Department of Bio-Nanotechnology and Bio-Convergence Engineering, Jeonbuk National University, Jeonju, South Korea.
Department of Animal Biotechnology & Agricultural Convergence Technology, Jeonbuk National University, Jeonju, South Korea.
J Transl Med. 2022 Dec 13;20(1):590. doi: 10.1186/s12967-022-03808-7.
Kinin B1 receptors (B1Rs) are implicated in the pathogenesis of fibrosis. This study examined the anti-fibrotic effects of B1R blockade with BI 113823 in two established mouse models of hepatic fibrosis induced by intraperitoneal carbon tetrachloride (CCl) injection or bile duct ligation (BDL). The mechanisms underlying the protection afforded by B1R inhibition were examined using human peripheral blood cells and LX2 human hepatic stellate cells (HSCs).
Fibrotic liver diseases were induced in mice by intraperitoneal carbon tetrachloride (CCl) injection for 6 weeks, and by bile duct ligation (BDL) for 3 weeks, respectively. Mice received daily treatment of vehicle or BI 113823 (B1R antagonist) from onset of the experiment until the end of the study.
B1Rs were strongly induced in fibrotic mouse liver. BI 113823 significantly attenuated liver fibrosis and portal hypertension (PH), and improved survival in both CCl and BDL mice. BI 113823 significantly reduced the expression of fibrotic proteins α-SMA, collagens 1, 3, 4, and profibrotic growth factors PDGF, TGFβ, CTGF, VEGF, proliferating cell nuclear antigen; and reduced hepatic Akt phosphorylation in CCl- and BDL-induced liver fibrosis. BI 113823 also reduced expression of Cytokines IL-1, IL-6; chemokines MCP-1, MCP-3 and infiltration of inflammatory cells; and inhibited human monocyte and neutrophil activation, transmigration, TNF-α & MPO production in vitro. BI 113823 inhibited TGF-β and B1R agonist-stimulated human-HSC activation, contraction, proliferation, migration and fibrosis protein expression, and inhibited activation of PI3K/Akt signalling pathway.
B1Rs merits consideration as a novel therapeutic target for chronic liver fibrosis and PH.
激肽 B1 受体（B1R）参与纤维化的发病机制。本研究在经腹腔注射四氯化碳（CCl）或胆管结扎（BDL）建立的两种肝纤维化小鼠模型中，研究了 B1R 阻断剂 BI 113823 的抗纤维化作用。使用人外周血细胞和 LX2 人肝星状细胞（HSCs）研究了 B1R 抑制所提供的保护作用的机制。
通过腹腔注射四氯化碳（CCl）6 周和胆管结扎（BDL）3 周分别在小鼠中诱导纤维性肝病。从实验开始到研究结束，小鼠每天接受载体或 BI 113823（B1R 拮抗剂）治疗。
B1R 在纤维化的小鼠肝脏中强烈诱导。BI 113823 显著减轻 CCl 和 BDL 小鼠的肝纤维化和门静脉高压（PH），并提高存活率。BI 113823 显著降低了α-SMA、胶原 1、3、4 和促纤维化生长因子 PDGF、TGFβ、CTGF、VEGF、增殖细胞核抗原的表达；并降低了 CCl 和 BDL 诱导的肝纤维化中肝 Akt 磷酸化。BI 113823 还降低了细胞因子 IL-1、IL-6；趋化因子 MCP-1、MCP-3 和炎症细胞浸润；并抑制了体外人单核细胞和中性粒细胞的激活、迁移、TNF-α 和 MPO 的产生。BI 113823 抑制了 TGF-β 和 B1R 激动剂刺激的人-HSC 激活、收缩、增殖、迁移和纤维化蛋白表达，并抑制了 PI3K/Akt 信号通路的激活。
B1R 作为慢性肝纤维化和 PH 的新型治疗靶点值得考虑。
