNFα、IL-1β口IL-6的分泌。 9. Western blot檢測(cè) 提取小鼠結(jié)腸粘膜蛋白和LPS處理的RAW2647細(xì)胞蛋白,用BCA法測(cè)定濃度,通過SDS-PAGE進(jìn)行蛋白分離,然后轉(zhuǎn)移到PVDF膜上。脫脂奶粉封閉后依次行一抗(NF-κB p65抗體)和辣根過氧化物酶標(biāo)記二抗孵育。ECL化學(xué)發(fā)光法檢測(cè)條帶。 結(jié)果 1.氯化釓對(duì)小鼠結(jié)腸粘膜巨噬細(xì)胞沒有清除作用 實(shí)驗(yàn)結(jié)果表明,靜脈應(yīng)用氯化釓后,小鼠結(jié)腸粘膜巨噬細(xì)胞比例未見明顯改變。此外,血清和結(jié)腸粘膜TNFα、IL-1β和IL-6的表達(dá)水平未見升高,表明氯化釓無致炎作用。 2.氯化釓可緩解TNBS和DSS誘導(dǎo)的腸炎 為探究氯化釓在小鼠腸炎模型中的潛在作用,我們應(yīng)用TNBS和DSS誘導(dǎo)的兩種小鼠腸炎模型進(jìn)行研究。在TNBS誘導(dǎo)的小鼠腸炎模型中,在TNBS灌腸后第3天,給予小鼠尾靜脈注射氯化釓。研究結(jié)果顯示,氯化釓尾靜脈注射后腸炎小鼠的死亡率、疾病嚴(yán)重程度、結(jié)腸縮短程度和組織學(xué)損傷程度均明顯改善。TNBS灌腸誘導(dǎo)小鼠腸炎模型后第3天起予氯化釓灌腸至第7天。研究結(jié)果顯示,氯化釓灌腸后腸炎小鼠的死亡率、疾病嚴(yán)重程度、結(jié)腸縮短程度和組織學(xué)損傷程度亦均明顯改善。而氯化釓尾靜脈注射組和氯化釓灌腸組小鼠之間無顯著的統(tǒng)計(jì)學(xué)差異。 將DSS (40,000MW)溶于飲用水中,使其終濃度為3%(w/v),給予小鼠連續(xù)飲用7天,對(duì)照組給予正常的飲用水飲用。在DSS誘導(dǎo)腸炎后第3天,給予小鼠尾靜脈注射氯化釓。研究結(jié)果顯示,氯化釓尾靜脈注射亦可顯著緩解DSS小鼠腸炎嚴(yán)重程度。DSS誘導(dǎo)小鼠腸炎模型后第3天起予氯化釓灌腸至第7天。研究結(jié)果顯示,氯化釓灌腸后腸炎小鼠的死亡率、疾病嚴(yán)重程度、結(jié)腸縮短程度和組織學(xué)損傷程度亦均明顯改善。而氯化釓尾靜脈注射組和氯化釓灌腸組小鼠之間無顯著的統(tǒng)計(jì)學(xué)差異。 3.氯化釓抑制TNBS和DSS誘導(dǎo)的TNFα、IL-1β和IL-6表達(dá) TNBS和DSS誘導(dǎo)腸炎后,靜脈或經(jīng)肛給予氯化釓。我們發(fā)現(xiàn),結(jié)腸粘膜巨噬細(xì)胞比例未見明顯改變,但ELISA結(jié)果表明腸炎小鼠血清和結(jié)腸黏膜TNFα、IL-1p和IL-6的表達(dá)水平降低。 4.氯化釓降低LPS活化的RAW264.7細(xì)胞的促炎性細(xì)胞因子分泌 氯化釓對(duì)RAW264.7細(xì)胞無毒性且不誘導(dǎo)其凋亡。給予LPS活化的RAW264.7細(xì)胞氯化釓,ELISA結(jié)果發(fā)現(xiàn)TNFα、IL-1β和IL-6的表達(dá)水平均明顯降低。 5.氯化釓抑制腸炎小鼠結(jié)腸粘膜和LPS活化RAW2G47細(xì)胞的NF-κB活性 給予腸炎小鼠氯化釓,結(jié)腸粘膜NF-κB p65的表達(dá)明顯降低。此外,體外研究發(fā)現(xiàn)氯化釓亦能降低LPS活化的RAW264.7細(xì)胞的NF-κB p65的表達(dá)。 結(jié)論 本研究應(yīng)用TNBS和DSS構(gòu)建了兩種IBD小鼠腸炎模型,首次發(fā)現(xiàn)氯化釓在TNBS和DSS誘導(dǎo)的腸炎模型中可緩解小鼠的死亡率、疾病嚴(yán)重程度、結(jié)腸縮短程度和組織學(xué)損傷程度,具有顯著的保護(hù)作用。此外,通過相關(guān)機(jī)制的深入研究,發(fā)現(xiàn)氯化釓主要是通過下調(diào)NF-KB信號(hào)通路的活性抑制巨噬細(xì)胞促炎性細(xì)胞因子TNFα、IL-1β和IL-6的分泌從而抑制結(jié)腸粘膜炎癥以緩解小鼠腸炎的嚴(yán)重程度。因此,干擾粘膜炎性巨噬細(xì)胞可能是IBD治療的新的有前景的靶點(diǎn)。
[Abstract]:background
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic nonspecific intestinal inflammatory disease involving the ileum, rectum and colonic mucosa,.IBD can occur at any age, more than 20-49 years old, and also in the elderly or children. Epidemiological studies have found that the incidence of IBD is in the world. There is no large-scale epidemiological survey in our country. There is a lack of large-scale epidemiological investigation in China, but there is also evidence that it is increasing year by year. Because the pathogenesis is not clear, the clinical manifestations are often repeated and