本文選題：巴多昔芬 + 子宮內(nèi)膜異位癥　； 參考：《鄭州大學(xué)》2017年碩士論文

【摘要】：背景和目的子宮內(nèi)膜異位癥(endometriosis,EMs)是臨床上常見的一種危害女性健康的慢性疾病,組織病理學(xué)上呈良性改變,但有很強(qiáng)的種植、侵襲、轉(zhuǎn)移能力。有研究提示子宮內(nèi)膜異位癥的生物學(xué)行為可能源于雌激素暴露,作用于雌激素受體(estrogen receptor,ER),啟動(dòng)對(duì)應(yīng)的信號(hào)通路,多條信號(hào)通路相互作用的結(jié)果促進(jìn)了逆流的子宮內(nèi)膜能在宮腔以外生長(zhǎng)。目前臨床上腹腔鏡手術(shù)作為治療子宮內(nèi)膜異位癥的金標(biāo)準(zhǔn)已經(jīng)取得了很好的效果,但有時(shí)仍需輔助藥物治療,而用于治療子宮內(nèi)膜異位癥的藥物多在于減少內(nèi)源性雌激素的產(chǎn)生,長(zhǎng)期用藥易導(dǎo)致機(jī)體低雌激素而出現(xiàn)一系列的圍絕經(jīng)期癥狀,而限制了這些藥物的臨床應(yīng)用。有研究證明巴多昔芬作為第三代選擇性雌激素受體調(diào)節(jié)劑(SERMs)能對(duì)大鼠EMs模型起到治療作用并使雌激素受體(ER)的表達(dá)明顯減少,因其表現(xiàn)出對(duì)大鼠EMs的治療作用,而逐漸進(jìn)入人們的視野,其臨床應(yīng)用前景廣闊。本課題通過建立大鼠EMs模型,免疫組化法檢測(cè)對(duì)照組大鼠子宮內(nèi)膜、大鼠EMs模型(模型組、巴多昔芬組)在位子宮內(nèi)膜和異位病灶中雌激素受體亞型α(ERα)、雌激素受體亞型β(ERβ)、AP-1組成成分c-jun蛋白、血管內(nèi)皮生長(zhǎng)因子(VEGF)表達(dá)情況,探討ERα、ERβ、AP-1、VEGF在大鼠EMs模型中的表達(dá)特點(diǎn)及巴多昔芬治療大鼠子宮內(nèi)膜異位癥的可能的作用機(jī)制。材料與方法1.材料河南省動(dòng)物實(shí)驗(yàn)中心購(gòu)買的清潔健康雌性未孕的SD大鼠100只,鼠齡60d~90d,質(zhì)量220~250g,進(jìn)入研究的各組(對(duì)照組、模型組、巴多昔芬組)大鼠的鼠齡、質(zhì)量之間均無明顯差異。2.方法觀察雌性大鼠的正常發(fā)情周期,選取連續(xù)觀察2個(gè)正常發(fā)情周期的大鼠進(jìn)行建模。建模前一天均肌注雌激素,使大鼠處于發(fā)情期,皮下移植法建立子宮內(nèi)膜異位癥的動(dòng)物模型:將剝除的子宮內(nèi)膜剪為5×5mm大小的片段;采用皮下種植法將子宮內(nèi)膜片段植入受體大鼠的腹肌和皮下筋膜之間,術(shù)后常規(guī)應(yīng)用硫酸慶大霉素0.1ml肌肉注射預(yù)防感染3天。術(shù)后常規(guī)喂養(yǎng)3周,選取建模成功的56只大鼠(4只為無效造模)隨機(jī)分為巴多昔芬組(3 mg·kg-1·d-1巴多昔芬灌胃,n=28)和模型組(每日等體積的生理鹽水灌胃,n=28)。另外隨機(jī)選取同一批次10只正常雌性大鼠作為對(duì)照組(喂養(yǎng)條件與術(shù)后實(shí)驗(yàn)組相同),4周后,在消毒、無菌條件下取模型組及巴多昔芬組異位病灶組織、在位子宮內(nèi)膜,對(duì)照組子宮內(nèi)膜分別固定于4%多聚甲醛,石蠟包埋,將蠟塊連續(xù)切片,部分切片常規(guī)HE染色,部分用免疫組化方法檢測(cè)ERα,ERβ,AP-1(c-jun蛋白)、VEGF的表達(dá)情況。結(jié)果1.對(duì)照組與模型組比較:(1)大鼠EMs模型在位內(nèi)膜及異位病灶腺體、間質(zhì)血管明顯增加。(2)在大鼠EMs模型的異位病灶與對(duì)照組子宮內(nèi)膜間ERα陽性率未見統(tǒng)計(jì)學(xué)差異(P=0.107),而其在在位內(nèi)膜中的表達(dá)高于對(duì)照組(P0.01)。ERβ、c-jun、VEGF在模型組在位內(nèi)膜及異位病灶中陽性率均高于對(duì)照組(P0.01),但其在位內(nèi)膜及異位病灶中的表達(dá)未見明顯差異。2.巴多昔芬組與模型組比較:巴多昔芬治療后,巴多昔芬組與模型組相比,ERα的表達(dá)未表現(xiàn)出明顯差異,但ERβ、AP-1、VEGF表達(dá)較模型組明顯下降(P0.01)。結(jié)論1.ERα、ERβ、AP-1、VEGF在大鼠EMs模型中的表達(dá)特點(diǎn)支持“在位內(nèi)膜決定論”。2.大鼠EMs模型在位內(nèi)膜中ERα和ERβ均高表達(dá),異位病灶中則僅表現(xiàn)為ERβ高表達(dá),同時(shí)上調(diào)c-jun,VEGF的表達(dá),ERβ可能在EMs的發(fā)生發(fā)展中起到較ERα更為重要的作用。3.巴多昔芬表現(xiàn)出對(duì)ERβ較強(qiáng)的的拮抗作用,并下調(diào)c-jun,VEGF的表達(dá),這種表達(dá)模式的改變可能是巴多昔芬治療大鼠EMs的一個(gè)重要機(jī)制。
[Abstract]:Background and objective endometriosis (EMs) is a clinically common chronic disease which is harmful to women's health. There is a benign pathological change in histopathology, but it has strong planting, invasion and metastasis. Estrogen receptor, ER), starting the corresponding signaling pathway, the results of multiple signal pathways interact to promote the reverse flow of endometrium outside the intrauterine growth. Clinical laparoscopic surgery as the gold standard for the treatment of endometriosis has achieved good results, but it is sometimes necessary to assist in the treatment of drugs, and for treatment. The drug of endometriosis is mainly due to the reduction of endogenous estrogen, which is easy to lead to a series of perimenopausal symptoms of low estrogen in the body, which restricts the clinical application of these drugs. It has been proved that baropoxifene as the third generation of selective estrogen receptor modulator (SERMs) can play a role in the EMs model of rats. The effect of the treatment and the expression of estrogen receptor (ER) is obviously reduced, because it shows the therapeutic effect of the rat EMs, and gradually enters the people's field of vision, and its clinical application is promising. In this subject, the rat endometrium of the control group was detected by the establishment of the rat EMs model and the immunohistochemical method was used in the rat