Han Kun, Zhang Yanting, Yang Zhenwei
Department of Gastroenterology, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China.
Exp Ther Med. 2019 Mar;17(3):2381-2388. doi: 10.3892/etm.2019.7207. Epub 2019 Jan 28.
Alcohol abuse and chronic alcohol consumption are major causes of alcoholic liver disease worldwide, particularly alcohol-induced hepatic fibrosis (AHF). Liver fibrosis is an important public health concern because of its high morbidity and mortality. The present study examined the mechanisms and effects of the phosphodiesterase III inhibitor cilostazol on AHF. Rats received alcohol infusions via gavage to induce liver fibrosis and were treated with colchicine (positive control) or cilostazol. The serum alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) activities and the albumin/globulin (A/G), enzymes and hyaluronic acid (HA), type III precollagen (PC III), laminin (LA), and type IV collagen (IV-C) levels were measured using commercially available kits. α-smooth muscle actin (α-SMA), collagen I and III, transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), adenosine 3',5'-cyclic monophosphate (cAMP) and exchange protein directly activated by cAMP (Epac) 1/2 expression in liver tissue were measured using western blotting. The results demonstrated that cilostazol significantly increased the serum ADH and ALDH activities and decreased the liver hydroxyproline levels. Cilostazol increased the serum A/G ratio and inhibited the total serum protein, enzymes, HA, PCIII, LA and IV-C levels. Western blotting revealed that cilostazol effectively decreased liver α-SMA, collagen I and III, TGF-β1 and CTGF expression. Cilostazol significantly increased the cAMP and Epac1 levels in hepatic tissue. The present study suggests that cilostazol protects rats against AHF via suppression of TGF-β1/CTGF activation and the cAMP/Epac1 pathway.
酒精滥用和长期饮酒是全球范围内酒精性肝病的主要原因，尤其是酒精性肝纤维化（AHF）。肝纤维化因其高发病率和死亡率而成为一个重要的公共卫生问题。本研究探讨了磷酸二酯酶III抑制剂西洛他唑对AHF的作用机制和影响。通过灌胃给大鼠输注酒精以诱导肝纤维化，并用秋水仙碱（阳性对照）或西洛他唑进行治疗。使用市售试剂盒测定血清乙醇脱氢酶（ADH）和乙醛脱氢酶（ALDH）活性以及白蛋白/球蛋白（A/G）、酶和透明质酸（HA）、III型前胶原（PC III）、层粘连蛋白（LA）和IV型胶原（IV-C）水平。使用蛋白质印迹法测定肝组织中α-平滑肌肌动蛋白（α-SMA）、I型和III型胶原、转化生长因子-β1（TGF-β1）、结缔组织生长因子（CTGF）、腺苷3',5'-环磷酸（cAMP）和cAMP直接激活的交换蛋白（Epac）1/2的表达。结果表明，西洛他唑显著提高了血清ADH和ALDH活性，并降低了肝脏羟脯氨酸水平。西洛他唑提高了血清A/G比值，并抑制了血清总蛋白、酶、HA、PCIII、LA和IV-C水平。蛋白质印迹显示，西洛他唑有效降低了肝脏α-SMA、I型和III型胶原、TGF-β1和CTGF的表达。西洛他唑显著提高了肝组织中cAMP和Epac1水平。本研究表明，西洛他唑通过抑制TGF-β1/CTGF激活和cAMP/Epac1途径保护大鼠免受AHF侵害。
