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研究生:王中麟
研究生(外文):Zhong-Lin Wang
論文名稱:腫瘤壞死因子-α相關之免疫調控機制對高泌乳素血症雄鼠勃起功能障礙的影響
論文名稱(外文):Immune modulation with TNF-α-related mechanism on erectile dysfunction induced by hyperprolactinemic status
指導教授:黃志賢黃志賢引用關係
指導教授(外文):William J. Huang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:中文
論文頁數:75
中文關鍵詞:高泌乳素血症腫瘤壞死因子-α勃起功能障礙睪固酮泌乳素
外文關鍵詞:hyperprolactinemiatumor necrosis factor-αerectile dysfunctiontestosteroneprolactin
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高泌乳素血症可能導致生殖系統功能障礙,活體動物表現出低睪固酮釋放,勃起功能障礙和生殖細胞製造障礙。從過去的研究了解泌乳素可刺激睪丸間質中的巨噬細胞分泌腫瘤壞死因子-α ,進而導致睪固酮釋放降低。在臨床上,因精神障礙或憂鬱症接受抗精神病藥或抗憂鬱藥治療的患者,會出現高泌乳素血症,通常會伴隨有勃起功能障礙。研究還表示,腫瘤壞死因子-α 對陰莖勃起具有壓抑作用。本論文的目的是研究腫瘤壞死因子-α 拮抗劑對高泌乳素血症誘發勃起功能障礙的大鼠模型之免疫調節作用。在8週齡的雄性Sprague-Dawley大鼠中,通過將腦下腺前葉移植到腎包膜下空間的方式(+ AP),誘導出高泌乳素血症。對照組則植入以大腦皮質(+CX)。在植入6週後,觀察其與雌鼠的交配行為,雌鼠先經去卵巢並以雌二醇刺激處理。另外,大鼠分別接受單一劑量的睪丸內注射腫瘤壞死因子-α 抗體(12.5 μg/kg)或接受肌內注射睪固酮(testosterone enanthate, TE, 3 mg/kg)處置。處置1週後犧牲,取下陰莖組織進行組織學分析。另一組實驗大鼠用單一劑量的睪丸內注射的 etanercept ( 0.4或0.8 mg/0.1ml/kg)治療。兩組實驗均在治療1週後觀察人類絨毛膜性腺激素(5 IU/kg)激發睪固酮釋放的活體研究。另外從正常大鼠睪丸中收集睪丸間質細胞進行體外研究,在不同濃度的 etanercept (分別為0,10^-9,10^-7或10^-5M)條件下同時暴露於泌乳素(0, 5或10 μg/ml)中評估睪丸間質細胞培養時的睪固酮釋放或在同時有人類絨毛膜性腺激素(0.05 IU/ml)激發下的睪固酮釋放。在實驗結果方面,對於交配行為的實驗,我們發現+ AP組的射精潛伏期比對照組+ CX大鼠為短。 + AP組血清睪固酮濃度較低,陰莖海綿體神經性一氧化氮生成酶(neuronal nitric oxide synthase,nNOS)表現較低,陰莖海綿體膠原蛋白III/I比值較高。然而,陰莖海綿體平滑肌含量在組間沒有顯著變化。在給予睪丸內注射腫瘤壞死因子-α抗體後1週,+ AP組膠原蛋白III/I比率顯著下降,平滑肌含量和nNOS表現也顯著增加。這些發現與僅接受肌肉注射睪固酮的+ AP大鼠所顯現的變化相近。在活體研究中,+AP組大鼠的人類絨毛膜性腺激素所激發的睪固酮釋放較+CX大鼠組為低。預先以睪丸內注射etanercept處理(0.8 mg/kg) 1週後亦呈現人類絨毛膜性腺激素誘導的睪固酮釋放顯著增加的現象。在離體培養研究中,當在含泌乳素培養基中施用較高濃度的etanercept (10^-5M)時,人類絨毛膜性腺激素刺激睪丸間質細胞釋放更多的睪固酮分泌。 綜上所述,高泌乳素血症誘導的勃起功能障礙的機制可能是來自睪丸間質腫瘤壞死因子-α的釋放,繼而抑制萊氏細胞睪固酮釋放並導致陰莖組織變化。這一發現可能意味著對於高泌乳素血症和勃起功能障礙患者,由睪丸內給予腫瘤壞死因子-α拮抗劑的治療是有其應用的價值。
Hyperprolactinemia (hyperPRL) and erectile dysfunction are both commonly seen in patients receiving antipsychotic or antidepressant treatments. Previous studies have shown that overproduction of prolactin (PRL) stimulates the secretion of tumor necrosis factor α (TNF-α) by the testicular interstitial macrophages and the situation results in lower testosterone release. Recent studies showed that TNF-α plays a suppressive role on penile erection in rodent. This study aimed to investigate the effects of hyperPRL and TNF-α antagonist on erectile dysfunction in a rat model. HyperPRL is induced in 8-week-old male Sprague-Dawley rats by allografting anterior pituitary (AP) glands under the renal capsule (+AP rats). Rats implanted with cerebral cortex (CX) are used as sham control (+CX rats). At 6 weeks post implantation, copulatory behaviors were observed with ovariectomized and estradiol-stimulated female rats. Another group of rats received either a single intra-testicular dose of TNF-α antibody (TNF-α Ab, 12.5 μg/kg) or intra-muscular testosterone injection (2 doses of testosterone enanthate [TE], 3 mg/kg), and they were sacrificed 1 week later, and the penes were retrieved for