美他多辛通过抑制巨噬细胞和中性粒细胞向肝脏浸润缓解急性酒精性肝损伤

doi:10.5246/jcps.2022.01.005

中国药学(英文版) ›› 2022, Vol. 31 ›› Issue (1): 47-54.DOI: 10.5246/jcps.2022.01.005

美他多辛通过抑制巨噬细胞和中性粒细胞向肝脏浸润缓解急性酒精性肝损伤

蒋雯², 韦亦霖¹, 温清¹, 史革鑫¹, 赵恒利¹^,²^,^*()

1. 山东第一医科大学附属中心医院临床研究中心, 山东济南 250013
2. 山东大学第二医院中心实验室, 山东济南 250033

收稿日期:2021-08-25 修回日期:2021-09-10 接受日期:2021-10-04 出版日期:2022-01-12 发布日期:2022-01-13
通讯作者: 赵恒利
作者简介:
+ Tel.: +86-531-5586500, E-mail: xiaolegold@163.com
基金资助:
Jinan Technology Development Program (Grant No. 201907035).

Metadoxine inhibits the infiltration of macrophages and neutrophils into liver tissue in acute alcoholic liver injury

Wen Jiang², Yilin Wei¹, Qing Wen¹, Gexin Shi¹, Hengli Zhao¹^,²^,^*()

1 Department of Clinical Research Center, Central Hospital Affiliated to First Medical University, Jinan 250013, China
2 Central Research Laboratory, the Second Hospital of Shandong University, Jinan 250033, China

Received:2021-08-25 Revised:2021-09-10 Accepted:2021-10-04 Online:2022-01-12 Published:2022-01-13
Contact: Hengli Zhao

摘要/Abstract

摘要：

大量饮酒常会引起显著的肝脏损伤, 包括肝脏炎症、纤维化、肝硬化, 甚至肝癌。美他多辛被认为是治疗酒精性肝损伤(ALD)的有效药物, 可以通过加速酒精代谢和排泄发挥肝脏保护作用, 但具体保护机制仍不明确。本研究中, 我们给大鼠以5 g/kg的剂量灌胃50%的酒精建立急性酒精性肝损伤模型, 收集大鼠血清及肝组织样本, 观察肝脏炎症及炎症细胞的浸润程度, 以研究美他多辛抑制肝脏炎症的具体作用机制。研究发现, 美他多辛可显著缓解ALD大鼠血清ALT、AST、ALP以及炎症因子TNF-α和IL-6水平的升高, 并可显著降低肝组织中NLRP3炎症小体的表达, 进一步研究发现, 美他多辛可显著抑制ALD大鼠肝组织中巨噬细胞和中性粒细胞的浸润程度。研究结果显示, 美他多辛可通过抑制酒精损伤诱导的巨噬细胞和中性粒细胞向受损肝脏的浸润, 抑制肝脏促炎环境, 降低促炎因子分泌, 继而发挥肝脏保护作用。

关键词: 美他多辛, 酒精性肝损伤, 巨噬细胞, 中性粒细胞, 炎症

Abstract:

Alcohol consumption causes significant liver damage, including hepatitis, fibrosis, cirrhosis, and even primary liver carcinoma. Metadoxine (MTDX) is considered to be a beneficial treatment for alcoholic liver disease (ALD) because it accelerates the metabolism and elimination of ethanol. However, the underlying mechanism is not well understood. Here, the rat model of ALD was developed by feeding with 50% ethanol at the dose of 5 g/kg, and samples of serum and liver tissue were collected to test the levels of liver injury and inflammation and evaluate the hepatoprotective function of MTDX in alcohol-induced liver injury. Further investigation on the infiltration of immune cells was performed to understand the potential hepatoprotective mechanism of MTDX in the ALD model. The results showed that MTDX attenuated liver injury, evidenced by decreased levels of alanine transaminase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Meanwhile, the liver proinflammatory environment was improved after MTDX treatment, evidenced by decreased levels of TNF-α, IL-6, and NLRP3 in the liver tissue. Furthermore, inhibited infiltrations of macrophages and neutrophils were observed in MTDX-treated ALD rats compared with the untreated ALD rats. Our results indicated that MTDX played an important role in preventing the progression of ALD, and the underlying mechanisms might be related to its function of attenuating liver inflammation by inhibiting immune cell infiltration.

