Arbutin alleviates LPS-induced acute lung injury in mice through PI3K/Akt/mTOR signaling pathway_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

MA Lin ^1,2 , LI Yan-mei ^1,2 ,  LI Duo ^1,2,3

1. Department of Pulmonary and Critical Care Medicine, The affiliated Hospital, Southwest Medical University, Luzhou, sichuan 64600, P.R.China;
2. Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R.China;
3. Department of Hospital Infection Management, The affiliated Hospital, Southwest Medical University, Luzhou, sichuan 64600, P.R.China;

Corresponding author：

LI Duo, Email: sclzliduo@163.com

Keywords：

Acute lung injury; arbutin; PI3K/Akt/mTOR; inflammatory response; oxidative stress

DOI：

10.7507/1671-6205.202401035

Video：

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Objective To investigate the protective effect and mechanism of arbutin on LPS induced Acute lung injury in mice. Methods SPF BCLB/C mice were randomly divided into control group, model group,arbutin group, and arbutin+PI3K inhibitor group.arbutin group and arbutin+PI3K group were intervened with corresponding drugs respectively; Constructing an ALI model by intranasal instillation of LPS into mice; After modeling for 6 hours, the mice were killed. After staining the lung tissue slices, observe the pathological changes of the lung tissue and evaluate the lung injury score, and calculate the wet to dry weight ratio (W/D); ELISA method was used to determine the levels of TNF-a and IL-6 in serum and bronchoalveolar lavage fluid (BALF); Measure the ROS content, MDA level,and MPO activity in the lungs; Western blot method was used to detect the expression of PI3K/Akt/mTOR pathway related proteins and autophagy related proteins Beclin-1 and LC3II/I. Results Compared with the control group, the pathological changes in the lung tissue of model group mice worsened, and the W/D and lung injury scores increased, The levels of IL-6 and TNF-a in BALF and serum was increased, The ROS content, MDA expression and MPO activity in the lungs was increased,the expression of Beclin-1 and LC3II/I in the lungs was increased. The expression of PI3K/Akt/mTOR pathway related proteins in the lungs decreased (P<0.05). Compared with the model group, the pathological changes in the lung tissue of arbutin group mice were alleviated, with a decrease in W/D and lung injury score, The levels of IL-6 and TNF-a in BALF and serum decrease,ROS content, MDA expression and MPO activity in lung were decreased.The expression of PI3K/Akt/mTOR pathway related proteins in the lung was increased, The expression of Beclin-1 and LC3II/I decreased. However, the appeal performance was partially blocked in the arbutin+PI3K group after the administration of LY294002.Conclusions Arbutin regulates autophagy through PI3K/Akt/mTOR pathway to inhibit inflammatory response and oxidative stress in LPS-induced ALI mice, and plays a protective role in LPS-induced ALI.

Citation： MA Lin, LI Yan-mei, LI Duo. Arbutin alleviates LPS-induced acute lung injury in mice through PI3K/Akt/mTOR signaling pathway. Chinese Journal of Respiratory and Critical Care Medicine, 2024, 23(4): 264-270. doi: 10.7507/1671-6205.202401035 Copy

