ZLN005通过上调PGC-1α表达诱导巨噬细胞的M2型分化减轻脓毒症引起的急性肺损伤

doi:10.3969/j.issn.1006-6233.2022.02.02

Abstract
Figure/Table
References
Related Citation (0)

Download: PDF (1931 KB) HTML (1 KB)
Export: BibTeX | EndNote (RIS)

Abstract Objective: To explore the role and mechanism of ZLN005 in sepsis induced acute lung injury (ALI). Methods: Sepsis induced acute lung injury model in mice was established by cecal ligation and puncture (CLP), and the mice were divided into four groups according to different treatment. Methods: sham group, ZLN005 group, CLP Group and CLP +ZLN005 group; RT-PCR, immunofluorescence staining and Western blot were used to detect peroxisome proliferator activated receptor (PPAR) in lung tissue of mice γ coactivator-1 α( PGC-1 α). The mRNA and protein expression levels were measured; ELISA was used to detect the contents of TNF-α,IL-1β,IL-6 and IL-10 in BALF; HE staining was used to observe the histopathological damage of lung tissue; the survival rate of mice in each group after 7 days of CLP modeling was analyzed by statistical method; RAW264.7 was cultured in vitro and transfected with si-PGC-1α siRNA. RT-PCR and Western blot were used to detect the transfection efficiency. RAW264.7 cells were divided into five groups: NC group, ZLN005 group, LPS group, LPS+ZLN005+si-NC and LPS+ZLN005+si-PGC-1 α. RT-PCR was used to detect the mRNA expression levels of M1 macrophage markers iNOS and MHC-Ⅱ, M2 macrophage markers Arg1 and CD206. The phosphorylation level of p-AMPK-α/AMPK-α and the key proteins in mitochondrial biogenesis of Nrf1, Nrf2 and mtTFA was detected by Western blot. Results: Compared with sham group, the mRNA and protein expression levels and fluorescence intensity of PGC-1α in lung tissues of ZLN005 group and CLP+ZLN005 group were significantly increased (P<0.05), while those in CLP group were significantly decreased (P<0.05). Compared with the CLP group, the above detection indexes in the CLP+ZLN005 group were significantly increased (P<0.05). BALF, HE staining and survival rate 7 days after operation of mice in each group showed that the expressions of pro-inflammatory factors TNF-α, IL-1β and IL-6 in BALF and the pathological injury level of lung tissue in CLP group and CLP+ZLN005 group were significantly higher than those in sham group or ZLN005 group (P<0.05). However, the survival rate of anti-inflammatory factor IL-10 and postoperative 7 days were significantly decreased (P<0.05). Compared with the CLP group, the change trends of the above indexes in the CLP+ZLN005 group were significantly decreased (P<0.05). Compared with NC group, mRNA expression levels of M1 iNOS and MHC-Ⅱ in LPS group, ZLN005+LPS+si-NC group and ZLN005+LPS+si-PGC-1α group were significantly increased (P<0.05), meanwhile, the mRNA expressions of Arg1 and CD206 in Zln005+LPS+Si-NC group were significantly increased (P<0.05), while the protein expressions of p-AMPK-α/AMPK-α and NRF1, NRF2 and mtTFA were decreased (P<0.05). Compared with ZLN005+LPS+si-NC group, the mRNA expressions of iNOS and MHC-Ⅱ in LPS group and ZLN005+LPS+si-PGC-1α were significantly increased (P<0.05). The mRNA expression of Arg1 and CD206 and protein expression of p-AMPK-α/AMPK-α and NRF1, NRF2 and mtTFA were significantly decreased (P<0.05). Conclusion: ZLN005 can promote the expression of PGC-1α and promote the polarization of M2 macrophages to protect sepsis induced lung injury, and the mechanism may be related to the promotion of mitochondrial biogenesis by ZLN005 through AMPK signaling pathway.

Key words： ZLN005 PGC-1α M2 macrophages Acute lung injury induced by sepsis

	Service

	E-mail this article
	Add to my bookshelf
	Add to citation manager
	E-mail Alert
	RSS
	Articles by authors
	ZHANG Hao
	TAN Yun
	YANG Luyu

Cite this article:

ZHANG Hao,TAN Yun,YANG Luyu. ZLN005 Alleviates Sepsis Induced Acute Lung Injury by Upregulating PGC-1α Expression to Induce M2-Type Differentiation of Macrophages[J]. HeBei Med, 2022, 28(2): 182-189.

URL:

http://www.hbyxzzs.cn/EN/10.3969/j.issn.1006-6233.2022.02.02 OR http://www.hbyxzzs.cn/EN/Y2022/V28/I2/182

[1] Coopersmith CM,De Backer D,Deutschman CS,et al.Surviving sepsis campaign:research priorities for sepsis and septic shock[J].Intensive Care Med,2018,44(9):1400~1426.
[2] Kumar V.Targeting macrophage immunometabolism:Dawn in the darkness of sepsis[J].Int Immunopharmacol,2018,9(58):173~185.
[3] Kumar V.Pulmonary innate immune response determines the outcome of inflammation during pneumonia and sepsis-associated acute Lung Injury[J].Front Immunol,2020,11(48):e1722.
[4] Chen X,Tang J,Shuai W,et al.Macrophage polarization and its role in the pathogenesis of acute lung injury/acute respiratory distress syndrome[J].Inflamm Res,2020,69(9):883~895.
[5] Rius-Perez S,Torres-Cuevas I,Millan I,et al.PGC-1α,Inflammation,and Oxidative Stress:An Integrative View in Metabolism[J].Oxid Med Cell Longev,2020,19(201):e1452696.
[6] 靳鑫.PGC-1α通过线粒体介导的肿瘤相关巨噬细胞极化状态对乳腺癌细胞转移潜能的作用及可能机制[D].重庆医科大学,2019.
[7] Xu Y,Kabba JA,Ruan W,et al.The PGC-1α Activator ZLN005 ameliorates ischemia-induced neuronal injury In vitro and in vivo[J].Cell Mol Neurobiol,2018,38(4):929~939.
[8] Xu Y,Kabba JA,Ruan W,et al.The PGC-1α Activator ZLN005 Ameliorates Ischemia-Induced Neuronal Injury In Vitro and In Vivo[J].Cell Mol Neurobiol,2018,38(4):929~939.
[9] Cruz-Bermudez A,Laza-Briviesca R,Vicente-Blanco RJ,et al.Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition[J].Free Radic Biol Med,2019,17(135):167~181.
[10] Qing J,Zhang Z,Novak P,et al.Mitochondrial metabolism in regulating macrophage polarization:an emerging regulator of metabolic inflammatory diseases[J].Acta Biochim Biophys Sin (Shanghai),2020,52(9):917~926.
[11] Thapa B,Lee K.Metabolic influence on macrophage polarization and pathogenesis[J].BMB Rep,2019,52(6):360~372.
[12] Pfanner N,Warscheid B,Wiedemann N.Mitochondrial proteins:from biogenesis to functional networks[J].Nat Rev Mol Cell Biol,2019,20(5):267~284.
[13] Dinulovic I,Furrer R,Di Fulvio S,et al,Handschin C.PGC-1α modulates necrosis inflammatory response and fibrotic tissue formation in injured skeletal muscle[J].Skelet Muscle,2016,6(109):38~95.
[14] Shah D,Torres C,Bhandari V.Adiponectin deficiency induces mitochondrial dysfunction and promotes endothelial activation and pulmonary vascular injury[J].Faseb,2019,33(12):13617~13631.