Key words: Metadoxine, Alcoholic liver injury, Macrophages, Neutrophils, Inflammatory

Supporting:

蒋雯, 韦亦霖, 温清, 史革鑫, 赵恒利. 美他多辛通过抑制巨噬细胞和中性粒细胞向肝脏浸润缓解急性酒精性肝损伤[J]. 中国药学(英文版), 2022, 31(1): 47-54.

Wen Jiang, Yilin Wei, Qing Wen, Gexin Shi, Hengli Zhao. Metadoxine inhibits the infiltration of macrophages and neutrophils into liver tissue in acute alcoholic liver injury[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(1): 47-54.

图/表 4

Figure 1. MTDX attenuates alcohol-induced acute liver injury. (A) Serum ALT, AST, and ALP levels of alcohol-treated rats with pre-exposure prophylaxis of MTDX and the controls (n = 3 per group) are shown. (B) Histological liver samples are imaged under the light microscope using TUNEL (n = 3). Statistical significance is determined as *, P < 0.05 and **, P < 0.01 compared with the normal rats, as well as #, P < 0.05 and ##, P < 0.01 compared with the untreated ALD rats.

Figure 2. MTDX downregulates the levels of proinflammatory cytokines in ALD. Serum was collected from MTDX-treated ALD and control rats, and cytokine levels were measured using ELISA (n = 3).

Figure 3. MTDX attenuates liver NLRP3/Caspase-1 signaling in ALD. (A) Representative Western blots of anti-NLRP3 protein levels in liver tissue from MTDX-treated ALD and control rats. (B) Immunostaining of caspase-1 (blank arrow) in liver tissue from MTDX-treated ALD and control rats under the light microscope (n = 3). Statistical significance is determined as *, P < 0.05 and **, P < 0.01 compared to that of normal rats, as well as #, P < 0.05 compared with the untreated ALD rats.

Figure 4. MTDX inhibits the infiltration of macrophages and neutrophils. (A) Histological liver samples of CD68-stained (blank arrow) slides under the light microscope (n = 3). (B) Histological liver samples of MPO-stained slides under the light microscope (n = 3). Statistical significance is determined as **, P < 0.01 compared with the normal rats, as well as #, P < 0.05 compared with the untreated ALD rats.

