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研究生:莊喬琳
研究生(外文):Chiao-Lin Chuang
論文名稱:門脈高壓大鼠腎臟血管反應性變化的研究
論文名稱(外文):Investigations of renal vascular reactivity in portal hypertensive rats
指導教授:吳肇卿李發耀李發耀引用關係
指導教授(外文):Jaw-Ching WuFa-Yauh Lee
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
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:2014
畢業學年度:103
語文別:英文
論文頁數:80
中文關鍵詞:內皮素腎臟脂多醣一氧化氮門脈高壓
外文關鍵詞:Endothelin-1KidneyLipopolysaccharideNitric oxidePortal hypertension
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肝硬化是臺灣常見的慢性病,急性寡尿性腎衰竭(肝腎症候群, HRS)則是末期肝硬化常見的致命併發症,目前仍然缺乏有效的治療。儘管肝硬化與門脈高壓的動物模式及相關研究已經十分成熟,併發急性腎臟損傷的詳細機制卻仍然不明,相關之預防與治療的研究當然更無法進展,主要關鍵在於缺乏理想的研究動物模式能模擬此一致命疾病的複雜面貌。
過去的臨床觀察結果顯示,嚴重肝硬化併發急性腎臟損傷的病患通常僅有腎功能異常的表現,卻沒有腎臟組織損傷的現象,因此,其腎臟可以捐贈並成功移植於尿毒病患身上;另一方面,一旦患者成功接受肝臟移植治療,腎功能異常也會復原。數十年來,肝腎症候群廣被醫學界接受的病生理機轉是肝硬化造成全身血管擴張、全身血管阻力減少、及平均動脈壓下降,使血管內有效血容量不足後,刺激內生性血管收縮劑分泌,使腎臟血管代償性收縮,導致腎臟血流不足及腎功能異常。然而,近年來的許多研究結果卻顯示,門脈高壓以及代償性肝硬化大白鼠的腎臟灌流壓低於正常鼠,且腎臟血管對血管收縮劑的反應性不佳(意即血管擴張)。為了解釋在肝硬化疾病進展過程中,腎臟血管先擴張而後嚴重收縮的變化原因,雙重打擊假說(2-hit hypothesis)應運而生並成為最合理的理論。也就是門脈高壓或肝硬化都只是背景因子(first hit),病患雖然會因為一氧化氮(nitric oxide, NO)的製造增加造成全身血管擴張使血管內有效血容量不足,但其心、腎仍然能藉著增加心跳及鹽份、水份的回收來提昇心輸出量以代償;一旦併發其它惡化因子,如利尿劑過度使用、大量放腹水、腸胃道出血、心肌病變、或自發性腹膜炎等“second hit”,血管內有效血容量不足的情形超越身體的調節及代償能力時,身體製造的內生性血管收縮劑將使腎臟血管嚴重收縮,腎臟將因灌流不足而導致功能衰竭。在“2-hit”假說內容中,門脈高壓以及代償性肝硬化的腎臟血管擴張現象已經由許多人體及動物實驗證實,然而,從門脈高壓或代償性肝硬化進展至失償性肝硬化的腎臟血管反應性變化及相關機制仍有待探討。
利用部份門靜脈結紮(partial portal vein ligation, PVL)誘導大白鼠產生門脈高壓狀態,是一種廣被接受的門脈高壓研究動物模式;而離體腎臟灌流模式(isolated perfused kidney model)則廣泛被用於腎臟病生理及藥理學動物研究,結合這兩種已經十分成熟的研究動物模式,進行門脈高壓大白鼠的腎臟血管反應性研究,希望可以對肝病患者的急性腎臟損傷機制有進一步的了解。實驗設計首先嘗試在部份門靜脈結紮的門脈高壓大白鼠執行準確而穩定的離體腎臟灌流實驗,建立一系列血流動力學的資料庫,證實在手術七天後,門脈高壓大白鼠的腎臟血管擴張且對內皮素(endothelin-1, ET-1)的反應性也變差,腎動脈的內皮型一氧化氮合成酶(endothelial nitric oxide synthase, eNOS)的表現增加可能扮演關鍵性角色。其次,再將門脈高壓大白鼠腹腔內注射內毒素(lipopolysaccharide, LPS)來模擬“2-hit”假說中的“second hit”(腹膜炎),這是失償性肝硬化患者常見的臨床情境。結果證實大白鼠在細菌感染時,血中內皮素分泌量會顯著增加,相異於正常大白鼠在細菌感染時的腎臟血管反應性下降(腎臟血管擴張),門脈高壓大白鼠在細菌感染時,原先對血管收縮劑反應不佳的腎臟血管對內皮素的反應性卻顯著增強(腎臟血管強烈收縮),且腎臟組織中第一型內皮素接受器(endothelin receptor type A, ETA)的表現增加,這可能是失償性肝硬化患者併發腎功能異常的重要機制。
這些實驗結果顯示門脈高壓大白鼠面對細菌感染時,腎臟血管反應性及腎功能變化的可能病生理機轉,有助於印證“2-hit”假說內容中,隨著肝病患者疾病嚴重度的進展,腎臟血管先擴張而後嚴重收縮的變化,同時,可作為肝腎症候群研究的試金石,可藉此進一步找尋具有潛力的治療藥物。

