探討脂多醣誘導的全身性炎症對於新生仔鼠暴露於高氧環境下的影響

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題名:	探討脂多醣誘導的全身性炎症對於新生仔鼠暴露於高氧環境下的影響 Effect of Lipopolysaccharide-induced Systemic Inflammation on Hyperoxia-exposed Newborn Rats
作者:	吳姿瑩 Wu, Tzu-Ying
關鍵詞:	高氧;脂多醣;高糖化終產物受體;Rho 激酶;大鼠;Hyperoxia;Lipopolysaccharide;RAGE;Rho kinase;Rat
日期:	2012-07-11
上傳時間:	2018-11-09 14:29:52 (UTC+8)
摘要:	支氣管肺發育不全 (bronchopulmonary dysplasia，BPD)是新生嬰兒在出生時由於呼吸窘迫，使用過高濃度氧氣和正壓呼吸器治療所產生的一種慢性肺疾病，它是造成童年和青年期罹病率和死亡率增加的主要原因，然而目前並無有效的治療方法。因此替支氣管肺發育不全的病童探索新的治療對策是很重要的，肺部發炎在支氣管肺發育不全複雜的發病機轉為一個中心決策角色，全身性炎症(systemic inflammation)會增加支氣管肺發育不全發生的風險;在流行病學研究顯示，全身性炎症和BPD病程發展有很強的關聯性，也指出全身性炎症是BPD的危險因子；腹腔注射脂多醣 (lipopolysaccharide，LPS)和產後暴露於高氧導致肺纖維化，此變化類似於支氣管肺發育不全，然而，全身性炎症和高氧導致肺損傷的機轉目前並不清楚。Rho kinase (ROCK) 是一種GTP結合蛋白，其會促進平滑肌收縮、細胞的貼附和移行，也與細胞的有絲分裂和基因表現有關；文獻指出，ROCK 也調控嗜中性白血球產生活性氧屬且其與血管內皮細胞異常增生和高血壓有關。高度糖化終產物受體 (receptor for advanced glycation end products， RAGE) 是屬於免疫蛋白球家族的一員，它在糖尿病、老人痴呆症及癌症上扮演重要的角色。RAGE與大部分組織的病程發展有關，其異構物可溶性RAGE (sRAGE)，則做為一誘導受體 (decoy receptor)的作用。過去的研究中指出，在發炎及氧化壓力下，TNFα會刺激細胞中活性氧屬的產生而影響到RAGE的表現。為了要探討全身性發炎和高氧所造成急性肺傷害的機轉，我們利用Sprague-Dawley (SD)母鼠，在其懷孕的第20天及21天以腹腔注射LPS誘導全身性發炎，在新生鼠出生後給予95%濃度的氧氣一週接著再給予60%濃度氧氣兩週後進行研究。實驗結果顯示，由LPS誘導全身性發炎會惡化在高氧環境下的新生鼠肺部組織，進而導致肺組織中膠原蛋白的生合成增加，是透過RAGE和Rho kinase的路徑。本論文期望可提供臨床上開發對於BPD新生兒治療的新方向，並進一步降低需要高氧或因感染而造成的肺臟傷害。 Bronchopulmonary dysplasia (BPD) is a chronic lung disease that develops in newborn infants treated with oxygen and positive pressure ventilation for respiratory distress at birth. BPD remains a major cause of morbidity and mortality throughout childhood and young adulthood. No effective therapy was established to improve BPD. Pulmonary inflammation has a central role in the multifactorial and complex pathogenesis of BPD. Systemic inflammation is associated with an increased risk of bronchopulmonary dysplasia. Epidemiological data suggest a strong association between systemic inflammation and the development of BPD, which indicates a systemic inflammatory response, are independent risk factors of BPD. Intraperitoneal lipopolysaccharide injection and postnatal hyperoxia exposure result in lung fibrosis that is similar to BPD. However, the mechanisms by which systemic inflammation and hyperoxia mediates these effects are not clear. Rho-kinase is a GTP-binding protein which is involved in smooth muscle contraction, cell adhesion and migration, cytokinesis and gene expression. Rho-kinase also regulates the production of reactive oxygen species (ROS) in neutrophils and it is linked to vascular proliferative disorders and hypertension. The receptor for advanced glycation end products (RAGE) belongs to the immunoglobulin superfamily and it has been implicated in the pathology of various disorders, including diabetic atherosclerosis, tumors and inflammation. RAGE is associated with pathology in most tissues, while its soluble form (sRAGE) acts as a decoy receptor. Previous study has showed that inflammation and oxidative stress can regulate RAGE expression through ROS formed as a result of TNFalpha stimulation. In order to study the mechanism of systemic inflammation and hyperoxia –induced acute lung injury, lipopolysaccharide (LPS) or normal saline was injected into the peritoneum of pregnant rats at 20 and 21 d gestation . After birth, rats were exposed to 95% oxygen or room air for 1wk and 60% oxygen or room air for next 2wk. The lung tissue was evaluated the expression of Rho-kinase and RAGE in the pathogenesis of lung injury in newborn rats. These data suggest systemic inflammation enhances the hyperoxia-induced lung fibrosis in newborn rats through RAGE-ROCK axis. This study will provide a novel strategy for BPD therapy and prevent lung injury from hyperoxia and inflammation.
描述:	碩士委員-黃昭蓮委員-林俊茂指導教授-汪棱芳
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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