本文選題：JNK絲裂原活化蛋白激酶類 + 肺纖維化��； 參考：《山西醫(yī)科大學(xué)》2012年碩士論文

【摘要】：研究背景：肺纖維化是一種病因不明的漸進(jìn)性加重的致命性彌漫性肺疾病。傳統(tǒng)治療主要是抑制炎癥反應(yīng)，但臨床療效甚微。為了顯著提高肺纖維化患者的生存率，進(jìn)一步探討其發(fā)病機(jī)制成為必然。成纖維細(xì)胞表型分化為特征性表達(dá)α-平滑肌肌動蛋白（α-SMA）的肌成纖維細(xì)胞為肺纖維化的關(guān)鍵步驟，但其發(fā)生機(jī)制不甚明了。近年來，信號通路成為其研究的熱點(diǎn)。c-jun氨基末端激酶（JNK）是絲裂原活化蛋白激酶家族的重要一員，JNK信號通路參與調(diào)控許多細(xì)胞增殖、分化與凋亡。已有研究表明JNK信號通路參與人肺成纖維細(xì)胞向肌成纖維細(xì)胞分化的過程,而關(guān)于體內(nèi)實驗JNK信號通路是否在肺纖維化轉(zhuǎn)分化過程中發(fā)揮作用尚未見相關(guān)研究報道。JNK激酶抑制劑SP600125可特異性阻斷JNK信號通路。本實驗使用SP600125進(jìn)行干預(yù)，通過測定大鼠肺組織中α-SMA和p-JNK蛋白的表達(dá)水平，從分子信號角度探討肺纖維化中JNK信號通路與肺纖維化成纖維細(xì)胞表型改變的關(guān)系，探討該途徑在肺纖維化中的地位。 目的：利用博萊霉素（BLM）誘導(dǎo)的大鼠肺纖維化模型，通過觀察健康對照組、模型組和SP600125組肺組織病理形態(tài)學(xué)的變化，測定肺組織羥脯氨酸（HYP）的含量，觀察肺組織中α-SMA和p-JNK蛋白的表達(dá)，進(jìn)一步分析JNK信號通路在肺纖維化成纖維細(xì)胞表型轉(zhuǎn)分化病理過程中的作用。 方法：將54只健康雄性Wistar大鼠（體重為200g±20g）隨機(jī)分為對照組、模型組和SP600125組，每組各18只。模型組于氣管內(nèi)滴注BLM生理鹽水(5mg/kg），，造模當(dāng)日腹腔內(nèi)注射二甲基亞砜（DMSO）液；SP600125組用同樣方法造模，造模當(dāng)日腹腔內(nèi)注射SP600125溶液（15mg/kg，溶于DMSO液中），一次性給藥；對照組氣管內(nèi)滴注生理鹽水，造模當(dāng)日腹腔內(nèi)注射DMSO液。分別于造模后第7、14、28天處死大鼠，取肺組織病理切片行蘇木素-伊紅（HE）染色和Masson染色，光鏡下觀察大鼠肺組織病理學(xué)變化；堿水解法檢測肺組織HYP含量；應(yīng)用免疫組織化學(xué)法檢測肺組織中α-SMA和p-JNK蛋白表達(dá)水平。 結(jié)果：1、模型組第7天肺泡炎程度嚴(yán)重，于第28天形成顯著肺纖維化，SP600125組各期病理變化較模型組減輕。2、模型組和SP600125組的HYP含量隨時間延長逐漸升高。第7天模型組較對照組升高（P＜0.01)，SP600125組與模型組和對照組比較差異無統(tǒng)計學(xué)意義，第14、28天模型組較對照組明顯升高（P＜0.01),SP600125組較模型組有所減低（P＜0.01)，但仍高于對照組。3、模型組各時間點(diǎn)α-SMA與p-JNK蛋白均明顯表達(dá)，以第14天最明顯。對照組及SP600125組第14、28天α-SMA與p-JNK蛋白表達(dá)均較模型組降低(P＜0.05)。4、模型組α-SMA與p-JNK蛋白含量呈顯著正相關(guān)(r=0.927，P＜0.05)。 結(jié)論：肺纖維化病理過程可能與p-JNK蛋白表達(dá)增加并活化α-SMA的表達(dá)有關(guān)，應(yīng)用SP600125對肺纖維化有抑制作用。
[Abstract]:Background: pulmonary fibrosis is a fatal diffuse pulmonary disease with unknown etiology and progressive exacerbation. The traditional treatment is mainly to suppress inflammatory reaction, but the clinical effect is very little. In order to improve the survival rate of patients with pulmonary fibrosis, it is necessary to further explore its pathogenesis. Phenotypic differentiation of fibroblasts into myofibroblasts expressing 偽 -smooth muscle actin (偽 -SMA) is a key step in pulmonary fibrosis, but its mechanism is not clear. In recent years, the signal pathway has become the focus of its research. C-jun amino-terminal kinase (JNKK) is an important member of the mitogen-activated protein kinase family. JNK signaling pathway plays an important role in regulating the proliferation, differentiation and apoptosis of many cells. It has been shown that JNK signaling pathway is involved in the differentiation of pulmonary fibroblasts into myofibroblasts. However, whether the JNK signaling pathway plays a role in the process of pulmonary fibrosis transdifferentiation has not been reported in vivo. JNK kinase inhibitor SP600125 can specifically block the JNK signaling pathway. The expression of 偽 -SMA and p-JNK protein in lung tissue of rats was measured by SP600125. The relationship between JNK signaling pathway and