Liver cirrhosis is a common disease in Taiwan, which may lead to a severe complication of oliguric acute renal failure, so called “hepatorenal syndrome” (HRS), without effective treatment. Although a great advance in the researches of portal hypertension and liver cirrhosis has been achieved with highly reproducible animal models, the mechanisms leading to altered renal blood flow and renal dysfunction in advanced liver cirrhosis are not entirely clear yet. The critical impediment lies mainly in the paucity of an ideal animal model to correctly mimic human disease and fulfill these complex manifestations of HRS.
Usually, acute kidney injury secondary to liver dysfunction occurred in the absence of significant alterations in renal histology. The functional nature of renal dysfunction in advanced liver disease was confirmed by the successful transplantation of cadaveric kidneys from patients with HRS as well as the normalization of renal dysfunction after liver transplantation. For decades, traditional consensus defined the HRS as hypo-perfusion of the kidneys resulting from combined intense renal vasoconstriction and decreased renal blood flow in response to generalized systemic arterial vasodilatation. However, cumulative studies demonstrated that the renal vasculature of portal hypertensive and compensated cirrhotic rats had lower perfusion pressure and hypo-responsiveness to endogenous vasoconstrictors, implying renal vasodilatation. In order to illustrate the evolution of renal vascular reactivity during disease progression of liver cirrhosis, the “2-hit” hypothesis seems to be the best accepted theory. Usually, the liver dysfunction appears to be an important background factor or “first hit” when the vasodilatation related hypovolemia can be compensated by the development of hyperdynamic circulation, such as increased heart rate, avid renal sodium and water retention, and higher cardiac output. Once the auto-regulatory mechanisms are overwhelmed by the precipitating event or “second hit”, extreme effective arterial underfilling will initiate extreme intra-renal vasoconstriction and subsequent renal impairment. Such events may include the overzealous use of diuretics, large volume paracentesis, gastrointestinal bleeding, cardiomyopathy, or development of spontaneous bacterial peritonitis in ascitic patients.
Partial portal vein ligation (PVL) rat is a well-established and reproducible animal model for studies in the field of portal hypertension. For decades, the isolated perfused kidney model has been established as a valid tool for the investigations of renal physiology and pathophysiology. The combination of both mature animal models might enable us to explore the potential mechanisms of renal dysfunction in advanced liver cirrhosis. At first, the technique of isolated kidney perfusion was established and successfully demonstrated poor renal vascular responsiveness to endothelin-1 (ET-1) in the PVL rats since the 7th post-operative day. Up-regulated endothelial nitric oxide synthase (eNOS) of renal arteries may play the major role in modulating the renal vascular hypo-reactivity of PVL rats. Furthermore, endotoxemia was, a common complication of cirrhotic patients, induced by intra-peritoneal injection of lipopolysaccharide (LPS) in the PVL rats to mimic the clinical condition of “2-hit” hypothesis. There was significantly higher serum level of ET-1 developed at 5 hours following LPS injection in both SHAM and PVL rats. In contrast with vascular hypo-reactivity and down-regulated renal endothelin receptor type A (ETA) in the LPS-injected SHAM rats, LPS-injected PVL rats demonstrated significantly increased renal vascular responsiveness to ET-1 and up-regulated renal ETA expression, which might contribute to the pathogenesis of renal dysfunction in portal hypertensive patients during endotoxemia.
These findings may help improve our understanding of the pathophysiology of renal dysfunction in advanced liver cirrhosis and lead to the development of useful therapeutic strategies.

CONTENTS

page
English Abstract 1
Chinese Abstract 3
List of Abbreviations 5
Introduction 7
Materials and Methods 17
Result 27
Discussion 33
Conclusion 42
Perspectives 44
References 46
Figures and Tables 59
Publications 80


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