Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis.
Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis.
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DOI：
10.1002/hep.23144
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发表时间：
2009-11
期刊：
影响因子：
13.5
通讯作者：
Schuppan, Detlef
中科院分区：
文献类型：
--
作者：
Patsenker, Eleonora;Popov, Yury;Stickel, Felix;Schneider, Vreni;Ledermann, Monika;Saegesser, Hans;Niedobitek, Gerald;Goodman, Simon L.;Schuppan, Detlef
玻连蛋白受体整合素α v β 3（αvβ3）通过介导内皮细胞的迁移和增殖促进血管生成，但也在体外驱动肝星状细胞（HSC）的纤维化活化。在预期抗纤维化协同作用的情况下，我们研究了αvβ3抑制剂在两种体内肝纤维化模型中的作用。通过胆管结扎（BDL）6周或硫代乙酰胺（TAA）注射12周诱导大鼠肝纤维化。在BDL期间或TAA给药后，以15 mg/kg的剂量i. p.给予特异性αvβ3（αvβ5）抑制剂（西仑吉肽），每日两次。肝胶原测定为羟脯氨酸和基因表达定量PCR。通过CD 31、CD 68和HIF-1α免疫组化检测肝脏血管生成、巨噬细胞浸润和缺氧情况。西仑吉肽减少了整体血管形成。这在BDL的汇管区和TAA纤维化大鼠的间隔区中是显著的，并且与肝胶原蛋白显著增加31%（BDL）和27%（TAA）以及促纤维化基因和基质金属蛋白酶-13的上调相关。治疗增加了两种模型中的GGT，而其他血清标志物保持不变。αvβ3抑制导致轻度肝脏缺氧，缺氧诱导基因上调证明了这一点。尽管TNF-α、IL-18和考克斯-2 mRNA的增加表明中度巨噬细胞活化，但巨噬细胞/枯否细胞的肝脏浸润未受影响。尽管在体外对HSC具有抗纤维化作用，但在体内特异性抑制整合素αvβ3（αvβ5）可减少血管生成，但可加重胆管（BDL）和间隔（TAA）纤维化。肝纤维化患者应慎用血管生成抑制剂。(248话）。
The vitronectin receptor integrin alpha v beta 3 (αvβ3) promotes angiogenesis by mediating migration and proliferation of endothelial cells, but also drives fibrogenic activation of hepatic stellate cells (HSC) in vitro. Expecting antifibrotic synergism, we studied the effect of αvβ3 inhibition in two in vivo models of liver fibrogenesis. Liver fibrosis was induced in rats by bile duct ligation (BDL) for 6 weeks or by thioacetamide (TAA) injections for 12 weeks. A specific αvβ3 (αvβ5) inhibitor (Cilengitide) was given i.p. twice daily at 15 mg/kg during BDL or after TAA-administration. Liver collagen was determined as hydroxyproline and gene expression was quantified by quantitative PCR. Liver angiogenesis, macrophage infiltration and hypoxia were assessed by CD31, CD68 and HIF-1α immunostaining. Cilengitide decreased overall vessel formation. This was significant in portal areas of BDL and septal areas of TAA fibrotic rats, and was associated with a significant increase of liver collagen by 31% (BDL) and 27% (TAA), and upregulation of profibrogenic genes and matrix metalloproteinase-13. Treatment increased GGT in both models, while other serum markers remained unchanged. αvβ3 inhibition resulted in mild liver hypoxia, as evidenced by upregulation of hypoxia inducible genes. Liver infiltration by macrophages/Kupffer cells was not affected, although increases in TNF-α, IL-18 and COX-2 mRNA indicated modest macrophage activation. Specific inhibition of integrin αvβ3 (αvβ5) in vivo decreased angiogenesis but worsened biliary (BDL) and septal (TAA) fibrosis, despite its antifibrogenic effect on HSC in vitro. Angiogenesis inhibitors should be used with caution in patients with hepatic fibrosis. (248 words).
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影响因子：
50.5
作者：
Hariharan, S.;Gustafson, D.;Eckhardt, S. G.
通讯作者：
Eckhardt, S. G.
影响因子：
13.5
作者：
Kitade, Mitsuteru;Yoshiji, Hitoshi;Fukui, Hiroshi
通讯作者：
Fukui, Hiroshi
DOI：
10.1163/156856207781034179
发表时间：
2007-06-01
影响因子：
3.6
作者：
Chung, Amy S.;Gao, Qiang;Kao, Weiyuan John
通讯作者：
Kao, Weiyuan John
影响因子：
8.4
作者：
Eskens, FALM;Dumez, H;van Oosterom, AT
通讯作者：
van Oosterom, AT
整联蛋白信号传导对于病理血管生成至关重要。
影响因子：
15.3
作者：
Mahabeleshwar, Ganapati H.;Feng, Weiyi;Phillips, David R.;Byzova, Tatiana V.
通讯作者：
Byzova, Tatiana V.