参考文献 34

[1]	Chrystoja, B.R.; Rehm, J.; Manthey, J.; Probst, C.; Wettlaufer, A.; Shield, K.D. A systematic comparison of the global comparative risk assessments for alcohol. Addiction. 2021, 116, 2026–2038.
[2]	Haber, P.S.; Kortt, N.C. Alcohol use disorder and the gut. Addiction. 2021, 116, 658–667.
[3]	Wang, X.; He, Y.; Mackowiak, B.; Gao, B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut. 2021, 70, 784–795.
[4]	Stornetta, A.; Guidolin, V.; Balbo, S. Alcohol-derived acetaldehyde exposure in the oral cavity. Cancers. 2018, 10. DOI:10.3390/cancers10010020.
[5]	Dunn, W.; Shah, V.H. Pathogenesis of alcoholic liver disease. Clin. Liver Dis. 2016, 20, 445–456.
[6]	Smyth, A.; Teo, K.K.; Rangarajan, S.; O'Donnell, M.; Zhang, X.H.; Rana, P.; Leong, D.P.; Dagenais, G.; Seron, P.; Rosengren, A.; Schutte, A.E.; Lopez-Jaramillo, P.; Oguz, A.; Chifamba, J.; Diaz, R.; Lear, S.; Avezum, A.; Kumar, R.; Yusuf, S. Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study. Lancet. 2015, 386, 1945–1954.
[7]	Xi, B.; Veeranki, S.P.; Zhao, M.; Ma, C.W.; Yan, Y.K.; Mi, J. Relationship of alcohol consumption to all-cause, cardiovascular, and cancer-related mortality in US adults. J. Am. Coll. Cardiol. 2017, 70, 913–922.
[8]	Duddempudi, A.T. Immunology in alcoholic liver disease. Clin. Liver Dis. 2012, 16, 687–698.
[9]	Li, M.; He, Y.; Zhou, Z.; Ramirez, T.; Gao, Y.Q.; Gao, Y.H.; Ross, R.A.; Cao, H.X.; Cai, Y.; Xu, M.J.; Feng, D.C.; Zhang, P.; Liangpunsakul, S.; Gao, B. MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p^47phox–oxidative stress pathway in neutrophils. Gut. 2017, 66, 705–715.
[10]	Acito, M.; Bartolini, D.; Ceccarini, M.R.; Russo, C.; Vannini, S.; Dominici, L.; Codini, M.; Villarini, M.; Galli, F.; Beccari, T.; Moretti, M. Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol. Vitro. 2020, 69, 105001.
[11]	Mahmoud, A.M.; Hussein, O.E.; Hozayen, W.G.; Bin-Jumah, M.; Abd El-Twab, S.M. Ferulic acid prevents oxidative stress, inflammation, and liver injury via upregulation of Nrf2/HO-1 signaling in methotrexate-induced rats. Environ. Sci. Pollut. Res. 2020, 27, 7910–7921.
[12]	Grabherr, F.; Grander, C.; Adolph, T.E.; Wieser, V.; Mayr, L.; Enrich, B.; Macheiner, S.; Sangineto, M.; Reiter, A.; Viveiros, A.; Zoller, H.; Bufler, P.; Moschen, A.R.; Dinarello, C.A.; Tilg, H. Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease. Liver Int. 2018, 38, 1095–1101.
[13]	Tilg, H.; Moschen, A.R.; Szabo, G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2016, 64, 955–965.
[14]	Mukhopadhyay, P.; Horváth, B.; Rajesh, M.; Varga, Z.V.; Gariani, K.; Ryu, D.; Cao, Z.X.; Holovac, E.; Park, O.; Zhou, Z.; Xu, M.J.; Wang, W.; Godlewski, G.; Paloczi, J.; Nemeth, B.T.; Persidsky, Y.; Liaudet, L.; Haskó, G.; Pacher, P. PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. J. Hepatol. 2017, 66, 589–600.
[15]	Zhou, Y.; Yuan, G.D.; Zhong, F.D.; He, S.Q. Roles of the complement system in alcohol-induced liver disease. Clin. Mol. Hepatol. 2020, 26, 677–685.
[16]	Zhang, M.; Zhang, Y.; Liu, L.; Prithweeraj, M.; Xu, H.; Wu, R.; Wen, X.; Niu, J. Neutrophil-to-lymphocyte ratio and albumin: new serum biomarkers to predict the prognosis of male alcoholic cirrhosis patients. Biomed. Res. Int. 2020, 2020, 7268459.
[17]	Tang, Y.M.; Banan, A.; Forsyth, C.B.; Fields, J.Z.; Lau, C.K.; Zhang, L.J.; Keshavarzian, A. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease. Alcohol. Clin. Exp. Res. 2008, 32, 355–364.
[18]	Affò, S.; Morales-Ibanez, O.; Rodrigo-Torres, D.; Altamirano, J.; Blaya, D.; Dapito, D.H.; Millán, C.; Coll, M.; Caviglia, J.M.; Arroyo, V.; Caballería, J.; Schwabe, R.F.; Ginès, P.; Bataller, R.; Sancho-Bru, P. CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis. Gut. 2014, 63, 1782–1792.
