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AM-1241 CB2受体激动剂减轻胆管结扎大鼠的炎症、细胞凋亡并刺激祖细胞

AM-1241 CB2 Receptor Agonist Attenuates Inflammation, Apoptosis and Stimulate Progenitor Cells in Bile Duct Ligated Rats.

作者信息

Mahmoud Hesham M, Osman Mona, Elshabrawy Osama, Abdallah Heba M I, Khairallah Ahmed

机构信息

Cairo University Kasr Alainy, Faculty of Medicine, Pharmacology, Cairo, Egypt.

National Research Centre, Pharmacology, Cairo, Egypt.

出版信息

Open Access Maced J Med Sci. 2019 Mar 29;7(6):925-936. doi: 10.3889/oamjms.2019.194. eCollection 2019 Mar 30.

DOI:10.3889/oamjms.2019.194
PMID:30976335
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6454175/
Abstract

BACKGROUND

The cannabinoid receptor 2 (CB2) plays a pleiotropic role in the innate immunity and is considered a crucial mediator of liver disease. Cannabinoid CB2 receptor activation has been reported to attenuate liver fibrosis in CCl4 exposed mice and also plays a potential role in liver regeneration in a mouse model of I/R and protection against alcohol-induced liver injury.

AIM

In this study, we investigated the impact of CB2 receptors on the antifibrotic and regenerative process associated with cholestatic liver injury.

METHODS

Twenty-six rats had bile duct ligation co-treated with silymarin and AM1241 for 3 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed.

RESULTS

Following bile duct ligation (BDL) for 3 weeks, there was increased aminotransferase levels, marked inflammatory infiltration and hepatocyte apoptosis with induced oxidative stress, as reflected by increased lipid peroxidation. Conversely, following treatment with the CB2 agonist, AM-1241, BDL rats displayed a reduction in liver injury and attenuation of fibrosis as reflected by expression of hydroxyproline and α-smooth muscle actin. AM1241 treatment also significantly attenuated lipid peroxidation end-products, p53-dependent apoptosis and also attenuated inflammatory process by stimulating IL-10 production. Moreover, AM1241 treated rats were associated with significant expression of hepatic progenitor/oval cell markers.

CONCLUSION

In conclusion, this study points out that CB2 receptors reduce liver injury and promote liver regeneration via distinct mechanisms including IL-10 dependent inhibition of inflammation, reduction of p53-reliant apoptosis and through stimulation of oval/progenitor cells. These results suggest that CB2 agonists display potent hepatoregenrative properties, in addition to their antifibrogenic effects.

摘要

背景

大麻素受体2（CB2）在先天免疫中发挥多效性作用，被认为是肝脏疾病的关键介质。据报道，大麻素CB2受体激活可减轻四氯化碳暴露小鼠的肝纤维化，并且在缺血/再灌注小鼠模型的肝脏再生以及预防酒精性肝损伤中也发挥潜在作用。

目的

在本研究中，我们调查了CB2受体对胆汁淤积性肝损伤相关的抗纤维化和再生过程的影响。

方法

26只大鼠接受胆管结扎，并连续3周联合水飞蓟宾和AM1241治疗。测定血清肝毒性标志物，并进行组织病理学评估。

结果

胆管结扎（BDL）3周后，转氨酶水平升高，出现明显的炎症浸润和肝细胞凋亡，并伴有氧化应激诱导，脂质过氧化增加反映了这一点。相反，用CB2激动剂AM-1241治疗后，BDL大鼠的肝损伤减轻，纤维化程度降低，这通过羟脯氨酸和α平滑肌肌动蛋白的表达得以体现。AM1241治疗还显著减轻了脂质过氧化终产物、p53依赖性凋亡，并通过刺激IL-10的产生减轻了炎症过程。此外，AM1241治疗的大鼠与肝祖细胞/卵圆细胞标志物的显著表达相关。

结论

总之，本研究指出，CB2受体通过不同机制减轻肝损伤并促进肝脏再生，这些机制包括IL-10依赖性炎症抑制、p53依赖凋亡的减少以及卵圆细胞/祖细胞的刺激。这些结果表明，CB2激动剂除了具有抗纤维化作用外，还具有强大的肝再生特性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/c6eb8b425517/OAMJMS-7-925-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/c9a03bb4504c/OAMJMS-7-925-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/32e898c10d44/OAMJMS-7-925-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/866d4983502b/OAMJMS-7-925-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/c6eb8b425517/OAMJMS-7-925-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/c9a03bb4504c/OAMJMS-7-925-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/4cc5c2d095af/OAMJMS-7-925-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/f3eb81e658b1/OAMJMS-7-925-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/0c48f23ae62b/OAMJMS-7-925-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/32e898c10d44/OAMJMS-7-925-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/866d4983502b/OAMJMS-7-925-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f9c/6454175/c6eb8b425517/OAMJMS-7-925-g007.jpg

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