消退素D1对H1N1流感病毒FM1感染小鼠肺组织的保护作用及机制Protective Effect and Mechanism of Action of Resolvin D1 on the Lung Tissue of Mice Infected with H1N1 Influenza Virus FM1
丁凌,冷报浪,董洪英,王海燕
摘要(Abstract):
NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor pyrin domain-containing 3,NLRP3)炎症小体的激活在H1N1流感病毒感染引起肺组织损伤中起关键作用;消退素D1(Resolvin-D1,RvD1)是具有抗炎活性的脂质介质,在多种脏器损伤模型中通过抑制NLRP3炎症小体的激活减轻组织损伤及炎症反应。为了研究RvD1对H1N1感染小鼠肺组织的保护作用及机制,本研究以雄性C57BL/6小鼠为对象、通过H1N1/FM1病毒株滴鼻的方式进行H1N1感染的建模,给予RvD1腹腔注射、空白(Negative control, NC)慢病毒或NLRP3慢病毒尾静脉注射干预。检测肺指数,肺组织病理改变,肺组织中病毒载量及NLRP3、凋亡相关斑点样蛋白(Apoptosis-associated speck-like protein, ASC)、Cleaved caspase-1的表达水平,支气管肺泡灌洗液(Bronchoalveolar lavage fluid, BALF)中IL-1β、IL-18的含量。与对照组比较,模型组小鼠肺组织出现了肺泡结构损伤、炎症细胞浸润等病理改变,肺指数及肺组织中病毒载量、NLRP3、ASC、Cleaved caspase-1的表达水平、BALF中IL-1β、IL-18的含量增加(P<0.05);与模型组比较,RvD1组小鼠肺组织的病理改变减轻,肺指数及肺组织中NLRP3、ASC、Cleaved caspase-1的表达水平、BALF中IL-1β、IL-18的含量降低(P<0.05),病毒载量无明显变化(P>0.05);与NC慢病毒+RvD1组比较,NLRP3慢病毒+RvD1组小鼠肺组织病理改变加重,肺指数及肺组织中NLRP3、ASC、Cleaved caspase-1的表达水平、BALF中IL-1β、IL-18的含量增加(P<0.05)。以上结果表明RvD1通过抑制NLRP3炎症小体减轻H1N1/FM1感染小鼠的肺损伤。
关键词(KeyWords): 甲型流感病毒;H1N1/FM1病毒株;消退素D1;NLRP3炎症小体;肺损伤;炎症反应
基金项目(Foundation): 杭州市科技计划引导项目(项目号:20211231Y040),题目:Notchl介导的肺血管内皮细胞凋亡干预慢性阻塞性肺疾病的作用机制研究~~
作者(Author): 丁凌,冷报浪,董洪英,王海燕
DOI: 10.13242/j.cnki.bingduxuebao.004363
参考文献(References):
- [1] Lobo SM,Watanabe ASA,Salom?o MLM,Queiroz F,Gandolfi JV,de Oliveira NE,Covello LHS, Sacillotto GH,de Godoy LG,Sim?es ES,Frini ICM,Da Silva Teixeira RER,Furlan NP,Dutra KR,Nogueira ML.Excess mortality is associated with influenza A(H1N1)in patients with severe acute respiratory illness[J/OL].J Clin Virol, 2019, 116:62-68. DOI:10.1016/j.jcv.2019.05.003.
- [2] Lazzeri C,Bonizzoli M,Cianchi G,Batacchi S,Peris A.H1N1-related ARDS requiring veno-venous extracorporeal membrane oxygenation and the heart[J/OL]. Intensive Care Med,2018,44(12):2307-2308.DOI:10.1007/s00134-018-5422-3.
- [3]师小函,吴本权,石云锋,杨洋,朱家馨,张天托.甲型流感病毒H1N1/FM1对小鼠巨噬细胞NLRP3炎症小体信号通路的影响[J].新医学,2017, 48(5):302-307.
- [4] Rodriguez AE, Bogart C, Gilbert CM, McCullers JA,Smith AM, Kanneganti TD, Lupfer CR. Enhanced IL-1beta production is mediated by a TLR2-MYD88-NLRP3 signaling axis during coinfection with influenza A virus and Streptococcus pneumoniae[J/OL]. PLoS One, 2019, 14(2):e0212236. DOI:10.1371/journal.pone.0212236.
- [5]时珺,曾静霞,赵劭懂,胡晓晨,缪红军,张琴.消退素D1对急性肺损伤小鼠肺部炎症反应和Nod样受体蛋白3表达的影响[J/OL].中华实用儿科临床杂志,2020,35(21):1668-1671. DOI:10.3760/cma. j. cn101070-20190827-00808.
- [6]王兵兵,胡翠,刘晓昌,鲍峻峻,丁少桢,梅咏玉,梅俏,许建明.消退素D1对急性胰腺炎小鼠NLRP3炎症小体通路的影响[J/OL].中华胰腺病杂志,2018, 18(6):401-403. DOI:10.3760/cma. j. issn. 1674-1935.2018.06.012.
- [7]方晨,梅咏玉,王晶,杨彬,刘晓昌,许建明,梅俏.消退素D1抑制NLRP3信号通路对DSS结肠炎小鼠的影响[J/OL].中国药理学通报,2019, 35(4):580-585.
- [8] Okda FA, Perry SS, Webby RJ, Russell CJ. Interplay between H1N1 influenza a virus infection, extracellular and intracellular respiratory tract pH, and host responses in a mouse model[J/OL]. PLoS One, 2021, 16(5):e0251473. DOI:10.1371/journal.pone.0251473.