[19]	Liang, S.; Zhong, Z.Y.; Kim, S.Y.; Uchiyama, R.; Roh, Y.S.; Matsushita, H.; Gottlieb, R.A.; Seki, E. Murine macrophage autophagy protects against alcohol-induced liver injury by degrading interferon regulatory factor 1 (IRF₁) and removing damaged mitochondria. J. Biol. Chem. 2019, 294, 12359–12369.
[20]	Zhang, L.; Pan, JC.; Ku, BS. Protective Effect of Ascorbate-Lysine on Carbon Tetrachloride and Alcohol-Induced Liver Injury in Mice. J. Chin. Pharm. Sci. 2004, 4, 288–290.
[21]	Huo, X.W.; Sun, X.K.; Cao, Z.P.; Qiao, J.Z.; Yang, S.; Meng, X.B.; Zhao, Y.Y. Optimal ratio of 18α- and 18β-glycyrrhizic acid for preventing alcoholic hepatitis in rats. Exp. Ther. Med. 2019, 18, 172–178.
[22]	Song, Z.Y.; Deaciuc, I.; Song, M.; Lee, D.Y.W.; Liu, Y.Z.; Ji, X.S.; McClain, C. Silymarin protects against acute ethanol-induced hepatotoxicity in mice. Alcohol. Clin. Exp. Res. 2006, 30, 407–413.
[23]	Addolorato, G.; Ancona, C.; Capristo, E.; Gasbarrini, G. Metadoxine in the treatment of acute and chronic alcoholism: a review. Int. J. Immunopathol. Pharmacol. 2003, 16, 207–214.
[24]	Díaz Martínez, M.C.; Díaz Martínez, A.; Villamil Salcedo, V.; Cruz Fuentes, C. Efficacy of metadoxine in the management of acute alcohol intoxication. J. Int. Med. Res. 2002, 30, 44–51.
[25]	Tijera, F.H.D.L.; Servín-Caamaño, A.I.; Cruz-Herrera, J.; Serralde-Zúñiga, A.E.; Abdo-Francis, J.M.; Gutiérrez-Reyes, G.; Pérez-Hernández, J.L. Treatment with Metadoxine and its impact on early mortality in patients with severe alcoholic hepatitis. Ann. Hepatol. 2014, 13, 343–352.
[26]	Testino, G.; Leone, S.; Fagoonee, S.; Pellicano, R. Alcoholic liver fibrosis: detection and treatment. Minerva Med. 2018, 109, 457–471.
[27]	Mazraati, P.; Minaiyan, M. Hepatoprotective effect of metadoxine on acetaminophen-induced liver toxicity in mice. Adv. Biomed. Res. 2018, 7, 67.
[28]	Gutiérrez-Ruiz, M.C.; Bucio, L.; Correa, A.; Souza, V.; Hernández, E.; Gómez-Quiroz, L.E.; Kershenobich, D. Metadoxine prevents damage produced by ethanol and acetaldehyde in hepatocyte and hepatic stellate cells in culture. Pharmacol. Res. 2001, 44, 431–436.
[29]	Wu, J.D.; Wu, D.Q.; Ma, K.L.; Wang, T.M.; Shi, G.X.; Shao, J.; Wang, C.Z.; Yan, G.M. Paeonol ameliorates murine alcohol liver disease via mycobiota-mediated Dectin-1/IL-1β signaling pathway. J. Leukoc. Biol. 2020, 108, 199–214.
[30]	Gu, G.X.; Huo, Y.F.; Xu, G.; Li, L.M.; Yu, J.; Sheng, L.X.; Yin, Z.Y. MicroRNA-204-GSDMD interaction regulates pyroptosis of fibroblast-like synoviocytes in ankylosing spondylitis. Int. Immunopharmacol. 2021, 91, 107227.
[31]	Xi, H.; Zhang, Y.; Xu, Y.; Yang, W.Y.; Jiang, X.; Sha, X.; Cheng, X.; Wang, J.; Qin, X.; Yu, J.; Ji, Y.; Yang, X.; Wang, H. Caspase-1 inflammasome activation mediates homocysteine-induced pyrop-apoptosis in endothelial cells. Circ. Res. 2016, 118, 1525–1539.
[32]	Ding, W.X.; Manley, S.; Ni, H.M. The emerging role of autophagy in alcoholic liver disease. Exp. Biol. Med. (Maywood). 2011, 236, 546–556.
[33]	Ding, W.X.; Li, M.; Chen, X.Y.; Ni, H.M.; Lin, C.W.; Gao, W.T.; Lu, B.F.; Stolz, D.B.; Clemens, D.L.; Yin, X.M. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology. 2010, 139, 1740–1752.
[34]	Wang, H.F.; Huang, J.; Zhang, S.; Jia, B.; Yang, D.W. Effect and mechanisms of the metadoxin attenuates steatosis in cultured hepatic cells by inducing autophagy. Chin. J. Clin. Pharmacol. 2019, 35, 1752–1755.

美他多辛通过抑制巨噬细胞和中性粒细胞向肝脏浸润缓解急性酒精性肝损伤

Metadoxine inhibits the infiltration of macrophages and neutrophils into liver tissue in acute alcoholic liver injury

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