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研究生:陳建生
研究生(外文):Chien-Sheng Chen
論文名稱:抗發炎性藥物對內毒素誘發大白鼠急性肺損傷作用之探討
論文名稱(外文):The Effect of Anti-inflammatory Drugs on Endotoxin-induced Acute Lung Injury in Rats
指導教授:吳清平吳清平引用關係
指導教授(外文):Chin-Pyng Wu
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
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:2005
畢業學年度:93
語文別:中文
論文頁數:123
中文關鍵詞:急性肺損傷抗發炎內毒素
外文關鍵詞:Acute lung injuryAnti-inflammationEndotoxin
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中文摘要

急性肺損傷可被定義為一種發炎性及微血管通透性增加的症後群,其臨床表徵為頑固性缺氧血症、降低肺臟的順應性以及胸部X光片呈現兩側性肺浸潤。過去數十年的研究已證實,肺微血管通透性增加是反映肺臟內皮細胞損傷的指標。臨床上會導致急性肺損傷的原因很多,而格蘭氏陰性敗血症和細菌產生的內毒素被認為是產生這種致命性病變的主要因素。脂多醣(Lipopolysaccharide, LPS)是格蘭氏陰性細菌細胞壁的成分,藉由直接損傷內皮細胞以及間接活化發炎細胞、誘發細胞激素和產生細胞毒性物質,進而對肺臟產生毒害作用。儘管有各式各樣的治療策略,內毒素誘導急性肺損傷的死亡率仍然沒有改變,意指嚴重性肺發炎反應的治療方式需要加以改進。本論文主要在研究兩種抗發炎藥物,探討其在內毒素誘導急性肺損傷之作用。
首先,我們建立靜脈注射LPS和Zymosan誘發雄性SD大白鼠產生急性肺損傷的動物模式,並評估Thalidomide在此肺外因素誘導急性肺損傷是否具有保護功能。靜脈注射LPS和Zymosan會引起有意義之肺發炎反應,譬如增加肺組織中性白血球的聚集、血清和支氣管肺泡灌洗液一氧化氮濃度,以及顯著增加支氣管肺泡灌洗液中蛋白質濃度和LDH活性。肺微血管通透性的測定,是以Evans blue染料在肺組織中的含量來估算。倘若靜脈注射LPS和Zymosan後造成肺微血管通透性增加,此現象即是引起急性肺損傷的指標。大白鼠在靜脈注射LPS之前兩小時給予100 mg/kg之Thalidomide,會顯著減少肺部一氧化氮產量、肺微血管通透性、以及支氣管肺泡灌洗液中蛋白質濃度和LDH活性。因此,我們的結論是Thalidomide可以減輕大白鼠肺部發炎反應以及降低靜脈注射LPS和Zymosan後造成之急性肺損傷。
第二、我們研究氣管內給予霧化之LPS以誘發大白鼠急性肺損傷的時間流程,並評估Baicalin在這種動物模式的治療效應。Baicalin是一種類黃鹼素(flavonoid),由植物黃芩的的乾燥根所提煉出來的混和物,據研究報告顯示其擁有抗發炎特性及抗氧自由基作用。在氣管內給予霧化之LPS後30分鐘以皮下注射方式給予Baicalin 20 mg/kg,會有意義的減少肺組織中性白血球聚集、肺微血管通透性和支氣管肺泡灌洗液蛋白質濃度和LDH活性。總之,我們的實驗結果顯示,Baicalin在氣管內給予霧化之LPS誘發大白鼠急性肺損傷的動物模式提供一個有效的治療方式。
英文摘要

Acute lung injury (ALI) can be defined as a syndrome of inflammation and increased microvascular permeability. Clinically, it is characterized by refractory hypoxemia, reduced lung compliance, and the presence of diffuse pulmonary infiltrates on chest radiograph. Studies during the past decade have suggested that increased pulmonary microvascular permeability is a reflection of damage to the pulmonary endothelium. Several clinical conditions have been associated with the development of ALI, with gram-negative sepsis and endotoxin from bacteria being the most common. Lipopolysaccharide (LPS), being unique to the gram-negative bacteria, may produce its toxic effects to the lungs by direct injury to endothelial cells and indirect activation of inflammatory cells, cytokines as well as cytotoxic agents. Despite a variety of therapeutic strategies, the mortality from endotoxin-related ALI has not been changed, indicating that the management of fulminant lung inflammation needs to be improved. In the present study, we investigate the effects of two anti-inflammatory drugs on endotoxin-induced ALI.