1.	Li X, Wei Y, Li S, et al. Zanubrutinib ameliorates lipopolysaccharide-induced acute lung injury via regulating macrophage polarization. Int Immunopharmacol. 2022, 111: 109138.
2.	Mowery NT, Terzian WTH, Nelson AC. Acute lung injury. Curr Probl Surg. 2020, 57(5): 100777.
3.	Li J, Deng SH, Li J, et al. Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses. Cell Mol Biol Lett. 2022, 27(1): 29.
4.	Huang CY, Deng JS, Huang WC, et al. Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Hispolon in Mice, Through Regulating the TLR4/PI3K/Akt/mTOR and Keap1/Nrf2/HO-1 Pathways, and Suppressing Oxidative Stress-Mediated ER Stress-Induced Apoptosis and Autophagy. Nutrients. 2020, 12(6): 1742.
5.	Ding D, Xu S, Zhang H, et al. 3-Methyladenine and dexmedetomidine reverse lipopolysaccharide-induced acute lung injury through the inhibition of inflammation and autophagy. Exp Ther Med. 2018, 15(4): 3516-3522.
6.	Painter JD, Galle-Treger L, Akbari O. Role of Autophagy in Lung Inflammation. Front Immunol. 2020, 11: 1337.
7.	王佳, 高恒波, 林雪容, 等. 血必净注射液减轻脓毒症诱导的小鼠急性肺损伤的作用及机制. 华西医学, 2021, 36(11): 1533-1538.
8.	祝上宾, 王英飒, 敬凡尘, 等. 熊果苷磷脂复合物的制备、表征及理化性质研究. 中草药, 2020, 51(22): 5698-5704.
9.	刘晓婷, 王鑫璇. 熊果苷的药理作用及机制研究进展. 食品与发酵工业, 2022, 48(2): 309-316.
10.	Bian XX, Zhao X, Ma CH, Shen CP. Arbutin Alleviates LPS Induced Sepsis Pneumonia in Mice. Evid Based Complement Alternat Med. 2022, 2022: 5863952.
11.	Dong WW, Liu YJ, Lv Z, et al. Lung endothelial barrier protection by resveratrol involves inhibition of HMGB1 release and HMGB1-induced mitochondrial oxidative damage via an Nrf2-dependent mechanism. Free Radic Biol Med. 2015, 88(Pt B): 404-416.
12.	徐晓荣, 王海滨, 白晓月, 等. miR-146a-3p靶向TLR4减轻脂多糖诱导的小鼠急性肺损伤. 中国呼吸与危重监护杂志, 2021, 20(7): 495-502.
13.	冯净净, 邵川, 李俊卿, 等. 抑制p38丝裂素活化蛋白激酶途径调控Th17和Treg失衡减轻脂多糖诱导的小鼠急性肺损伤. 中国呼吸与危重监护杂志, 2023, 22(1): 44-51.
14.	Ma C, Zhu L, Wang J, et al. Anti-inflammatory effects of water extract of Taraxacum mongolicum hand. -Mazz on lipopolysaccharide-induced inflammation in acute lung injury by suppressing PI3K/Akt/mTOR signaling pathway. JEthnopharmacol. 2015, 168: 349-355.
15.	Zhang B, Zeng M, Li B, et al. Arbutin attenuates LPS-induced acute kidney injury by inhibiting inflammation and apoptosis via the PI3K/Akt/Nrf2 pathway. Phytomedicine. 2021, 82: 153466.
16.	Tian Y, Zhu CL, Li P, et al. Nicotinamide Mononucleotide Attenuates LPS-Induced Acute Lung Injury With Anti-Inflammatory, Anti-Oxidative and Anti-Apoptotic Effects. J Surg Res. 2023, 283: 9-18.
17.	Yin N, Peng Z, Li B, et al. Isoflurane attenuates lipopolysaccharide-induced acute lung injury by inhibiting ROS-mediated NLRP3 inflammasome activation. Am J Transl Res. 2016, 8(5): 2033-2046.
18.	Zheng X, Zhang B, Zeng M, et al. Inhibition of oxidative stress and autophagy by arbutin in lipopolysaccharide-induced myocardial injury. Pharmacogn Mag, 2019, 15: 507-513.
19.	Cao W, Li J, Yang K, Cao D. An overview of autophagy: Mechanism, regulation and research progress. Bull Cancer. 2021, 108(3): 304-322.
20.	Mizumura K, Cloonan S, Choi ME, et al. Autophagy: Friend or Foe in Lung Disease?Ann Am Thorac Soc. 2016, 13 Suppl 1(Suppl 1): S40-S47.
21.	Liu B, Zhao H, Wang Y, Zhang H, Ma Y. Astragaloside IV Attenuates Lipopolysaccharides-Induced Pulmonary Epithelial Cell Injury through Inhibiting Autophagy. Pharmacology. 2020, 105(1-2): 90-101.
22.	Ma C, Zhang D, Ma Q, Liu Y, Yang Y. Arbutin inhibits inflammation and apoptosis by enhancing autophagy via SIRT1. Adv Clin Exp Med. 2021, 30(5): 535-544.
23.	Kma L, Baruah TJ. The interplay of ROS and the PI3K/Akt pathway in autophagy regulation. Biotechnol Appl Biochem. 2022, 69(1): 248-264.
24.	Li X, Liu H, Lv C, et al. Gypenoside-Induced Apoptosis via the PI3K/AKT/mTOR Signaling Pathway in Bladder Cancer. Biomed Res Int. 2022, 2022: 9304552.
25.	Han F, Xiao QQ, Peng S, et al. Atorvastatin ameliorates LPS-induced inflammatory response by autophagy via AKT/mTOR signaling pathway. J Cell Biochem. 2018, 119(2): 1604-1615.

