A strategy of vascular-targeted therapy for liver fibrosis.
A strategy of vascular-targeted therapy for liver fibrosis.
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DOI：
10.1002/hep.32299
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发表时间：
2022-09
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目前尚无有效的治疗方法可用于肝纤维化。血管生成与肝纤维化密切相关。然而，目前有争议的结果表明，通过血管靶向治疗肝纤维化是困难的。肝脏中有三种不同的微血管：门静脉血管、肝窦和中央血管。这三种不同血管在肝纤维化过程中的变化和作用尚不清楚。我们认为，它们在肝纤维化过程中发挥着不同的作用，单一的血管内皮细胞（EC）调节剂不足以完全调节这三种血管来治疗肝纤维化。因此，联合调控多种不同的EC调控信号通路可能为肝纤维化的治疗提供新的策略。在本文中，我们提出了一种概念验证策略，将白细胞源性趋化因子2（LECT 2）/酪氨酸激酶与免疫球蛋白样和表皮生长因子样结构域1信号传导的调节与血管内皮生长因子（VEGF）/重组VEGF（rVEGF）信号传导的调节相结合。CCl 4诱导的小鼠肝纤维化模型和NASH模型均使用。在肝纤维化形成过程中，肝血管的改变发生在肝纤维化形成的早期，不同的肝血管表现出不同的变化，并发挥不同的作用：门静脉血管减少，血窦毛细血管化增加，中央血管增多。门静脉血管增多促进肝纤维化，中央血管增多促进肝纤维化，血窦毛细血管化增多促进肝纤维化。腺相关病毒载体血清型9（AAV 9）-LECT 2-短发夹RNA（shRNA）和rVEGF的联合治疗显示出改善的治疗效果，但它导致了严重的副作用。AAV 9-LECT 2-shRNA和贝伐珠单抗的组合显示出改善的治疗效果和降低的副作用。肝纤维化早期即出现肝血管改变。不同的血管在肝纤维化中起着不同的作用。AAV 9-LECT 2-shRNA联合贝伐单抗治疗肝纤维化可显著提高治疗效果。
No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof‐of‐concept strategy by combining the regulation of leukocyte cell‐derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin‐like and epidermal growth factor–like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling. The CCl4‐induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno‐associated viral vector serotype 9 (AAV9)–LECT2–short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9‐LECT2‐shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects. Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9‐LECT2‐shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
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Itzkovitz S
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16.6
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Lin Y;Fang ZP;Liu HJ;Wang LJ;Cheng Z;Tang N;Li T;Liu T;Han HX;Cao G;Liang L;Ding YQ;Zhou WJ
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Zhou WJ
影响因子：
5.1
作者：
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Kim, W. Ray
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13.5
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Kantari-Mimoun, Chahrazade;Castells, Magali;Stockmann, Christian
通讯作者：
Stockmann, Christian
影响因子：
23.9
作者：
Matsumoto, Tomonori;Wakefield, Leslie;Grompe, Markus
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Grompe, Markus