How can transforming growth factor beta be targeted usefully to combat liver fibrosis?
How can transforming growth factor beta be targeted usefully to combat liver fibrosis?
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DOI：
10.1097/00042737-200402000-00001
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发表时间：
2004-02-01
影响因子：
2.1
通讯作者：
Benyon, RC
中科院分区：
文献类型：
--
作者：
Shek, FW;Benyon, RC
在动物模型中，阻断转化生长因子β (tgf - β)活性已被证明是抑制各种器官损伤纤维化反应的有效手段。同样，人工增强TGF-beta1表达的转基因动物表现出明显的自发纤维化或对损伤的纤维化反应增强。已知tgf - β影响纤维增生，不仅通过其众所周知的增加细胞外基质合成的作用，还通过协调调节介导结缔组织稳态的关键蛋白。这包括间质胶原酶和其他基质金属蛋白酶的下调和抗蛋白酶如金属蛋白酶I的组织抑制剂和纤溶酶原激活物抑制剂的上调。虽然对tgf - β活性的抑制在啮齿类动物中表现出数周的良好耐受性，但tgf - β 1敲除小鼠的最终致死表型警告我们，这种多能细胞因子对正常健康至关重要。因此，tgf - β激活的下游通路可能对其纤维化作用具有特异性，可能是人类纤维化疾病治疗中更有用的靶点。例如，tgf - β反应蛋白结缔组织生长因子可能是抗纤维化的良好靶点，但明确的证据有待于合适的转基因动物模型和特异性抑制剂的发展。(C) 2004利平科特·威廉姆斯·威尔金斯。
Blockade of transforming growth factor beta (TGF-beta) activity in vivo in animal models has proven to be an effective means of inhibiting the fibrotic response to injury in various organs. Similarly, transgenic animals in which TGF-beta1 expression is artificially enhanced show marked spontaneous fibrosis or increased fibrotic response to injury. TGF-beta is known to effect fibroplasias, not only by its well known action of increasing extracellular matrix synthesis but also by coordinately regulating key proteins which mediate connective tissue homeostasis. This includes down-regulation of interstitial collagenase and other matrix metalloproteinases and up-regulation of antiproteases such as tissue inhibitor of metalloproteinase I and plasminogen activator inhibitor. Whilst inhibition of TGF-beta activity appears to be well tolerated in rodents over several weeks, the ultimately lethal phenotype of TGF-beta1 knockout mice warns us that this pluripotent cytokine is essential for normal health. Therefore, downstream pathways activated by TGF-beta, which might be specific for its fibrotic effects, might be more useful targets for human fibrotic disease therapy. For example, the TGF-beta response protein connective tissue growth factor may be a good target for antifibrotics but definitive evidence awaits development of suitable genetically modified animal models and specific inhibitors. (C) 2004 Lippincott Williams Wilkins.