Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection
Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection
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DOI：
10.1016/j.hepres.2005.09.027
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发表时间：
2005-10-01
影响因子：
4.2
通讯作者：
Buckingham, RE
中科院分区：
文献类型：
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作者：
Buckingham, RE
过氧化物酶体增殖体激活受体γ (PPAR γ)是一种核转录因子，是噻唑烷二酮（TZD）胰岛素增敏药物的主要分子靶点。虽然在人类的许多组织中表达，但它在脂肪组织中的大量表达被认为是TZDs调节参与糖脂代谢的基因的焦点，并通过这些药物最终改善2型糖尿病的高血糖。然而，tzd表现出许多额外的特性，尤其是一系列表明炎症过程广泛攻击的效应。因此，TZDs已被证明可以降低血浆趋化因子、单核细胞趋化蛋白-1 （MCP-1）、抗纤溶蛋白、纤溶酶原激活物抑制剂-1 （PAI-1）、内皮细胞粘附分子、e-选择素和细胞间粘附分子-1 （ICAM-1）、白细胞活化分子CD40L和组织重塑酶基质金属蛋白酶-9 （MMP-9）的水平。进一步的确凿证据表明，TZDs减少了经典代谢综合征患者的全身性炎症，其原因是白细胞计数、p选择素阳性血小板以及急性期炎症蛋白、c反应蛋白、血清淀粉样蛋白a和纤维蛋白原的下降。在组织水平上，TZDs改善血管内皮功能，降低颈动脉内膜-内侧增厚的进展速度和2型糖尿病的微量白蛋白尿。此外，TZDs已被证明对牛皮癣、溃疡性结肠炎和非酒精性脂肪性肝炎（NASH）等广泛的炎症性疾病有效。在后者的情况下，可以看到广泛的tzd相关特性。在这里，这些药物改善胰岛素对葡萄糖代谢的敏感性，减少高胰岛素血症，肝脂肪变性，炎症和纤维化，降低肝脏转氨酶（ALT， AST），碱性磷酸酶和γ谷氨酰转移酶的循环水平。这些对人类的影响也得到了动物调查和体外研究的充分支持。对肝纤维化的改善作用特别令人感兴趣，因为它们表明tzd能够激活一个纠正组织重塑的程序。这种作用的基础可能部分是抑制肝星状细胞分泌基质蛋白的能力。类似的作用也见于肾系膜细胞。总之，tzd是重要的新药，目前用于治疗2型糖尿病，但具有一系列特性，表明它们有可能治疗许多退行性炎症性疾病，包括NASH。然而，需要对TZD进行全面、长期的临床试验，以测试其治疗NASH的潜力，不仅是因为原型TZD曲格列酮的（肝毒性）遗产，而且还因为肝病负担的不断增加，伴随着全球临床肥胖和2型糖尿病的日益流行。2005爱思唯尔爱尔兰有限公司版权所有。
Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear transcription factor that comprises the primary molecular target For thiazolidinedione (TZD) insulin-sensitizing drugs. Whilst expressed in many tissues in humans, its abundant expression in adipose tissue is believed to be the focal point through which TZDs regulate genes involved in glucose and lipid metabolism and via which these agents ultimately improve the hyperglycemia of type 2 diabetes. However, TZDs exhibit many additional properties, not least an array of effects which suggest a broad attack oil the inflammatory process. Thus, TZDs have been shown to reduce plasma levels of the chemokine, monocyte chemotactic protein-1 (MCP-1), the anti-fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1), the endothelial cell adhesion molecules, e-selectin and inter-cellular adhesion molecule-1 (ICAM-1), the leucocyte-activating molecule, CD40L, and the tissue-remodeling enzyme, matrix metalloproteinase-9 (MMP-9). Further tangible evidence of a reduction by TZDs of' systemic inflammation in patients with the classical metabolic syndrome sterns from falls in the white blood cell Count, P-selectin-positive platelets and in the acute-phase inflammatory proteins, C-reactive protein, serum amyloid A and fibrinogen.At the tissue level, TZDs improve vascular endothelial function, and reduce the rate of progression of intimal-medial thickening of the carotid artery and the microalbuminuria of type 2 diabetes. Further, TZDs have been shown to be efficacious ill inflarnmatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis (NASH). In the case of the latter, a broad spectrum of TZD-related properties is visible. Here, these drugs improve insulin sensitivity for glucose metabolism, reduce hyperinsulinemia, hepatic steatosis, inflammation and fibrosis, and lower the circulating levels of liver transaminases (ALT, AST), alkaline phosphatase and gamma glutamyl transferase. These effects in humans are also well-supported by investigative animal and in vitro studies. The ameliorative effects on liver fibrosis are of particular interest since they suggest that TZDs are able to activate a program of corrective tissue-remodeling. The basis for this action may be partly an ability to inhibit matrix protein secretion by hepatic stellate cells. An analogous action has also been seen in kidney mesangial cells.In conclusion, TZDs are important new drugs, presently indicated for the treatment of type 2 diabetes but with a spectrum of properties which suggests their potential for treating a number of degenerative inflammatory diseases, including NASH. However, full-scale, long-term clinical trials are needed with TZDs to test their potential to treat NASH, not least because of the (hepatotoxic) legacy of the prototype TZD, troglitazone, but also ill view of the escalating burden of liver disease which is accompanying the increasing global prevalence of clinical obesity and type 2 diabetes. (c) 2005 Elsevier Ireland Ltd. All rights reserved.