histological studies. The other group of rats were treated with etanercept (0.4 or 0.8 mg/0.1ml/kg) for 1 week and serum were collected for testosterone measurement. For in vitro studies, testosterone release at testicular interstitial cells (TIC) incubation was assessed in various concentration of etanercept (0, 10^-9, 10^-7, or 10^-5 M respectively) when exposed to 0, 5, or 10 µg/ml of ovine prolactin in the incubation medium, at the presence or absence of human chorionic gonadotropin (hCG, 0.05 IU/ml). Compared to +CX rats, the +AP group had shorter ejaculation latency. The +AP group had lower serum testosterone concentration and neuronal nitric oxide synthase (nNOS) expression, but exhibited a higher ratio of collagen III/I in the corpus cavernosum. Smooth muscle content exhibited no significant changes. At 1 week post TNF-α Ab injection, the collagen III/I ratio in the +AP group was found decreased, and the smooth muscle content and nNOS expression increased significantly. These findings were comparable to those observed in +AP rats receiving TE injection. In the in vivo +AP rats study, hCG induced less testosterone release than did in +CX rats. Intra-testicular etanercept pre-treatment (0.8 mg/kg) significantly increased the hCG-induced testosterone release. In vitro TIC incubation exhibited higher hCG-induced testosterone secretion when etanercept (10^-5M) was administered in PRL-conditioned medium. In summary, testicular TNF-α suppresses testosterone release in hyperPRL, which results in the erectile dysfunction. Intra-testicular TNF-α antagonist treatment is as effective as intra-muscular testosterone supplementation on the normalization of penile structure in the hyperPRL model. These findings imply that intra-testicular administration of TNF-α antagonist might be clinically feasible for patients presented with hyperPRL-induced erectile dysfunction.
目 錄
誌謝……………………………………………………………………. i
中文摘要……………………………………………………………… ii
英文摘要……………………………………………………………… iv
目錄………………………………………………………………… vi
圖目錄……………………………………………………………… x
表目錄……………………………………………………………… xii
重要名詞中英文對照表……………………………………………… xiii
第一章、緒論………………………………………………………… 1
一、概述………………………………………………………… 1
二、勃起功能障礙……………………………………………… 1
1、雄性(哺乳類)動物生殖生理…………………………… 1
2、陰莖的發育與解剖 ……………………………………… 2
3、勃起反應 ………………………………………………… 3
4、勃起功能障礙與治療…………………………………… 3
三、泌乳素……………………………………………………… 5
1、泌乳素的分泌與功能 …………………………………… 5
2、泌乳素與生殖功能的關係……………………………… 6
3、高泌乳素血症與勃起功能障礙的關係………………… 7
四、睪固酮……………………………………………………… 7
1、睪固酮的分泌與功能…………………………………… 7
2、睪固酮與高泌乳素血症 ………………………………… 8
3、睪固酮在高泌乳素血症引起勃起功能障礙中的角色… 8
五、腫瘤壞死因子-α…………………………………………… 9
1、腫瘤壞死因子-α的分泌與功能………………………… 9
2、腫瘤壞死因子-α與勃起功能障礙的關係……………… 10
3、腫瘤壞死因子-α在高泌乳素血症引發睪固酮低下的角色………………………………………………………… 10
六、抗腫瘤壞死因子-α療法…………………………………… 11
第二章、目的與假說………………………………………………… 12
第三章、高泌乳素血症對雄鼠交配行為的影響…………………… 13
一、緒言………………………………………………………… 13
二、材料與方法………………………………………………… 13
1、實驗動物………………………………………………… 13
2、高泌乳素血症動物模式………………………………… 13
3、高泌乳素血症雄鼠交配行為觀察……………………… 14
4、泌乳素檢測……………………………………………… 15