1. Li X, Wei Y, Li S, et al. Zanubrutinib ameliorates lipopolysaccharide-induced acute lung injury via regulating macrophage polarization. Int Immunopharmacol. 2022, 111: 109138.
2. Mowery NT, Terzian WTH, Nelson AC. Acute lung injury. Curr Probl Surg. 2020, 57(5): 100777.
3. Li J, Deng SH, Li J, et al. Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses. Cell Mol Biol Lett. 2022, 27(1): 29.
4. Huang CY, Deng JS, Huang WC, et al. Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Hispolon in Mice, Through Regulating the TLR4/PI3K/Akt/mTOR and Keap1/Nrf2/HO-1 Pathways, and Suppressing Oxidative Stress-Mediated ER Stress-Induced Apoptosis and Autophagy. Nutrients. 2020, 12(6): 1742.
5. Ding D, Xu S, Zhang H, et al. 3-Methyladenine and dexmedetomidine reverse lipopolysaccharide-induced acute lung injury through the inhibition of inflammation and autophagy. Exp Ther Med. 2018, 15(4): 3516-3522.
6. Painter JD, Galle-Treger L, Akbari O. Role of Autophagy in Lung Inflammation. Front Immunol. 2020, 11: 1337.
7. 王佳, 高恒波, 林雪容, 等. 血必净注射液减轻脓毒症诱导的小鼠急性肺损伤的作用及机制. 华西医学, 2021, 36(11): 1533-1538.
8. 祝上宾, 王英飒, 敬凡尘, 等. 熊果苷磷脂复合物的制备、表征及理化性质研究. 中草药, 2020, 51(22): 5698-5704.
9. 刘晓婷, 王鑫璇. 熊果苷的药理作用及机制研究进展. 食品与发酵工业, 2022, 48(2): 309-316.
10. Bian XX, Zhao X, Ma CH, Shen CP. Arbutin Alleviates LPS Induced Sepsis Pneumonia in Mice. Evid Based Complement Alternat Med. 2022, 2022: 5863952.
11. Dong WW, Liu YJ, Lv Z, et al. Lung endothelial barrier protection by resveratrol involves inhibition of HMGB1 release and HMGB1-induced mitochondrial oxidative damage via an Nrf2-dependent mechanism. Free Radic Biol Med. 2015, 88(Pt B): 404-416.
12. 徐晓荣, 王海滨, 白晓月, 等. miR-146a-3p靶向TLR4减轻脂多糖诱导的小鼠急性肺损伤. 中国呼吸与危重监护杂志, 2021, 20(7): 495-502.
13. 冯净净, 邵川, 李俊卿, 等. 抑制p38丝裂素活化蛋白激酶途径调控Th17和Treg失衡减轻脂多糖诱导的小鼠急性肺损伤. 中国呼吸与危重监护杂志, 2023, 22(1): 44-51.
14. Ma C, Zhu L, Wang J, et al. Anti-inflammatory effects of water extract of Taraxacum mongolicum hand. -Mazz on lipopolysaccharide-induced inflammation in acute lung injury by suppressing PI3K/Akt/mTOR signaling pathway. JEthnopharmacol. 2015, 168: 349-355.
15. Zhang B, Zeng M, Li B, et al. Arbutin attenuates LPS-induced acute kidney injury by inhibiting inflammation and apoptosis via the PI3K/Akt/Nrf2 pathway. Phytomedicine. 2021, 82: 153466.
16. Tian Y, Zhu CL, Li P, et al. Nicotinamide Mononucleotide Attenuates LPS-Induced Acute Lung Injury With Anti-Inflammatory, Anti-Oxidative and Anti-Apoptotic Effects. J Surg Res. 2023, 283: 9-18.
17. Yin N, Peng Z, Li B, et al. Isoflurane attenuates lipopolysaccharide-induced acute lung injury by inhibiting ROS-mediated NLRP3 inflammasome activation. Am J Transl Res. 2016, 8(5): 2033-2046.
18. Zheng X, Zhang B, Zeng M, et al. Inhibition of oxidative stress and autophagy by arbutin in lipopolysaccharide-induced myocardial injury. Pharmacogn Mag, 2019, 15: 507-513.
19. Cao W, Li J, Yang K, Cao D. An overview of autophagy: Mechanism, regulation and research progress. Bull Cancer. 2021, 108(3): 304-322.
20. Mizumura K, Cloonan S, Choi ME, et al. Autophagy: Friend or Foe in Lung Disease?Ann Am Thorac Soc. 2016, 13 Suppl 1(Suppl 1): S40-S47.
21. Liu B, Zhao H, Wang Y, Zhang H, Ma Y. Astragaloside IV Attenuates Lipopolysaccharides-Induced Pulmonary Epithelial Cell Injury through Inhibiting Autophagy. Pharmacology. 2020, 105(1-2): 90-101.
22. Ma C, Zhang D, Ma Q, Liu Y, Yang Y. Arbutin inhibits inflammation and apoptosis by enhancing autophagy via SIRT1. Adv Clin Exp Med. 2021, 30(5): 535-544.
23. Kma L, Baruah TJ. The interplay of ROS and the PI3K/Akt pathway in autophagy regulation. Biotechnol Appl Biochem. 2022, 69(1): 248-264.
24. Li X, Liu H, Lv C, et al. Gypenoside-Induced Apoptosis via the PI3K/AKT/mTOR Signaling Pathway in Bladder Cancer. Biomed Res Int. 2022, 2022: 9304552.
25. Han F, Xiao QQ, Peng S, et al. Atorvastatin ameliorates LPS-induced inflammatory response by autophagy via AKT/mTOR signaling pathway. J Cell Biochem. 2018, 119(2): 1604-1615.

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Arbutin alleviates LPS-induced acute lung injury in mice through PI3K/Akt/mTOR signaling pathway

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