Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Centro de investigación biomédica en red de enfermedades hepáticas y digestivas, University of Barcelona, Barcelona, Catalonia, Spain.
Hepatology. 2010 Mar;51(3):942-52. doi: 10.1002/hep.23419.
There is no effective therapy for advanced liver fibrosis. Angiotensin type 1 (AT1) receptor blockers attenuate liver fibrogenesis, yet their efficacy in reversing advanced fibrosis is unknown. We investigated whether the specific delivery of an AT1 receptor blocker to activated hepatic stellate cells (HSCs) reduces established liver fibrosis. We used a platinum-based linker to develop a conjugate of the AT1 receptor blocker losartan and the HSC-selective drug carrier mannose-6-phosphate modified human serum albumin (losartan-M6PHSA). An average of seven losartan molecules were successfully coupled to M6PHSA. Rats with advanced liver fibrosis due to prolonged bile duct ligation or carbon tetrachloride administration were treated with daily doses of saline, losartan-M6PHSA, M6PHSA or oral losartan during 3 days. Computer-based morphometric quantification of inflammatory cells (CD43), myofibroblasts (smooth muscle alpha-actin [alpha-SMA]) and collagen deposition (Sirius red and hydroxyproline content) were measured. Hepatic expression of procollagen alpha2(I) and genes involved in fibrogenesis was assessed by quantitative polymerase chain reaction. Losartan-M6PHSA accumulated in the fibrotic livers and colocalized with HSCs, as assessed by immunostaining of anti-HSA and anti-alpha-SMA. Losartan-M6PHSA, but not oral losartan, reduced collagen deposition, accumulation of myofibroblasts, inflammation and procollagen alpha2(I) gene expression. Losartan-M6PHSA did not affect metalloproteinase type 2 and 9 activity and did not cause apoptosis of activated HSCs.
Short-term treatment with HSC-targeted losartan markedly reduces advanced liver fibrosis. This approach may provide a novel means to treat chronic liver diseases.
对于晚期肝纤维化，尚无有效的治疗方法。血管紧张素 1 型（AT1）受体阻滞剂可减轻肝纤维化，但尚不清楚其逆转晚期纤维化的疗效。我们研究了将 AT1 受体阻滞剂特异性递送至活化的肝星状细胞（HSCs）是否可减少已建立的肝纤维化。我们使用基于铂的接头，开发了血管紧张素 1 型受体阻滞剂氯沙坦与 HSC 选择性药物载体甘露糖-6-磷酸修饰的人血清白蛋白（氯沙坦-M6PHSA）的缀合物。成功地将平均 7 个氯沙坦分子偶联到 M6PHSA 上。用长期胆管结扎或四氯化碳给药导致的晚期肝纤维化大鼠，在 3 天内每天接受盐水，氯沙坦-M6PHSA，M6PHSA 或口服氯沙坦治疗。通过计算机形态计量学定量测定炎性细胞（CD43），肌成纤维细胞（平滑肌α-肌动蛋白[α-SMA]）和胶原沉积（天狼星红和羟脯氨酸含量）。通过定量聚合酶链反应评估肝内前胶原 α2（I）和纤维化相关基因的表达。通过免疫染色抗 HSA 和抗-α-SMA 评估氯沙坦-M6PHSA 在纤维化肝脏中的积聚及其与 HSCs 的共定位。氯沙坦-M6PHSA，而不是口服氯沙坦，可减少胶原沉积，肌成纤维细胞积聚，炎症和前胶原 α2（I）基因表达。氯沙坦-M6PHSA 不影响基质金属蛋白酶 2 和 9 的活性，也不会引起活化的 HSCs 凋亡。
短期治疗 HSC 靶向氯沙坦可显著减轻晚期肝纤维化。这种方法可能为治疗慢性肝病提供一种新方法。
