Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites
Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites
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DOI：
10.1182/blood-2009-07-231209
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发表时间：
2009-12-17
期刊：
影响因子：
20.3
通讯作者：
Kontoyiannis, Dimitrios P.
中科院分区：
文献类型：
--
作者：
Ben-Ami, Ronen;Lewis, Russell E.;Kontoyiannis, Dimitrios P.
在易感宿主中，烟曲霉的血管侵入触发血栓形成、缺氧和促炎细胞因子释放，所有这些都是血管生成的刺激物。我们试图确定烟曲霉是否直接调节血管生成。烟曲霉培养物显著抑制人脐静脉内皮细胞的分化、迁移和毛细血管形成。为了测量感染部位的血管生成，我们设计了一种在环磷酰胺治疗的皮肤侵袭性曲霉病BALB/c小鼠体内基质胶测定。与未感染对照小鼠的基质胶栓塞相比，植入烟曲霉感染小鼠的基质胶栓塞的血管生成受到显著抑制。烟曲霉的抗血管生成作用被完全废除删除的全球调节剂的次级代谢，laeA，并在较小程度上删除gliP，它控制gliotoxin生产。此外，纯胶胶毒素在体外以剂量依赖性方式有效地抑制血管生成。最后，在早期侵袭性曲霉病期间，在可的松治疗的小鼠的肺中观察到多个血管生成介导物编码基因的过表达，而在环磷酰胺/可的松治疗的小鼠中，基因表达迅速恢复到基线水平。综上所述，这些结果表明，抑制血管生成的烟曲霉在体外和在小鼠模型中介导的次级代谢产物的产生。（血。2009; 114：5393-5399）
In susceptible hosts, angioinvasion by Aspergillus fumigatus triggers thrombosis, hypoxia, and proinflammatory cytokine release, all of which are stimuli for angiogenesis. We sought to determine whether A fumigatus directly modulates angiogenesis. A fumigatus culture filtrates profoundly inhibited the differentiation, migration, and capillary tube formation of human umbilical vein endothelial cells in vitro. To measure angiogenesis at the site of infection, we devised an in vivo Matrigel assay in cyclophosphamide-treated BALB/c mice with cutaneous invasive aspergillosis. Angiogenesis was significantly suppressed in Matrigel plugs implanted in A fumigatus-infected mice compared with plugs from uninfected control mice. The antiangiogenic effect of A fumigatus was completely abolished by deletion of the global regulator of secondary metabolism, laeA, and to a lesser extent by deletion of gliP, which controls gliotoxin production. Moreover, pure gliotoxin potently inhibited angiogenesis in vitro in a dose-dependent manner. Finally, overexpression of multiple angiogenesis mediator-encoding genes was observed in the lungs of cortisone-treated mice during early invasive aspergillosis, whereas gene expression returned rapidly to baseline levels in cyclophosphamide/cortisone-treated mice. Taken together, these results indicate that suppression of angiogenesis by A fumigatus both in vitro and in a neutropenic mouse model is mediated through secondary metabolite production. (Blood. 2009; 114: 5393-5399)