it is difficult to cure. The existing research has confirmed that genetic susceptibility, intestinal flora, mucosal immune abnormalities and environmental factors are common. The main therapeutic purpose of IBD is to inhibit mucous membrane inflammation. The commonly used drugs include 5- amino salicylic acid, glucocorticoid, antibiotics and some immunosuppressants. Although these treatments have achieved good therapeutic effects in many patients, many patients are still unable to be remission, so it needs to be studied. Effective treatment.
The infiltration of colitis macrophages is an important feature of IBD, which plays an important role in the pathogenesis of IBD. In IBD patients and experimental colitis models, peripheral blood mononuclear cells can raise the colonic mucosa and differentiate into inflammatory macrophages, including TNF alpha, IL-1, and IL-6, the.NF- kappa B signal, including TNF alpha, IL-1 and IL-6 Activation of the pathway is considered to be a strong inducer of proinflammatory cytokines expression and secretion, and there is an obvious activation of NF- kappa B signaling pathway in the macrophages of IBD patients. In addition, the secretion of macrophage proinflammatory cytokines is one of the important factors of IBD. Therefore, the therapeutic strategy for targeting mucositis macrophages can be used. It has an important role and value for the development of new therapeutic drugs. However, due to the lack of effective intervention, the study of macrophage intervention in colonic mucosa is very limited.
Gadolinium chloride (GdCl3) has been widely used in experimental research. In experimental animals, gadolinium chloride has the role of removing macrophages in the liver and has the effect of prevention or treatment in liver injury. In addition, the experimental animals have found that gadolinium chloride has selective inhibition on macrophages. It is proved that gadolinium chloride has no scavenging effect on macrophages in rat lung tissue, but can inhibit the expression of TNF alpha and IL-6 after LPS stimulation. However, little is known about the effect of gadolinium chloride on macrophages in colonic mucosa.
objective
1. to study the severity and severity of colitis in mice with gadolinium chloride.
2. to explore the mechanism of gadolinium chloride inhibiting the mucositis of enteritis mice.
3. in vitro, RAW264.7 cells were used to verify the inhibitory effect of gadolinium chloride on macrophage activity.
