【作者】 李蕙蕙；

【导师】 王玉兰； 唐惠儒；

【作者基本信息】 中国科学院研究生院（武汉物理与数学研究所） ， 分析化学， 2014， 博士

【摘要】 炎症是具有血管系统的活体组织对各种损伤因子刺激所发生的以防御反应为主的基本病理过程。它常常表现为红、肿、热、痛和功能障碍。通常情况下,作为机体防御反应的炎症是有益的；但是如果炎症反应没有及时终止而发展成慢性低度状态时,可能导致机体过度应激和组织损伤,从而引发一系列重大疾病。为深入了解炎症疾病机制,本论文采用角叉胶诱导的大鼠胸膜炎模型并给予了塞来昔布治疗,运用基于NMR的代谢组学方法和基于GC-FID的脂肪酸检测方法,动态研究了炎症急性期和恢复期大鼠血浆及各组织器官的代谢应答。主要内容包括以下两个方面。首先,本论文动态分析了胸膜炎过程中大鼠的胸腺、血、肝脏和附睾脂肪组织的代谢变化。研究发现,胸膜炎急性期时不仅产生大量的胸腔积液等病理改变,而且还引起大鼠全身系统性的代谢变化。此时,脂类变化异常剧烈：附睾脂肪分解增强；肝脏中脂肪p-氧化及酮体生成被激活；血浆中n6/n3脂肪酸比例显著升高且脂蛋白出现扰动。急性期时除脂类代谢变化之外,炎症还引起以下的代谢通路的改变：脂肪组织及血浆中三羧酸循环增强,血浆及肝脏中出现急性期蛋白和氨基酸扰动,肝脏及附睾脂肪组织中核苷酸代谢受到影响。胸膜炎恢复期时,结合炎症的理化指标与大鼠胸腺、血浆的代谢组和脂肪酸数据,我们发现此时炎症大鼠表现出显著的个体差异。恢复不佳的大鼠部分仍含有胸腔积液、胸腺肿大且脾脏重量较轻；而恢复良好的亚组在胸腺脂类代谢、糖代谢、胆碱、牛磺酸及核酸通路上有所缓解。另外此时附睾脂肪组织的脂肪酸含量上升出现逆转,此时机体以脂类合成为主。其次,本论文研究了塞来昔布干预后,大鼠胸腺、附睾脂肪、血浆和肝脏的代谢组变化。我们发现在炎症恢复期时,塞来昔布能显著改善恢复不佳大鼠的胸腺代谢状况；但对正常大鼠给药塞来昔布会引起胸腺小叶间隔区中性粒细胞聚集,上调氨基酸和胆碱的含量,激活核酸分解通路,塞来昔布可能对胸腺有一定的损伤作用。不论是在炎症基础上给药,还是对正常大鼠给药,塞来昔布都能显著上调附睾脂肪组织中脂肪酸含量。附睾脂肪中上调的脂肪酸不仅包括饱和脂肪酸和单不饱和脂肪酸,也包括n3和n6系列的多不饱和脂肪酸。综上所述,本论文研究了角叉胶诱导的胸膜炎及塞来昔布给药后体液及多器官的代谢变化。这些结果有助于我们深入理解炎症疾病的机制,为疾病的个体化治疗提供参考；同时这些研究有助于深入了解塞来昔布药物的作用机制及其毒副作用。更多还原

【Abstract】 Inflammation is a part of the complex biological response of vascular tissues to harmful stimuli. The classical signs of acute inflammation are pain, heat, redness, swelling, and loss of function. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. But in some instances when inflammation occurred in an uncontrolled or inappropriate manner and proceeded to a low grade and chronic state, it always associates with metabolic disorders, cardiovascular disease or even cancer. For these reasons, we employed the NMR based metabonomics approaches and GC-based fatty acid analysis to study rat metabonome responses to pleurisy induced by carrageenan and celecoxib treatment.First, the dynamic metabolic changes in rat thymus, plasma, epididymal adipose and liver in response to carrageenan induced pleurisy were investigated. The results showed that the inflammation in acute phase not only produced approximately4.6mL pleurisy exudates in local site, but also elicited system metabolic alterations involving dramatically lipid metabolism. The epididymal adipose lipolysis activated drastically while hepatic fatty acid β-oxidation was enhanced. And the ratio of n6/n3also increased in plasma. Besides the change of lipid, many metabolic pathways also altered including disrupted amino acid and the production of acute phase protein in liver and plasma, perturbed TCA cycles in adipose tissure and plasma, disordered nucleotide metabolism in adipose and liver. In inflammatory resolution phase, the great individual differences in thymus and plasma were confirmed by NMR date, GC data and physicochemical index of inflammation. Poor recovered rats had more pleurisy exudates and swollen thymus while well recovered subgroup basically restored in lipid metabolism, carbohydrate metabolism and amino acid metabolism and partly relief in choline metabolism, taurine metabolism and nucleic acid metabolism. In addition, the fatty acids in adipose and plasma shifted into reverse. Compareing with the decoposition in acute phase, in resolution phase the fatty acid in epididymal adipose increased.Second, the metabolic changes in response to celecoxib treatement were detected. The results showed that wether administrated to inflammatory rats or normal rats, celecoxib could up regulate the fatty acids in epididymal adipose. The up regulated fatty acids not only included saturated fatty acids, but also included monounsaturated fatty acids, n3polyunsaturated fattyacids and n6polyunsaturated fatty acids. What is more, celecoxib might do harm to thymus.On one hand, the histopathology assessments showed the thymus of celecoxib administrated induced polymorphonuclear neutrophil accumulation. On the other hand celecoxib could elicit metabolic disorder including amino acid pathway, nucleotide pathway and choline pathway. In conclusion, this thesis studies on the matabonomics changes in carrageenan induced pleurity and celecoxib treatement. The results provided metabonimics information to enhance our understanding of the inflammtion mechanism, celecoxib’s safty and its work mechanism.更多还原