Crisby Milita
Neurotec, Division of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Drugs Today (Barc). 2003 Feb;39(2):137-43. doi: 10.1358/dot.2003.39.2.740209.
Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.
他汀类药物通过竞争性抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶来降低胆固醇水平，该酶是调节胆固醇合成的关键酶。他汀类药物的降胆固醇作用还归因于细胞内胆固醇耗竭和低密度脂蛋白（LDL）受体表达增强导致细胞对胆固醇摄取增加。他汀类药物作为降脂药物的使用已使缺血性心脏病的治疗和预防发生了显著变化。对缺血性心脏病患者进行的大型临床试验结果表明，他汀类药物可降低炎症标志物，如C反应蛋白，这是该疾病的一个独立危险因素。他汀类药物具有超出其降脂作用的特性。这些非降脂特性包括通过减少许多非甾体类异戊二烯化合物的合成来抑制类异戊二烯途径。对他汀类药物免疫调节作用的关注源于普伐他汀治疗心脏移植患者的积极结果，以及血管造影回归研究表明，尽管心脏事件大幅减少，但冠状动脉狭窄程度变化不显著。尽管LDL胆固醇与中风风险没有直接关联，但他汀类药物治疗可降低缺血性中风的风险。这一观察结果促使人们研究他汀类药物在炎症和免疫系统中的作用。最近的研究数据表明，他汀类药物可抑制干扰素-γ（IFN-γ）诱导的主要组织相容性（MHC）II类表达，从而抑制MHC II介导的T细胞活化。此外，他汀类药物可抑制单核细胞、黏附分子以及整合素依赖性白细胞黏附上特定细胞表面受体的表达。虽然他汀类药物可能会刺激外周血单核细胞分泌半胱天冬酶-1、白细胞介素-1β和白细胞介素-18以应对结核分枝杆菌，但它们在体外通过减少人血管平滑肌细胞（VSMC）中白细胞介素-6的合成对炎症表现出额外的作用。本专著的重点是突出他汀类药物在调节免疫系统和炎症过程中的作用。