Method
1. animal treatment
Body weight 20-25g, male C57BL/6J mice of 8-10 weeks of age were used in this study. Intravenous gadolinium chloride was given to different concentrations. The proportion of macrophages in colonic mucosa of mice was detected by PBS. flow cytometry in the control group.
Induction of 2. enteritis
(1) TNBS enterocolitis model
The TNBS of 2mg was dissolved in 50% ethanol solution. The final volume was O.1ml. using a syringe (0.1m1) to absorb the configured TNBS solution. Then it was connected to a polyethylene plastic tube (the inner diameter of 1.2mm), and the end of the catheter was fully lubricated with paraffin oil. The end of the catheter was about 2-3cm from the anus of the mouse. The TNBS in the syringe was slowly pushed into the colon. The mice were given the same dose of saline.
TNBS enema was used from third to seventh days after enema. The collocated gadolinium chloride (10mg/kg body) solution enema was absorbed with a syringe (0.1m1). The control group was given the same amount of PBS enema. The mice were killed seventh days or fourteenth days after TNBS enema.
TNBS from third to seventh days after enema was used to absorb the collocated gadolinium chloride (10mg/kg body) solution with a syringe (O.1m1). The caudal vein was injected. The control group was given the same amount of PBS enema. The mice were killed seventh days or fourteenth days after TNBS enema.
(2) DSS induced enteritis
DSS (40000MW) was dissolved in drinking water and the final concentration was 3% (w/v). Mice were given 7 days of continuous drinking, and the control group was given normal drinking water.
After drinking DSS for third days, using a syringe (O.1m1) to absorb the configured gadolinium chloride (10mg/kg body) solution, then connected to a polyethylene plastic tube (the inner diameter of 1.2mmm), the end of the catheter was fully lubricated with paraffin oil, the end of the catheter was about 2-3cm from the anus of the mouse, and the gadolinium chloride in the syringe was slowly pushed into the colon. The control group was given the equal amount of PBS irrigation. The mice were killed on the seventh or fourteenth day after DSS induced enteritis.
Drinking DSS induced enteritis for third days, using a syringe (O.1m1) to absorb the collocated gadolinium chloride (10mg/kg body) solution, injecting the tail vein. The control group was given the same amount of PBS enema. The mice were killed at seventh days or fourteenth days after DSS induced enteritis.
3. evaluation of severity of enteritis
The weight of the mice was monitored daily. The degree of enteritis was assessed by the disease activity index (DAI). The disease activity index score was mainly assessed for weight loss, blood stool and fecal hardness. Each group was evaluated with a score of 0-4, a total of 12 points. The rats were killed seventh days or fourteenth days after the induced inflammation, and the colon was taken to take the colon. Specimens were fixed with formaldehyde, and the histological degree of inflammation was scored on the experimental design and the totally blind doctors.
4. flow cytometry to detect the proportion of macrophages in colonic mucosa
Colonic mucosal cells were extracted, F4/80 antibody was incubated, and the proportion of macrophages in the colonic mucosa was detected by flow cytometry.
Detection of cytokine levels in 5. serum and colonic mucosa
The peripheral blood serum of mice was collected, and the colonic mucosal protein was extracted. The levels of TNF, IL-1 and IL-6 were detected by ELISA.
6. cell processing
RAW264.7 was cultured in DMEM+10%FBS medium, and RAW264.7 was cultured in 96 well plates. After culture 12h, different concentrations of gadolinium chloride were treated at different time points.
Detection of cell activity and apoptosis after gadolinium chloride treatment with 7. gadolinium chloride
The RAW264.7 cells were treated with gadolinium chloride and MTT was added to detect the cell viability. In addition, RAW264.7 was treated with gadolinium chloride and treated with 24h, and the apoptosis level was detected by flow cytometry.
Detection of cytokine secretion by 8.LPS stimulator cells
After stimulation of RAW264.7 seeds on 24 Kong Banzhong and LPS, ELISA was used to detect the secretion of TNF alpha and IL-1 beta IL-6.