phenotypic changes of fibroblasts in pulmonary fibrosis was studied from the molecular signal perspective. To explore the role of this pathway in pulmonary fibrosis. Objective: to observe the pathological changes of lung tissue in control group, model group and SP600125 group, and to determine the content of hydroxyproline (HYP) in lung tissue of rats induced by bleomycin (BLM). To observe the expression of 偽 -SMA and p-JNK protein in lung tissue and to further analyze the role of JNK signaling pathway in the pathological process of phenotypic transdifferentiation of pulmonary fibrosis fibroblasts. Methods: 54 healthy male Wistar rats (body weight was 200g 鹵20g) were randomly divided into control group, model group and SP600125 group with 18 rats in each group. The model group was treated with intratracheal instillation of BLM saline (5 mg / kg) and intraperitoneal injection of dimethyl sulfoxide (DMSO) solution in SP600125 group on the same day. On the same day, SP600125 solution was injected intraperitoneally with 15 mg / kg SP600125 solution and dissolved in DMSO solution. In the control group, normal saline was injected into trachea and DMSO solution was injected intraperitoneally on the day of modeling. The rats were killed on day 7, 1428, respectively. The pathological sections of lung tissue were stained with hematoxylin-eosin) and Masson staining. The pathological changes of lung tissue were observed under light microscope, and the content of HYP in lung tissue was detected by alkaline hydrolysis. The expression of 偽 -SMA and p-JNK protein in lung tissue was detected by immunohistochemical method. Results the severity of alveolitis in the model group was severe on the 7th day. The pathological changes of each stage in SP600125 group were lighter than those in the model group on the 28th day. The content of HYP in the model group and SP600125 group gradually increased with the prolongation of time. On the 7th day, there was no significant difference between the model group and the model group and the control group (P < 0.01). On the 14th day, the expression of 偽 -SMA and p-JNK protein in model group was significantly higher than that in control group (P < 0.01), but still higher than that in control group (P < 0.01). The expression of 偽 -SMA and p-JNK protein in model group was the most obvious on the 14th day. The expression of 偽 -SMA and p-JNK protein in the control group and SP600125 group was significantly lower than that in the model group on the 28th day (P < 0.05). There was a significant positive correlation between 偽 -SMA and p-JNK protein content in the model group (P < 0.05). Conclusion: the pathological process of pulmonary fibrosis may be related to the increased expression of p-JNK protein and activation of 偽 -SMA expression. The application of SP600125 can inhibit pulmonary fibrosis.
【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】：2012
【分類號】：R563.9

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