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有效针对新冠肺炎的“炎症风暴”——Omega-3多不饱和脂肪酸(亚麻籽油中含有不饱和脂肪酸高达50%以上)

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      新冠肺炎“炎症风暴”是近期公众关注的诸多热点话题之一;所谓“炎症风暴”即全身炎症反应综合征(SIRS),人体的炎症因子,不仅可以杀掉病毒,也会给自身造成损害,某些新冠患者后期可能突然启动了一个“炎症风暴”,结果导致各个器官的功能衰竭。那么应该如何应对“炎症风暴”呢?中南大学湘雅医学院林韶辉博士撰文“有效针对新冠肺炎的“炎症风暴”——Omega-3多不饱和脂肪酸”,表达了自己的一些观点,或许会给大家一些思考和启发。


一、新冠肺炎专家说

1. 武汉金银潭医院:上海中山医院重症医学科副主任钟鸣医生(2020年1月24到达武汉),2020年2月3日,南方人物周刊对钟医生进行独家专访,提到救治初期,所面临的困难之中,有的新冠患者后期可能突然启动了一个“炎症风暴”,这种炎症风暴导致了各个器官的功能衰竭,一旦进入这个状态,我们的治疗很难把它拉回来。


2. 武汉大学中南医院:《美国医学会杂志》2月7日在线发布了武汉大学中南医院重症监护室(ICU)主任彭志勇博士领衔的一项回顾性分析,研究团队认为,新冠肺炎致死的三大主要机制:


中性粒细胞增多,与细胞因子风暴有关;

D-二聚体升高反映凝血激活,提示持续的炎症反应;

血尿素升高提示急性肾损伤,这是感染、休克和缺氧的综合结果。


3. 种种迹象表明,这些重症患者中发生了不可逆转的“炎症风暴”。而一旦患者发生“炎症风暴”,糖皮质激素是对抗炎症风暴的武器之一,可以给免疫系统“灭火”,减轻机体损伤。不过,糖皮质激素是一把“双刃剑”。一方面它可以减轻炎症反应,有利于改善缺氧、呼吸窘迫症状;但长期大剂量使用也可能引发诸多不良反应。不少经过大剂量激素治疗的“非典”患者,都留下了如股骨头坏死等严重后遗症。


二、“炎症风暴”与Omega-3多不饱和脂肪酸

1. 炎症反应的发生:免疫应激保护
过度炎症反应是ICU患者常见并发症的主要诱因。促炎反应与抗炎反应的平衡状态,对机体全身性免疫反应发生与否发挥重大作[1]应激状态下,炎性细胞如巨噬细胞、单核细胞、成纤维细胞和内皮细胞活化,释放促炎性细胞因子、血栓素A2、白三烯、血小板活化因子及氧自由基等炎症介[2]炎性细胞因子和炎性介质一方面杀伤局部细胞和组织,另一方面刺激组织修复愈合。炎症反应是一把“双刃剑”,需要抗炎介质与促炎介质在不同的环节上相互作用、相互拮抗,形成复杂的炎症调控网[3]
2. 炎症反应的失控:过度炎症反应(抗炎-促炎代谢失衡)会导致全身性炎症反应综合征
如果抗炎性介质分泌和释放不足,炎症反应诱因持续强化,超出身体的代偿能力,导致促炎性反应调节失控,促炎-抗炎平衡失[4],促炎介质占主导地[5],从而出现过度炎症反应。大量促炎介质突破了局部的自限制作用,渗入血浆分布到身体其它部位。重要脏器的上皮细胞和血管内皮细胞,可识别受损组织的炎症信号, 启动内源性报警信号相关的免疫反应, 进而引发全身性炎症反应,最终导致全身多个器官出现功能性障碍,如急性肺损伤、多器官功能障碍综合症,甚至功能衰[6-8]

3. Omega-3 PUFA对抗炎症反应的作用机制

3.1 炎症与脂肪酸代谢的关系
脂肪酸的代谢衍生物参与细胞代谢调控,和炎症过程密不可分,图1显示的是不同脂肪酸的代谢途径。
花生四烯酸(AA)是一种Omega 6 PUFA,代谢产生花生酸类(eicosanoids),花生四烯酸类脂质经一系列酶催化,产生促炎症调节作用的前列腺素(PGE2)和白三烯B4等。这些促炎性介质进而可激活中性粒细胞、巨噬细胞,刺激炎症细胞因子TNF-α、IL-1、IL-2、IL-8、干扰素(Interferon, IFN )等释放增多。
另一类 PUFA同样经酶催化产生如消散素(resolvins)和保护素(protectins),刺激中性粒细胞和巨噬细胞等分泌产生抗炎性细胞因子IL-4、IL-10、IL-13等,来减弱炎症反应,调节机体炎症水[9, 10]


