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研究生:張正誼
研究生(外文):Cheng-Yi Chang
論文名稱:厚朴酚改善大鼠肺動脈高壓之療效
論文名稱(外文):Protective effect of magnolol on pulmonary arterial hypertension in rats
指導教授:張宏張宏引用關係周志中
指導教授(外文):Hung ChangTz - Chong Chou
口試委員:吳清平
口試委員(外文):Chin-Pyng Wu
口試日期:2014-05-23
學位類別:碩士
校院名稱:國防醫學院
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:2013
畢業學年度:102
語文別:中文
論文頁數:88
中文關鍵詞:肺高壓厚朴酚
外文關鍵詞:pulmonary arterial hypertensionmagnolol
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Pulmonary Arterial Hypertension(PAH)肺動脈高壓是一種慢性肺部疾病,其發病機制目前並不明瞭,其特徵是肺動脈壓增高和右心室肥厚。當肺高壓發生時,血管內皮細胞功能失調刺激血管收縮因子Endothelin-1 (ET-1) 、Angiotensin II (Ang II)及肺部Renin-Angiotensin System (RAS) 相關蛋白反應量增加,在與接受器結合後,引發下游因子 PI3K / Akt 或MAPK / Erk訊息路徑,促使肺部血管平滑肌 (pulmonary arterial smooth muscle cells, PASMCs) 過度增生 (proliferation),造成肺血管重塑 (remodeling),並同時刺激肌漿網釋出鈣離子,使肺血管收縮,肺血管阻力逐漸增加,影響氣體交換功能,引發hypoxia進而導致病患死亡。近年研究已證實中藥厚朴酚 (magnolol) 不僅有抗氧化作用,也可抑制smooth muscle cells proliferation,促進血管放鬆及抑制發炎等功能,文獻指出利用magnolol透過抑制GSK3beta /beta-catenin,治療多種癌症可減輕腫瘤細胞proliferation 和減緩轉移情形。而Glycogen Synthase Kinase 3beta (GSK3beta) 參與許多信號傳導途徑的下游調節開關,GSK3beta在未發生磷酸化前,是有活性即有功能狀態,可使-catenin結合形成一複合體後發生磷酸化反應使之降解,GSK3beta受上游因子PI3K / Akt或MAPK / Erk訊息路徑所調控,誘發GSK3beta磷酸化反應,而GSK3beta在磷酸化後活性減低即失去功能,無法與beta-catenin結合亦無法使之降解,故beta-catenin進入細胞核,與T cell specific transcrfice factor (TCF) 結合,產生下游產物ET-1進行gene transcription繼而引發PASMCs proliferation。由野百合花鹼 (monocrotaline;MCT) 所誘發肺動脈高壓的大鼠GSK3beta/ pGSK3beta蛋白質表現也有增加情形。本實驗設計為肺葉切除後第7天皮下注射MCT (60 mg/kg),第8天投與magnolo (10 mg/kg) 腹腔注射,每隔兩天投與一次,在第35天將動物犧牲,結果得知magnolol對活性氧 (reactive oxygen species , ROS) 有抑制作用,並證實透過抑制GSK3beta/beta-catenin之作用機制,包括抑制ET-1、type A endothelin receptor (ETAR)、Erk、Akt、GSK3beta、beta-catenin蛋白表現量,及抑制b-catenin進入細胞核內,繼而減輕PASMCs proliferation。實驗也證實magnolol可抑制Angiotensin-converting enzyme (ACE)、Ang II、type 1 angiotensin II receptor (AT-1R) 蛋白質表現量,減輕血管收縮和proliferation情形。近年有許多文獻證實,透過增加Angiotensin-converting enzyme 2 (ACE2)、type 2 angiotensin II receptor (AT2R)反應,可使肺部血管收縮和舒張及prliferation和抗增生(anti-proliferation) 狀態回覆平衡,進而改善PAH。本實驗也證實ACE2和AT2R蛋白表現量有增加情形,促使血管擴張和抗增生(anti-proliferation) 反應,減輕PAH。
Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary resistance, abnormal vascular remodeling in pulmonary arteries (PAs), and right ventricular (RV) hypertrophy. Magnolol extracted from Chinese herb has an antioxidant and anti-inflammatory activity, and an inhibitory effect in endothelial cell proliferation. The aim of this study was to investigate whether magnolol alleviates the symptoms of pneumonectomy and monocrotaline ( PE + MCT ) - induced PAH in rats. The PAH model was established in rats injected with monocrotaline (60 mg/kg) at 7 day after pneumonectomy, and the rats randomly received a vehicle or various doses of magnolol intraperitoneally from Day 6 to Day 35 after pneumonectomy. The histological assay and related molecular studies were preformed. Magnolol significantly decreases pulmonary arterial pressure from 70 mmHg down to 30 mmHg. Treatment with magnolol of PAH rats reduced the RV weight / left ventricular (LV) + septum weight ratio accompanied by decreased pulmonary vascular medial thickness in PAH rats. In addition, the increased protein expression of ET-1、ETAR、Akt、Erk、Ang II and ACE、AT-1 and GSK3-catenin observed in rats with PAH was markedly attenuated by magnolol. We also explored the lungs ACE2, AT2R protein expression, in recent years many papers confirmed PAH occurs when increased ACE2 and AT2R reaction conditions can be improved. The mechanisms involved may be associated with down-regulation of ET-1 and Ang II-related processes. For ACE2, AT2R protein expression, but also by magnolol increase its protein expression. In conclusion, magnolol exerts a beneficial effect in PE + MCT induced PAH through inhibition of GSK 3 beta/beta-catenin in the mechanism and would increase the ACE2, AT2R protein expression, improve PAH.
目錄-----------------------------------------------------Ⅰ
圖目錄---------------------------------------------------Ⅱ
中文摘要-------------------------------------------------V
英文摘要-------------------------------------------------VII
英文縮寫對照表-------------------------------------------VIII
第一章 緒論-----------------------------------------------1
第二章 研究目的------------------------------------------17
第三章 材料與方法----------------------------------------18
第四章 實驗結果------------------------------------------29
第五章 討論----------------------------------------------41
第六章 結論----------------------------------------------46
圖次-----------------------------------------------------48
參考文獻-------------------------------------------------69







參考文獻

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