- [9]杨延龙,涂明利,谢明水. PI3K抑制剂对甲型流感病毒FM1感染诱导病毒性肺炎小鼠肺组织中NO生成及炎症反应的影响[J/OL].病毒学报,2019, 35(5):713-720.DOI:10.13242/j.cnki.bingduxuebao.003597.
- [10]Zhao L, Hao Y, Song Z, Fan Y, Li S. TRIM37negatively regulates inflammatory responses induced by virus infection via controlling TRAF6 ubiquitination[J/OL]. Biochem Biophys Res Commun, 2021, 4(556):87-92. DOI:10.1016/j.bbrc.2021.03.147.
- [11]Gopal R, Lee B, McHugh KJ, Rich HE, Ramanan K,Mandalapu S, Clay ME, Seger PJ, Enelow RI, Manni ML, Robinson KM, Rangel-Moreno J, Alcorn JF.STAT2 signaling regulates macrophage phenotype during influenza and bacterial super-infection[J/OL].Front Immunol, 2018, 25(9):2151. DOI:10.3389/fimmu.2018.02151.
- [12]Ferrero MR, Garcia CC, Dutra de Almeida M, Torres Braz da Silva J, Bianchi Reis Insuela D, Teixeira Ferreira TP, de SáCoutinho D, Trindade de Azevedo C, Machado Rodrigues E Silva P, Martins MA. CCR5antagonist maraviroc inhibits acute exacerbation of lung inflammation triggered by influenza virus in cigarette smoke-exposed mice[J/OL]. Pharmaceuticals(Basel),2021, 14(7):620. DOI:10.3390/ph14070620.
- [13]Mattos MS, Ferrero MR, Kraemer L, Lopes GAO,Reis DC, Cassali GD, Oliveira FMS, Brandolini L,Allegretti M, Garcia CC, Martins MA, Teixeira MM,Russo RC. CXCR1 and CXCR2 inhibition by ladarixin improves neutrophil-dependent airway inflammation in mice[J/OL]. Front Immunol, 2020, 2(11):566953.DOI:10.3389/fimmu.2020.566953.
- [14]Cheng T, Ding S, Liu S, Li X, Tang X, Sun L.Resolvin D1 improves the Treg/Th17 imbalance in systemic lupus erythematosus through miR-30e-5p[J/OL]. Front Immunol, 2021, 19(12):668760. DOI:10.3389/fimmu.2021.668760.
- [15]Liu GJ, Tao T, Zhang XS, Lu Y, Wu LY, Gao YY,Wang H, Dai HB, Zhou Y, Zhuang Z, Hang CH, Li W. Resolvin D1 attenuates innate immune reactions in experimental subarachnoid hemorrhage rat model[J/OL]. Mol Neurobiol, 2021, 58(5):1963-1977. DOI:10.1007/s12035-020-02237-1.
- [16]Li Z, Liu Z, Lu H, Dai W, Chen J, He L. RvD1attenuated susceptibility to ischemic AKI in diabetes by downregulating nuclear factor-κB signal and inhibiting apoptosis[J/OL]. Front Physiol, 2021, 13(12):651645. DOI:10.3389/fphys.2021.651645.
- [17]Salas-Hernández A, Espinoza-Pérez C, Vivar R,Espitia-Corredor J, Lillo J, Parra-Flores P, SánchezFerrer CF, PeiróC, Díaz-Araya G. Resolvin D1 and E1promote resolution of inflammation in rat cardiac fibroblast in vitro[J/OL]. Mol Biol Rep, 2021, 48(1):57-66. DOI:10.1007/s11033-020-06133-8.
- [18]Wei C, Guo S, Liu W, Jin F, Wei B, Fan H, Su H,Liu J, Zhang N, Fang D, Li G, Shu S, Li X, He X,Zhang X, Duan C. Resolvin D1 ameliorates inflammation-mediated blood-brain barrier disruption after subarachnoid hemorrhage in rats by modulating A20 and NLRP3 inflammasome[J/OL]. Front Pharmacol, 2021, 3(11):610734. DOI:10.3389/fphar.2020.610734.
- [19]Yarmohammadi F, Hayes AW, Karimi G. Possible protective effect of resolvin D1 on inflammation in atrial fibrillation:involvement of ER stress mediated the NLRP3 inflammasome pathway[J/OL]. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394(8):1613-1619. DOI:10.1007/s00210-021-02115-0.
- [20]Wang L, Lei W, Zhang S, Yao L. MCC950, a NLRP3inhibitor, ameliorates lipopolysaccharide-induced lung inflammation in mice[J/OL]. Bioorg Med Chem, 2021,15(30):115954. DOI:10.1016/j.bmc.2020.115954.
- [21]He DK, Xu N, Shao YR, Shen J. NLRP3 gene silencing ameliorates phosgene-induced acute lung injury in rats by inhibiting NLRP3 inflammasome and proinflammatory factors, but not anti-inflammatory factors[J/OL]. J Toxicol Sci, 2020, 45(10):625-637.DOI:10.2131/jts.45.625.
- [22]Qu J, Yuan Z, Wang G, Wang X, Li K. The selective NLRP3 inflammasome inhibitor MCC950 alleviates cholestatic liver injury and fibrosis in mice[J/OL]. Int Immunopharmacol, 2019, 70:147-155. DOI:10.1016/j.intimp.2019.02.016.
- [23]Wu M, Yang Z, Zhang C, Shi Y, Han W, Song S,Mu L, Du C, Shi Y. Inhibition of NLRP3inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy[J/OL]. Metabolism, 2021, 4(118):154748. DOI:10.1016/j.metabol.2021.154748.