图1. 长链不饱和脂肪酸代谢示意图



4. 多种文献证明,为了减少患者还可能发生爆发性炎症反应,使用高纯度的  Omega-3 PUFA制剂,可以减低炎症风暴的发生风险。具体表现

4.1 Omega-3 PUFA富集于细胞膜,参与炎症反应调控过程,减少炎性细胞产生促炎性细胞因子;

Omega-3 PUFA富集于细胞膜,提高细胞膜EPA和DHA脂肪酸的比[11, 12],影响胞内信号传导,抑制炎症相关的转录因子NF-kappa B的转录活[13, 14],从而减少促炎性细胞因子TNF-alphaIL-6 和IL-8等的表[15]

4.2 Omega-3 PUFA竞争性抑制花生四烯酸代谢产生的促炎性介质;

花生四烯酸类脂质经一系列酶催化产生促炎症调节作用的前列腺素(PGE2)和白三烯B4等。这些促炎性介质进而可激活中性粒细胞、巨噬细胞,刺激炎症细胞因子TNF-α、IL-1、IL-2、IL-8和干扰素(Interferon, IFN)等释放增多。Omega-3和Omega-6两类 PUFA竞争相同的脂肪酸代谢酶(Elovl5和FADS2)系[16-18],从而干扰促炎性介质的生成。

4.3 Omega-3 PUFA代谢生成具有消炎、止痛等生理活性的衍生物;

EPA和DHA经代谢产生消散素(Resolvins)和保护素(Protections)。实验研究证实,消散素和保护素在关节[19]、结肠[20]、哮[21, 22]等多种炎性疾病中发挥重要的抗炎作[23, 24] 。例如,resolvin E1,resolvin D1和protectin D1能抑制浸润性中性粒细胞的细胞迁移,从而减轻局部炎[24]。此外,resolvin D1和protectin D1还能抑制TNF-α and IL-1β的产生,从而减弱炎症反[25, 26]

因此,Omega-3 PUFA能在各个层面调节炎症反应,缓解全身性炎症反应综合征的发生,从而为重症疾患病人带来临床获益。

5. Omega-3 PUFA缓解炎症的具体临床获益

5.1 C反应蛋白等炎症指标显著下降,血红蛋白和白细胞、血小板等细胞类群总量显著上升。

德国汉诺威医院一项面向重症创伤病人的前瞻性、随机、双盲、对照试[27] 证实,ICU监护期间开始使用含大约4克Omega-3 PUFA的营养液,可以显著降低患者的CRP水平。另一项针对脓血症儿童的前瞻性,随机,双盲,对照试[28]发现,补充Omega-3 PUFA显著降低患者CRP、ESR、IL-6和白蛋白等炎性指标的含量,还能明显增加血红蛋白含量和白细胞、血小板等细胞类群的细胞数量,从而缩短患者的ICU监护时间。


表1. ICU患者使用Omega-3 PUFA带来的生理指标和临床指标获益



5.2 败血症状明显下降,治疗用抗生素使用时间缩短,全身炎症反应综合征减少,器官功能障碍后遗症发生率减少,死亡率下降;

美国田纳西大学附属医院和西班牙多所医院的临床研究表明,对于重症创伤患者和脓毒症患者等ICU患者,每天1~3克Omega-3 PUFA营养液可以有效降低菌血症、败血症并发症发生(下降14%[29]~35%[30]),明显降低治疗用抗生素使用时间和腹腔内脓肿发生率[30]。而使用更高Omega-3 PUFA含量(4克以上)的营养液后,创伤病人全身炎症反应综合征发生人数显著下[27];脓毒症、败血症患者的器官功能障碍发生率减少达到43%[31],死亡率显著下降13.1%[29]~19.4%[31]



表2. 创伤患者和败血症患者使用Omega-3 PUFA的临床获益



5.3 改善氧合状态,减少呼吸机使用,缩短ICU监护时间;

如表3所示,不同疾患类型的ICU患者补充Omega-3 PUFA,均能起到尽早脱离机械呼吸,缩短ICU监护时间的临床效果。


表3. 不同疾患类型的ICU患者补充Omega-3 PUFA对呼吸机使用时间和ICU监护时间的影响


6. 推荐急性炎症患者使用Omega-3 PUFA的特点
6.1 补充剂量和时间充分,保证对抗炎症的。

6.2 生物利用度高,保证体内有效富集。

6.3 添加中链甘油三酯(MCTs),促进Omega-3 PUFA快速细胞富集,为重症患者的症状缓解赢得时间。添加MCT的Omega-3脂肪乳的体内富集时间更短(术后第六天即检测到病患血清磷脂和红细胞细胞膜中的EPA和DHA显著升高[35],激发免疫更强(第六天起外周血细胞释放的白三烯B5含量已增长约2倍)[36]; 

三、总结
炎症反应的发展和体内脂肪酸代谢的关系密不可分。Omega-3 PUFA富集于细胞膜,参与炎症反应调控过程,减少炎性细胞产生促炎性细胞因子,竞争性降低炎性介质的生成,调节免疫反[34, 37],从而缓解过度炎症反[38],有效缩减患者的ICU监护时间,减少全身性炎症反应患者的感染率和死亡[29, 39-41]。欧洲肠外肠内营养学会和美国肠内肠外营养学会一致推荐,手术患者、危重患者应及早补充Omega-3 PUFA肠内营养液。

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