First, we evaluated the effect of thalidomide, a chemical modulating both acute and chronic inflammation, on ALI induced by intravenous administration of LPS and zymosan in male Sprague-Dawley rats. Injection of rats with LPS and zymosan induced significant lung inflammation, as evidenced by increased neutrophil sequestration in lung tissue as well as enhanced nitric oxide metabolite production in the serum and bronchoalveolar lavage (BAL) fluid. Lactate dehydrogenase (LDH) activity and protein concentration in BAL fluid were significantly increased after administration of LPS and zymosan. Pulmonary microvascular permeability was determined by using the Evans blue retention method, which showed a significant increase in microvascular permeability after LPS and zymosan administration, indicating the development of ALI. Animals that received thalidomide (100 mg/kg) 2 h prior to LPS injection had significantly reduced pulmonary nitric oxide metabolite production, pulmonary microvascular permeability, and LDH activity and protein concentration in BAL fluid. We therefore conclude that thalidomide ameliorates lung inflammation and reduces ALI induced by combined LPS and zymosan administration in rats.
Second, we investigated the time course of the rat model of ALI induced by intratracheal aerosolization of LPS. In addition, we also evaluated the effect of baicalin on this animal model. Baicalin is a flavonoid compound purified from the root of Scutellaria baicalensis Georgi and has been reported to possess anti-inflammatory activity and antioxidant action. Posttreatment with baicalin (20mg/kg subcutaneously) significantly reduced neutrophil sequestration, pulmonary microvascular permeability, and protein concentration and LDH activity in the BAL fluid. In conclusion, our findings indicate that baicalin is an efficacious treatment in the rat model induced by intratracheal aerosolization of LPS.
正文目錄 頁次
第一章、緒論 ------------------------------------------------------- 1
第一節、急性肺損傷 -------------------------------------------------- 2
壹.定義 --------------------------------------------------- 2
貳.致病因素 ------------------------------------------------ 2
參.致病機轉 ------------------------------------------------ 3
肆.組織病理學----------------------------------------------- 5
伍.治療策略 ------------------------------------------------ 7
第二節、抗發炎性藥物與急性肺損傷之治療--------------------------------- 9
壹. Thalidomide之臨床應用---------------------------------- 10
貳. Baicalin之臨床應用------------------------------------- 12
第三節、研究目的---------------------------------------------------- 14
第二章、實驗材料與方法----------------------------------------------- 15
第一節、實驗動物 --------------------------------------------------- 16
第二節、肺外因素誘導急性肺損傷---------------------------------------- 16
壹.急性肺損傷動物模式建立------------------------------------ 16
貳.Thalidomide對於肺外因素誘導急性肺損傷之影響---------------- 17
第三節、肺內因素誘導急性肺損傷--------------------------------------- 18
壹.急性肺損傷動物模式建立----------------------------------- 18
貳.Thalidomide對於肺內因素誘導急性肺損傷之影響-----------------19
參.Baicalin對於肺內因素誘導急性肺損傷傷之影響----------------- 20
第四節、急性肺損傷指標測定------------------------------------------- 21
壹.濕乾肺重比測定------------------------------------------- 22
貳.Myeloperoxidase含量測定---------------------------------- 22
參.支氣管肺泡灌洗液分析-------------------------------------- 23
肆.一氧化氮濃度測定------------------------------------------ 23
伍.腫瘤壞死因子-α濃度測定------------------------------------24
陸.肺微血管通透性測定----------------------------------------24
柒.肺組織病理切片--------------------------------------------------- 25
第五節、儀器設備---------------------------------------------------- 27
第六節、材料及實驗藥物----------------------------------------------- 27
第七節、統計分析 --------------------------------------------------- 29
第三章、結果--------------------------------------------------------31
第四章、討論------------------------------------------------------- 50
第五章、結論------------------------------------------------------- 66
第六章、未來展望---------------------------------------------------- 68
第七章、參考文獻 -------------------------------------------------- 107
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