本文選題：潰瘍性結(jié)腸炎 + 4-ASA��； 參考：《山西醫(yī)科大學(xué)》2014年碩士論文

【摘要】：潰瘍性結(jié)腸炎（ulcerative colitis，UC）是一種反復(fù)發(fā)作的慢性的非特異性結(jié)、直腸炎，以腹痛、腹瀉、里急后重、粘液膿血便等為主要臨床癥狀[1-3]。該病起病緩慢，病程遷延不愈，長達幾年甚至數(shù)十年，癥狀易反復(fù)發(fā)作，是胃腸道中除惡變外最嚴重的疾病之一。目前，藥物治療仍然是UC的主要治療手段。其中，5-氨基水楊酸（5-aminosalicylic acid，5-ASA）及其前藥是治療輕、中度廣泛性UC的一線藥物。近年來，許多實驗研究證實4-氨基水楊酸（4-aminosalicylic acid，4-ASA）在UC的治療上與5-ASA有相近的療效，已用于不能耐受柳氮磺胺吡啶（sulfasalazine，SASP）的輕、中度UC。本論文由三章組成，分別從動物水平和細胞水平研究4-ASA和5-ASA的抗炎作用，并對兩者發(fā)揮抗炎作用的作用機制進行了研究。 第一章采用TNBS法誘導(dǎo)大鼠潰瘍性結(jié)腸炎模型后，分別設(shè)正常組、模型組、SASP組、4-ASA組和5-ASA組，觀察4-ASA和5-ASA對大鼠UC的治療作用。實驗結(jié)果顯示：模型組大鼠疾病活動指數(shù)評分、大體評分和組織學(xué)評分均較對照組明顯增高，而造模后給予SASP、4-ASA、5-ASA后，各組大鼠結(jié)腸炎癥程度明顯減輕，，DAI評分、大體評分、組織學(xué)評分均較模型組大鼠顯著減低（P＜0.05）。 第二章采用脂多糖（lipopolysaccharide，LPS）誘導(dǎo)小鼠單核巨噬細胞（RAW264.7）炎癥后，考察低（10μg/ml）、中（100μg/ml）、高（1000μg/ml）濃度4-ASA和5-ASA對炎性細胞IL-6、NO、iNOSmRNA及iNOS蛋白表達的抑制作用。實驗結(jié)果顯示：4-ASA：與正常組比較，模型組細胞內(nèi)IL-6、NO、iNOSmRNA及iNOS蛋白表達表達均顯著上調(diào)（P＜0.05）。與模型組相比，造模后給予10μg/ml4-ASA處理組的細胞內(nèi)IL-6、iNOSmRNA及iNOS蛋白表達未見明顯下調(diào)（P＞0.05），NO表達明顯下調(diào)（P＜0.05）。造模后給予100μg/ml和1000μg/ml4-ASA處理組的細胞內(nèi)IL-6、NO、iNOSmRNA及iNOS蛋白表達均明顯下調(diào)（P＜0.05）。5-ASA：與正常組比較，模型組細胞內(nèi)IL-6、NO、iNOSmRNA及iNOS蛋白表達表達均顯著上調(diào)（P＜0.05）。與模型組相比，造模后給予10、100和1000μg/ml5-ASA處理組的細胞內(nèi)IL-6、NO、iNOSmRNA及iNOS蛋白表達均明顯下調(diào)（P＜0.05）。 第三章采用脂多糖（lipopolysaccharide，LPS）誘導(dǎo)小鼠單核巨噬細胞（RAW264.7）炎癥后，考察低（10μg/ml）、中（100μg/ml）、高（1000μg/ml）濃度4-ASA和5-ASA對炎性細胞JNK1/2、p38MAPK磷酸化及IκBα表達的抑制作用。實驗結(jié)果顯示：4-ASA：與正常組比較，模型組細胞內(nèi)p-JNK1/2、p-p38及IκBα蛋白表達均顯著上調(diào)（P＜0.05）。與模型組相比，造模后給予10和100μg/ml4-ASA處理組的細胞內(nèi)p-JNK1/2蛋白表達未見明顯下調(diào)（P＞0.05），1000μg/ml4-ASA處理組的細胞內(nèi)p-JNK1/2蛋白表達明顯下調(diào)（P＜0.05）。造模后給予10、100和1000μg/ml4-ASA處理組的細胞內(nèi)p-p38和IκBα蛋白表達均未見顯著下調(diào)（P＞0.05）。5-ASA：與正常組比較，模型組細胞內(nèi)p-JNK1/2、p-p38及IκBα蛋白表達均顯著上調(diào)（P＜0.05）。與模型組相比，造模后給予10和100μg/ml5-ASA處理組的細胞內(nèi)p-JNK1/2蛋白表達未見明顯下調(diào)（P＞0.05），1000μg/ml5-ASA處理組的細胞內(nèi)p-JNK1/2蛋白表達明顯下調(diào)（P＜0.05）。造模后給予10、100和1000μg/ml4-ASA處理組的細胞內(nèi)p-p38蛋白表達均顯著下調(diào)（P＜0.05），IκBα蛋白表達均未見顯著下調(diào)（P＞0.05）。 由以上三部分實驗結(jié)果可以得出結(jié)論：4-ASA和5-ASA均具有明顯抗炎作用，但二者發(fā)揮抗炎作用的機制有所不同。4-ASA主要通過抑制JNK1/2的磷酸化而發(fā)揮作用，而5-ASA同時抑制JNK1/2和p38的磷酸化而發(fā)揮作用。
[Abstract]:Ulcerative colitis (ulcerative colitis, UC) is a chronic, chronic, nonspecific knot, proctitis, with abdominal pain, diarrhea, heavy weight in the back, mucus and blood and urine as the main clinical symptoms, [1-3]., the disease is slow, the course of the disease is prolonged for several years or even ten years, and the symptoms are prone to relapse, which is the most serious outside of the gastrointestinal tract. At present, drug therapy is still the main treatment for UC. Among them, 5- amino salicylic acid (5-aminosalicylic acid, 5-ASA) and their prodrugs are the first-line drugs for the treatment of mild, moderate and extensive UC. In recent years, many experimental studies have confirmed that 4- amino salicylic acid (4-aminosalicylic acid, 4-ASA) is similar to 5-ASA in the treatment of UC. It has been used for the light and moderate UC., which is not tolerable to sulfasalazine (SASP). This paper is composed of three chapters. The anti-inflammatory effects of 4-ASA and 5-ASA are studied from animal level and cell level, and the mechanism of anti-inflammatory action of both of them has been studied.