EMs model (model group, barooxifene group). Estrogen receptor subtype alpha (ER alpha), estrogen receptor subtype beta (ER beta), AP-1 component c-jun protein and vascular endothelial growth factor (VEGF) expression in endometrium and ectopic lesions, and explore the expression of ER alpha, ER beta, AP-1, VEGF in rat EMs model and the possible mechanism of barooxifen in the treatment of endometriosis in rats. Materials and methods 1. SD rats were purchased from the animal experiment center of Henan Province, 100 rats of clean and healthy female unpregnant, rat age 60d~90d, and quality 220~250g. The rats of all groups (control group, model group, barooxifen group) had no obvious difference between the quality of the rats and the normal estrous cycle of female rats was observed by.2. method, and 2 continuous observation was selected. Rats in the normal oestrus cycle were modeled. A day before modeling, the rats were injected with estrogen to make the rats in the oestrus period. The animal model of endometriosis was established by subcutaneous transplantation: the stripped endometrium was cut into 5 x 5mm size fragments; the intrauterine fragment was implanted into the abdominal and subcutaneous fascia of the rat by subcutaneous implantation. For 3 days after operation, routine feeding of gentamicin sulfate 0.1ml was used to prevent infection for 3 days. After 3 weeks of routine feeding, 56 rats with successful modeling were randomly divided into barmoxifen group (3 mg. Kg-1. D-1 basoloxifen gavage, n=28) and model group (n=28). 10 normal female rats were used as the control group (the same as the control group). After 4 weeks, the ectopic tissue of the model group and batotecoxifene group were taken under disinfection and aseptic conditions. The endometrium was found in the endometrium. The endometrium in the control group was fixed to 4% polyformaldehyde and the paraffin was embedded. The paraffin blocks were sliced continuously, and some sections were stained with HE staining. Partial immunohistochemistry was used to detect the expression of ER alpha, ER beta, AP-1 (c-jun protein) and VEGF. Results the 1. control groups were compared with the model group: (1) the eutopic and ectopic lesion glands of the rat EMs model and the interstitial blood vessels were significantly increased. (2) there was no statistical difference between the ectopic lesion of the rat EMs model and the endometrium ER alpha positive rate in the control group (P=0.107). The expression in the eutopic endometrium (P0.01) was higher than that of the control group (P0.01).ER beta, and the positive rate of c-jun and VEGF in the eutopic and ectopic focus of the model group was higher than that of the control group (P0.01), but there was no significant difference in the expression of the eutopic and ectopic focus in the eutopic and ectopic focus group from the.2. barbadoxifen group and the model group: baruoxiifene group and the model group after treatment with barpecoxifene. The expression of ER beta, AP-1, and VEGF decreased significantly compared with that of the model group (P0.01). Conclusion 1.ER alpha, ER beta, AP-1, VEGF in the rat EMs model support the "eutectist of eutopic endometrium" in the intima of.2. rat EMs model. At the same time, the expression of c-jun, VEGF, ER beta may play a more important role in the development of EMs than ER alpha,.3. barbadoxifene shows strong antagonism to ER beta, and reduces the expression of c-jun and VEGF. The change of this expression pattern may be an important mechanism for the treatment of EMs in rats.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R711.71;R-332

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