Szuster-Ciesielska Agnieszka, Plewka Krzysztof, Daniluk Jadwiga, Kandefer-Szerszeń Martyna
Department of Virology and Immunology, Maria Curie-Skłodowska University, Agnieszka Szuster-Ciesielska, Akademicka 19, 20-033 Lublin, Poland.
Biochem Pharmacol. 2009 Aug 1;78(3):301-14. doi: 10.1016/j.bcp.2009.04.009. Epub 2009 Apr 17.
BACKGROUND/AIMS: Zinc has been reported to prevent and reverse liver fibrosis in vivo; however, the mechanisms of its action are poorly understood. We therefore aimed to determine the antifibrotic potential of zinc.
Assessed was the influence of preincubation of rat HSCs with 30 microM ZnCl2 on ethanol- (in the presence of 4-methyl pyrazole (4-MP)) or acetaldehyde-induced toxicity, apoptosis, migration, expression of smooth muscle alpha-actin (alpha-SMA) and procollagen I, release of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-alpha), tumor growth factor-beta1 (TGF-beta1), metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases (TIMPs) production. Intracellular signals such as nuclear factor-kappaB (NFkappaB), C-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) induced by ethanol and its metabolite were also assessed.
30 microM zinc protected HSCs against ethanol and acetaldehyde toxicity and inhibited their apoptosis. Zinc inhibited the production of ROS by HSCs treated with ethanol and acetaldehyde and inhibited their migration. Zinc also inhibited ethanol- and acetaldehyde-induced TGF-beta1 and TNF-alpha production. Zinc down-regulated ethanol- and acetaldehyde-induced production of TIMP-1 and TIMP-2 and decreased the activity of MMP-2. In ethanol- and acetaldehyde-induced HSCs, zinc inhibited the activation of the p38 MAPK as well as the JNK transduction pathways and phosphorylation of IkappaB and Smad 3.
The results indicated that zinc supplementation inhibited ethanol- and acetaldehyde-induced activation of HSCs on different levels, acting as an antioxidant and inhibitor of MAPK, TGF-beta and NFkappaB/IkappaB transduction signaling. The remarkable inhibition of several markers of HCS activation makes zinc a promising agent for antifibrotic combination therapies.
背景/目的：据报道，锌在体内可预防和逆转肝纤维化；然而，其作用机制尚不清楚。因此，我们旨在确定锌的抗纤维化潜力。
评估用30微摩尔/升氯化锌预孵育大鼠肝星状细胞（HSCs）对乙醇（在4-甲基吡唑（4-MP）存在下）或乙醛诱导的毒性、凋亡、迁移、平滑肌α-肌动蛋白（α-SMA）和I型前胶原表达、活性氧（ROS）释放、肿瘤坏死因子-α（TNF-α）、肿瘤生长因子-β1（TGF-β1）、金属蛋白酶-2（MMP-2）和金属蛋白酶组织抑制剂（TIMPs）产生的影响。还评估了乙醇及其代谢产物诱导的细胞内信号，如核因子-κB（NFκB）、C-Jun氨基末端激酶（JNK）和p38丝裂原活化蛋白激酶（p38 MAPK）。
30微摩尔/升锌可保护HSCs免受乙醇和乙醛毒性，并抑制其凋亡。锌抑制乙醇和乙醛处理的HSCs产生ROS，并抑制其迁移。锌还抑制乙醇和乙醛诱导的TGF-β1和TNF-α产生。锌下调乙醇和乙醛诱导的TIMP-1和TIMP-2产生，并降低MMP-2活性。在乙醇和乙醛诱导的HSCs中，锌抑制p38 MAPK以及JNK转导途径的激活和IkappaB和Smad 3的磷酸化。
结果表明，补充锌可在不同水平上抑制乙醇和乙醛诱导的HSCs激活，作为MAPK、TGF-β和NFκB/IκB转导信号的抗氧化剂和抑制剂。对HCS激活多种标志物的显著抑制使锌成为抗纤维化联合治疗的有前景药物。