5、統計分析………………………………………………… 15
三、結果………………………………………………………… 19
1、誘發高泌乳素血症雄鼠之泌乳素檢測………………… 19
2、高泌乳素血症雄鼠之交配行為………………………… 19
四、討論………………………………………………………… 19
第四章、抗腫瘤壞死因子-α抗體與睪固酮對高泌乳素血症雄鼠陰莖組織的影響………………………………………………… 23
一、緒言………………………………………………………… 23
二、材料與方法………………………………………………… 24
1、實驗動物………………………………………………… 24
2、高泌乳素血症動物模式………………………………… 24
3、藥物注射………………………………………………… 24
3.1睪丸內注射TNF-α抗體…………………………… 24
3.2肌肉注射 testosterone enanthate…………………… 25
4、組織處理與染色………………………………………… 25
4.1組織固定與包埋…………………………………… 25
4.2組織陣列切片法…………………………………… 25
4.3組織抗原染色……………………………………… 25
4.4組織化學染色……………………………………… 26
4.4.1 Masson’s trichrome stain……………………… 26
4.4.2 Picrosirius red stain…………………………… 26
4.5 組織染色定量……………………………………… 26
5、睪固酮之放射免疫測定………………………………… 27
6、TNF-α之酵素免疫測定………………………………… 27
7、統計分析………………………………………………… 28
三、結果………………………………………………………… 30
1、高泌乳素血症對陰莖組織的影響……………………… 30
2、睪丸內注射TNF-α抗體對陰莖組織的影響…………… 30
3、肌肉注射testosterone enanthate對陰莖組織的影響…… 30
4、睪丸內注射TNF-α抗體與肌肉注射testosterone enanthate 對血清睪固酮濃度的影響……………………………… 31
5、高泌乳素血症對雄鼠血清與陰莖TNF-α表現的影響… 31
四、討論………………………………………………………… 31
第五章、Etanercept對高泌乳素血症雄鼠睪固酮分泌的影響…… 45
一、緒言………………………………………………………… 45
二、材料與方法………………………………………………… 46
1、實驗動物………………………………………………… 46
2、高泌乳素血症動物模式………………………………… 46
3、動物實驗設計…………………………………………… 46
3.1睪丸內注射TNF-α抗體…………………………… 46
3.2睪丸內注射etanercept……………………………… 47
4、活體即時連續採血……………………………………… 47
5、睪丸間質細胞離體培養………………………………… 47
6、睪固酮之放射免疫測定………………………………… 48
7、統計分析………………………………………………… 49
三、結果………………………………………………………… 50
1、睪丸內注射TNF-α Ab與etanercept對hCG誘導的血清睪固酮濃度的影響………………………………………… 50
2、Etanercept對離體培養的睪丸間質細胞(1×10^5個細胞)睪固酮分泌的影響……………………………………… 50
四、討論………………………………………………………… 51
第六章、總結………………………………………………………… 61
參考文獻……………………………………………………………… 64
附錄…………………………………………………………………… 75
已發表之論文及相關代表作………………………………………… 75


圖目錄

圖3-1大鼠性行為模式示意圖……………………………………… 17
圖3-2性行為參數示意圖…………………………………………… 18
圖3-3 +CX與+AP大鼠血漿中泌乳素濃度………………………… 21
圖4-1陰莖組織微陣列石蠟包埋與切片染色情形………………… 29
圖4-2A睪丸內注射TNF-α Ab或肌肉注射TE後陰莖第一型膠原蛋白和第三型膠原蛋白的 picrosirius red染色結果顯微照片… 35
圖4-2B睪丸內注射TNF-α Ab或肌肉注射TE 後陰莖第三型/第一型膠原蛋白比例………………………………………………… 36
圖4-3A睪丸內注射TNF-α Ab或肌肉注射TE後陰莖大鼠陰莖海綿體平滑肌含量………………………………………………… 37
圖4-3B睪丸內注射TNF-α Ab或肌肉注射TE後平滑肌含量作為陰莖海綿體的百分比…………………………………………… 38
圖4-4A睪丸內注射TNF-α Ab或肌肉注射TE 後大鼠陰莖背神經中nNOS的表現………………………………………………… 39
圖4-4B睪丸內注射TNF-α Ab或肌肉注射TE後nNOS表現在陰莖背神經區域的百分比………………………………………… 40
圖4-5睪丸內注射TNF-α Ab或肌肉注射TE的大鼠血清中睪固酮濃度的變化……………………………………………………… 41
圖4-6 TNF-α在陰莖海綿體中的表現……………………………… 42
圖4-7 +CX與+AP大鼠血漿中TNF-α濃度………………………… 43
圖4-8陰莖海綿體巨噬細胞中ED1表現…………………………… 44
圖5-1A睪丸內注射TNF-α Ab在+ CX和+ AP大鼠對hCG誘導的血清睪固酮濃度的影響 ………………………………………… 54
圖 5-1B、睪丸內注射TNF-α Ab在+ CX和+ AP大鼠對hCG誘導的血清睪固酮濃度的影響之曲線下面積。…………………… 55
圖5-2A睪丸內注射etanercept在+ CX和+ AP大鼠對hCG誘導的血清睪固酮濃度的影響………………………………………… 56
圖 5-2B、睪丸內注射etanercept在+ CX和+ AP大鼠對hCG誘導的血清睪固酮濃度的影響之曲線下面積……………………… 57
圖5-3 Etanercept對離體培養的睪丸間質細胞(1×10^5個細胞)睪固酮分泌的影響………………………………………………… 58
圖5-4 Etanercept對離體培養的睪丸間質細胞(1×10^5個細胞)之hCG刺激睪固酮分泌的影響 ………………………………… 59
圖5-5 TNF-α拮抗劑etanercept能夠恢復睪丸萊氏細胞釋放睪固酮的假設機制……………………………………………………… 60


表目錄

表3-1+CX與+AP大鼠交配行為參數表…………………………… 22
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