基于鸟枪法脂质组学研究环氧酶-2抑制剂对关节炎模型血清脂代谢的干预作用

摘要

Rheumatoid arthritis( RA)is an inflammatory disease leading to joint swollen,pain and even deformity. Cardiovascular disease( CVD)is regarded as a major cause of morbidity in patients. Chronic systemic inflammation in patients is an independent CVD risk factor. Cycloox-ygenase-2( COX-2)inhibitor,a commonly used drug in the treatment of RA,can increase the risk of CVD. Lipid metabolic disorder is highly correlated with the occurrence of CVD,thus we investigated the serum lipid changes caused by RA and drug treatment to help to elucidate the mechanism of CVD in RA. Collagen-induced arthritis( CIA)is employed as a model of RA. After modeling,COX-2 inhibitor-meloxicam was orally administrated for three weeks,and the serum lipid profiles were analyzed by the multi-dimensional mass spectrometry-based shotgun lipido-mics(MDMS-SL). Totally 105 lipids were detected in serum,including 35 phosphatidylcholines ( PCs),18 lysophosphatidylcholines( LysoPCs),15 phosphatidyl inositols( PIs),3 phosphati-dyl glycerols( PGs),19 sphingomyelins( SMs)and 15 ceramides( Cers). In the principle com-ponent analysis,it was observed that the lipid profiles of CIA model rats were very different from those of the control rats,and the COX-2 inhibitor can improve the lipid metabolism partly. Further,ANOVA analysis revealed that 39 of the 105 identified lipids were up-regulated in CIA rats,including 7 PIs,15 SMs,5 Cers,10 PCs and 2 LysoPCs. Most of these lipids were down-regulated under the treatment of COX-2 inhibitor. In addition,the five PCs and one LysoPC were abnormally regulated by the drug. The MDMS-SL discovered lipid disturbance in CIA mod-el rats that might be related to risk factors of atherosclerosis;the COX-2 inhibitor can greatly repair the lipid disorder caused by modeling,while induce abnormal changes of some PCs and LysoPC which may cause side-effect.%心血管疾病（ CVD）是类风湿关节炎（ RA）患者死亡的重要原因之一，脂代谢紊乱与 CVD 发生有密切关联，因而有必要对 RA和药物治疗导致的脂代谢改变进行探讨。该研究采用胶原诱导法（ CIA）构建关节炎模型，引入多维质谱鸟枪法开展血清脂质分析，检测了血清中105种脂质分子，发现模型大鼠体内7种磷脂酰肌醇、15种鞘磷脂、5种神经酰胺、10种磷脂酰胆碱和2种溶血磷脂酰胆碱异常上调，环氧酶-2（ COX-2）抑制剂可部分修复紊乱的脂代谢，但对5种磷脂酰胆碱和1种溶血磷脂酰胆碱具有异常调控作用。该研究从脂质分子水平探讨了 RA 及COX-2抑制剂对脂代谢的干预作用，可以为 RA的心血管风险研究提供信息。