CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis.
CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis.
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DOI：
10.1136/gutjnl-2013-306294
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发表时间：
2014-12
期刊：
影响因子：
24.5
通讯作者：
Tacke F
中科院分区：
文献类型：
--
作者：
Ehling J;Bartneck M;Wei X;Gremse F;Fech V;Möckel D;Baeck C;Hittatiya K;Eulberg D;Luedde T;Kiessling F;Trautwein C;Lammers T;Tacke F
在慢性肝损伤中，血管生成，即从先前存在的血管形成新血管，可能有助于进行性肝纤维化和肝细胞癌的发展。虽然缺氧诱导的血管内皮生长因子（VEGF）的表达发生在晚期纤维化，我们假设，炎症可能支持肝血管生成已经在纤维化的早期阶段。在肝脏Microfil灌注后，使用体内对比增强微计算机断层扫描（CT）和离体解剖μCT无创监测四氯化碳（CCl 4）或胆管结扎（BDL）诱导的慢性肝损伤后c57 BL/6小鼠肝脏中的血管生成。通过使用Spiegelmer mNOX-E36对CCL 2的药理学抑制来探索单核细胞衍生的巨噬细胞亚群对血管生成的功能贡献。对比度增强的体内μCT成像允许无创监测血管生成的密切相关性，通过功能性肝血管扩张反映，与实验性纤维化进展。在细胞水平上，炎性单核细胞衍生的巨噬细胞大量积聚在损伤的肝脏中，与汇管区中新形成的血管共定位，并表现出促血管生成基因谱，包括上调的VEGF和MMP 9。功能性体内和解剖学离体μCT分析表明，通过靶向趋化因子CCL 2抑制单核细胞浸润可预防纤维化相关的血管生成，但不能预防纤维化进展。单核细胞衍生的巨噬细胞主要促进门静脉道内的萌芽血管生成。门静脉直径作为门静脉高压的衡量标准依赖于纤维化，但不依赖于血管生成。炎症相关血管生成在纤维化进展期间由CCL 2依赖性单核细胞促进。创新的体内μCT方法可以准确监测实验性肝纤维化的血管生成和抗血管生成治疗效果。
In chronic liver injury, angiogenesis, the formation of new blood vessels from pre-existing ones, may contribute to progressive hepatic fibrosis and to development of hepatocellular carcinoma. Although hypoxia-induced expression of vascular endothelial growth factor (VEGF) occurs in advanced fibrosis, we hypothesized that inflammation may endorse hepatic angiogenesis already at early stages of fibrosis. Angiogenesis in livers of c57BL/6 mice upon carbon tetrachloride (CCl4) or bile duct ligation (BDL) induced chronic hepatic injury was non-invasively monitored using in vivo contrast-enhanced micro-computed tomography (CT) and ex vivo anatomical μCT after hepatic Microfil perfusion. Functional contributions of monocyte-derived macrophage subsets for angiogenesis were explored by pharmacological inhibition of CCL2 using the Spiegelmer mNOX-E36. Contrast-enhanced in vivo μCT imaging allowed non-invasively monitoring the close correlation of angiogenesis, reflected by functional hepatic blood vessel expansion, with experimental fibrosis progression. On a cellular level, inflammatory monocyte-derived macrophages massively accumulated in injured livers, co-localized with newly formed vessels in portal tracts and exhibited pro-angiogenic gene profiles including up-regulated VEGF and MMP9. Functional in vivo and anatomical ex vivo μCT analyses demonstrated that inhibition of monocyte infiltration by targeting the chemokine CCL2 prevented fibrosis-associated angiogenesis, but not fibrosis progression. Monocyte-derived macrophages primarily fostered sprouting angiogenesis within the portal vein tract. Portal vein diameter as a measure of portal hypertension depended on fibrosis, but not on angiogenesis. Inflammation-associated angiogenesis is promoted by CCL2-dependent monocytes during fibrosis progression. Innovative in vivo μCT methodology can accurately monitor angiogenesis and anti-angiogenic therapy effects in experimental liver fibrosis.
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影响因子：
29.4
作者：
Huwart, Laurent;Sempoux, Christine;Van Beers, Bernard E.
通讯作者：
Van Beers, Bernard E.
DOI：
10.1084/jem.20120690
发表时间：
2013-11-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Avraham-Davidi I;Yona S;Grunewald M;Landsman L;Cochain C;Silvestre JS;Mizrahi H;Faroja M;Strauss-Ayali D;Mack M;Jung S;Keshet E
通讯作者：
Keshet E
影响因子：
6.7
作者：
Ehling J;Lammers T;Kiessling F
通讯作者：
Kiessling F
影响因子：
13.5
作者：
Bedossa, P;Dargère, D;Paradis, V
通讯作者：
Paradis, V
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.