9. Western blot detection
The protein of mouse colon mucous membrane protein and the RAW2647 cell protein treated by LPS were extracted and the concentration was measured by BCA. The protein was separated by SDS-PAGE and then transferred to the PVDF membrane. After the skimmed milk powder was closed, the first anti (NF- kappa B p65 antibody) and the horseradish peroxidase labeling two anti incubation.ECL chemiluminescence method were used to detect the strip.
Result
1. gadolinium chloride has no scavenging effect on macrophages in mouse colonic mucosa.
The results showed that the proportion of macrophages in the colon mucosa of mice was not significantly changed after intravenous gadolinium chloride. The expression level of TNF alpha, IL-1 beta and IL-6 in the serum and colonic mucosa did not increase, indicating that gadolinium chloride has no inflammatory effect.
2. gadolinium chloride can relieve TNBS and DSS induced enteritis
In order to explore the potential role of gadolinium chloride in the mouse enteritis model, we studied two mice enteritis models induced by TNBS and DSS. In the TNBS induced mouse enteritis model, the gadolinium chloride was injected into the tail vein of the mice at the third day after TNBS enema. The severity of the disease, the degree of colonic shortening and the degree of histological damage significantly improved the gadolinium enema to seventh days after the.TNBS enema induced mouse enteritis model. The results of the study showed that the mortality, the severity of the disease, the degree of colonic contraction and the degree of histological damage were also significantly improved in the mice after gadolinium chloride enema. There was no significant difference between gadolinium tail vein injection group and gadolinium chloride enema group.
DSS (40000MW) was dissolved in drinking water, the final concentration was 3% (w/v), and the mice were given a continuous drinking water for 7 days. The control group was given normal drinking water. The gadolinium chloride was injected into the tail vein of the mice for third days after DSS induced enteritis. The results showed that the gadolinium chloride tail vein injection could also significantly relieve the severity of DSS mice's enteritis to be.DSS induced to be small. The results of the study showed that the mortality, the severity of the disease, the degree of colon shortening and the degree of histological damage were also significantly improved in mice after gadolinium chloride enema, and there was no significant difference between the gadolinium chloride tail vein group and the gadolinium chloride enema group in the third days after the rat enterocolitis model.
3. gadolinium chloride inhibits TNBS and DSS induced TNF, IL-1, and IL-6 expression.
After TNBS and DSS induced enteritis, gadolinium chloride was given to the veins or through the anus. We found that the proportion of macrophages in the colonic mucosa was not significantly changed, but the ELISA results showed that the levels of TNF alpha, IL-1p and IL-6 in the serum and colonic mucosa of the colitis mice were reduced.
4. gadolinium chloride reduces proinflammatory cytokine secretion in LPS activated RAW264.7 cells
Gadolinium chloride was nontoxic to RAW264.7 cells and did not induce apoptosis. Gadolinium chloride was given to RAW264.7 cells activated by LPS. ELISA results showed that the expression level of TNF alpha, IL-1 beta and IL-6 decreased significantly.
5. gadolinium chloride inhibits NF- kappa B activity in colonic mucosa and LPS activated RAW2G47 cells of enteritis mice
The expression of NF- kappa B p65 in colonic mucosa was significantly reduced in mice treated with colitis. In addition, the in vitro study showed that gadolinium chloride could also reduce the expression of NF- kappa B p65 in LPS activated RAW264.7 cells.
conclusion
In this study, two IBD mouse enteritis models were constructed with TNBS and DSS. It was found for the first time that gadolinium chloride could alleviate the mortality of mice, the severity of the disease, the degree of colon shortening and the degree of histological damage in the model of TNBS and DSS induced enteritis. The inhibition of colonic mucositis by inhibiting the secretion of macrophage proinflammatory cytokines, TNF a, IL-1 beta and IL-6, can inhibit the severity of colitis in mice by reducing the activity of NF-KB signaling pathway. Therefore, interfering with mucositis macrophages may be a new and promising target for the treatment of IBD.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R574.62

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