Traber Peter G, Zomer Eliezer
Galectin Therapeutics Inc, Norcross, Georgia, United States of America ; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Galectin Therapeutics Inc, Norcross, Georgia, United States of America.
PLoS One. 2013 Dec 18;8(12):e83481. doi: 10.1371/journal.pone.0083481. eCollection 2013.
Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without effective therapy. Some data suggest that galectin-3 null mice are resistant to the development of NASH with fibrosis. We examined the ability of two complex carbohydrate drugs that bind galectin-3, GM-CT-01 and GR-MD-02, to treat NASH with fibrosis in a murine model. GR-MD-02 treatment resulted in marked improvement in liver histology with significant reduction in NASH activity and collagen deposition. Treatments seemed also to improve both glomerulopathy and interstitial fibrosis observed in kidneys. The improvement in liver histology was evident when animals were treated early in disease or after establishment of liver fibrosis. In all measures, GM-CT-01 had an intermediate effect between vehicle and GR-MD-02. Galectin-3 protein expression was increased in NASH with highest expression in macrophages surrounding lipid laden hepatocytes, and reduced following treatment with GR-MD-02, while the number of macrophages was unchanged. Treatment with GR-MD-02 also reduced the expression of pathological indicators including iNOS, an important TH1 inflammatory mediator, CD36, a scavenger receptor for lipoproteins on macrophages, and α-smooth muscle actin, a marker for activated stellate cells which are the primary collagen producing cells in liver fibrosis. We conclude that treatment with these galectin-3 targeting drugs improved histopathological findings of NASH and markedly reduced fibrosis in a murine model of NASH. While the mechanisms require further investigation, the treatment effect is associated with a reduction of galectin-3 expressed by activated macrophages which was associated with regression of NASH, including hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory infiltrate, and deposition of collagen. Similar effects were found with GM-CT-01, but with approximately four-fold lower potency than GR-MD-02. The results, in combination with previous experiments in toxin-induced fibrosis, suggest that these galectin-targeting drugs may have potential in human NASH with fibrosis.
非酒精性脂肪性肝炎（NASH）及由此导致的肝纤维化是一个缺乏有效治疗方法的重大健康问题。一些数据表明，半乳糖凝集素-3基因敲除小鼠对NASH伴纤维化的发展具有抗性。我们研究了两种能与半乳糖凝集素-3结合的复合碳水化合物药物GM-CT-01和GR-MD-02在小鼠模型中治疗NASH伴纤维化的能力。GR-MD-02治疗使肝脏组织学显著改善，NASH活性和胶原沉积明显减少。治疗似乎还改善了在肾脏中观察到的肾小球病变和间质纤维化。当在疾病早期或肝纤维化形成后对动物进行治疗时，肝脏组织学的改善很明显。在所有指标中，GM-CT-01的作用介于赋形剂和GR-MD-02之间。在NASH中，半乳糖凝集素-3蛋白表达增加，在脂质负载肝细胞周围的巨噬细胞中表达最高，GR-MD-02治疗后表达降低，而巨噬细胞数量不变。GR-MD-02治疗还降低了包括诱导型一氧化氮合酶（iNOS，一种重要的TH1炎症介质）、CD36（巨噬细胞上脂蛋白的清道夫受体）和α-平滑肌肌动蛋白（肝纤维化中主要的胶原产生细胞——活化星状细胞的标志物）等病理指标的表达。我们得出结论，在NASH小鼠模型中，用这些靶向半乳糖凝集素-3的药物治疗可改善NASH的组织病理学表现并显著减少纤维化。虽然其机制需要进一步研究，但治疗效果与活化巨噬细胞表达的半乳糖凝集素-3减少有关，这与NASH的消退相关，包括肝细胞脂肪堆积、肝细胞气球样变、门静脉和小叶内炎症浸润以及胶原沉积。GM-CT-01也有类似效果，但效力约为GR-MD-02的四分之一。这些结果与之前毒素诱导纤维化的实验相结合，表明这些靶向半乳糖凝集素的药物可能对人类NASH伴纤维化具有潜在作用。