In the first chapter, the rat model of ulcerative colitis was induced by TNBS, and the normal group, model group, SASP group, 4-ASA group and 5-ASA group were set up to observe the therapeutic effect of 4-ASA and 5-ASA on UC in rats. The results showed that the score of disease activity index, gross score and histological score of the model group were significantly higher than those of the control group, and the model was given after the model group. After SASP, 4-ASA, 5-ASA, the degree of colitis in each group was significantly reduced, DAI score, gross score and histological score were significantly lower than those in the model group (P < 0.05).
In the second chapter, after lipopolysaccharide (LPS) was used to induce mononuclear macrophage (RAW264.7) inflammation in mice, the inhibitory effects of low (10 g/ml), medium (100 u g/ml), and high (1000 mu) concentration of 4-ASA and 5-ASA on the expression of IL-6, NO, iNOSmRNA and iNOS protein in inflammatory cells were investigated. The expression of IL-6, NO, iNOSmRNA and iNOS increased significantly (P < 0.05). Compared with the model group, the expression of IL-6, iNOSmRNA and iNOS protein was not significantly down (P > 0.05) and NO expression decreased significantly (P < 0.05) after the model group was given to the 10 micron g/ml4-ASA treatment group. The expression of NOSmRNA and iNOS protein decreased significantly (P < 0.05).5-ASA. Compared with the normal group, the expression of IL-6, NO, iNOSmRNA and iNOS protein in the cells of the model group were significantly up (P < 0.05). Compared with the model group, the IL-6 in the cells of the 10100 and 1000 mu g/ml5-ASA treated groups was significantly down (0). .05).
In the third chapter, after lipopolysaccharide (LPS) was used to induce mononuclear macrophage (RAW264.7) inflammation in mice, the inhibitory effects of low (10 g/ml), medium (100) g/ml, and high (1000 mu) concentration of 4-ASA and 5-ASA on inflammatory cells JNK1/2, p38MAPK phosphorylation and I B alpha expression were investigated. Experimental results showed that the model group cells were compared with the normal group. The expression of p-JNK1/2, p-p38 and I kappa B alpha protein was significantly up-regulated (P < 0.05). Compared with the model group, the expression of p-JNK1/2 protein in the cells of 10 and 100 mu g/ml4-ASA treated groups was not significantly down (P > 0.05). The intracellular p-JNK1/2 protein table of the 1000 UU treatment group was down significantly down (P < 0.05). 10100 and 1000 micron were given after the model group. The expression of p-p38 and I kappa B alpha in the l4-ASA treatment group did not decrease significantly (P > 0.05).5-ASA: compared with the normal group, the expression of p-JNK1/2, p-p38 and I kappa B alpha protein in the cells of the model group was significantly up (P < 0.05). Compared with the model group, the expression of intracellular protein in the 10 and 100 micron groups was not obvious after the model group. Down regulation (P > 0.05), the expression of intracellular p-JNK1/2 protein in the 1000 g/ml5-ASA treatment group decreased significantly (P < 0.05). The expression of p-p38 protein in the cells of the treatment group was significantly down regulated (P < 0.05), and the expression of I kappa B alpha protein was not significantly down (P > 0.05).
From the experimental results of the above three parts, we can conclude that both 4-ASA and 5-ASA have obvious anti-inflammatory effects, but the mechanisms of the two anti inflammatory effects are different by inhibiting the phosphorylation of JNK1/2, while 5-ASA inhibits the phosphorylation of JNK1/2 and p38 at the same time.
【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R574.62

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