Lipoxin and synthetic lipoxin analogs: An overview of anti-inflammatory functions and new concepts in immunomodulation
Lipoxin and synthetic lipoxin analogs: An overview of anti-inflammatory functions and new concepts in immunomodulation
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DOI：
10.2174/187152806776383125
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发表时间：
2006-04-01
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影响因子：
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通讯作者：
Parkinson, John F.
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文献类型：
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作者：
Parkinson, John F.
脂氧素A（4）（LXA（4））和脂氧素B-4（LXB 4）是由Serhan及其同事于1984年首次鉴定的活化白细胞的5-和15-脂氧合酶相互作用产物。LXA（4）和LXB 4的内源性跨细胞生物合成通过白细胞与上皮、内皮或血小板的相互作用发生。阿司匹林对环氧合酶-2（考克斯-2）的乙酰化可触发15-epi-LXA（4）（ATL）的生物合成。1988年Nicolaou及其同事通过全合成LXA 4促进了脂氧素和ATL的药理作用的阐明。1994年，Fiore及其同事使用[H-3]-LXA（4）鉴定了人G蛋白偶联的高亲和力LXA（4）和ATL受体（ALX-R/FPRL-1）的cDNA，为脂氧素作用的分子基础提供了第一个线索。由于认识到脂氧素和ATL经历前列腺素脱氢酶（PGDH）介导的快速代谢失活，Serhan、Petasis及其同事在1995-1998年设计和合成了第一代PGDH抗性LXA（4）、LXB 4和ATL类似物。这些相对稳定的药理学药物，与骨髓特异性ALX-R表达转基因小鼠一起，为探索体内脂氧素功能提供了有力的工具。在这里，我们简要回顾了大量的证据支持脂氧素ALX-R途径作为一种新的和有效的机制，预防/解决急性炎症。重点也将放在最近的研究结果，脂氧素通过调节巨噬细胞，树突状细胞和T淋巴细胞效应器功能的极化T辅助细胞反应（Th-1和Th-2）的设置中发挥新的作用，在“免疫调节”。这些研究表明脂氧素作为过敏和适应性免疫的新型调节剂的作用，脂氧素可能在慢性免疫疾病中具有治疗潜力。
Lipoxin A(4) (LXA(4)) and lipoxin B-4 (LXB4) were first identified in 1984 by Serhan and colleagues as 5- and 15-lipoxygenase interaction products of activated leukocytes. Endogenous transcellular biosynthesis of LXA(4) and LXB4 occurs via interaction of leukocytes with epithelium, endothelium or platelets. Acetylation of cyclooxygenase-2 (COX-2) by aspirin can trigger 15-epi-LXA(4) (ATL) biosynthesis. Elucidating the pharmacological actions of lipoxins and ATL was facilitated by total synthesis of LXA4 in 1988 by Nicolaou and colleagues. In 1994, Fiore and colleagues used [H-3]-LXA(4) to identify the cDNA for a human G-protein-coupled, high affinity LXA(4) and ATL receptor (ALX-R/FPRL-1), providing the first hints for the molecular basis of lipoxin actions. The recognition that lipoxins and ATL undergo rapid, prostaglandin dehydrogenase (PGDH)-mediated metabolic inactivation led do the design and synthesis of first-generation PGDH-resistant LXA(4), LXB4 and ATL analogs in 1995-1998 by Serhan, Petasis and colleagues. These relatively stable pharmacological agents, together with myeloid-specific ALX-R-expressing transgenic mice, have provided powerful tools to explore lipoxin functions in vivo. Here we briefly review the substantial body of evidence supporting the lipoxin ALX-R pathway as a novel and potent mechanism for preventing/resolving acute inflammation. Emphasis will also be placed on recent findings that lipoxins play new roles in "immunomodulation" via regulation of macrophage, dendritic cell, and T-lymphocyte effector functions in the setting of polarized T-helper cell responses (Th-1 and Th-2). These studies suggest roles for lipoxins as novel regulators of allergy and adaptive immunity and that lipoxins may have therapeutic potential in chronic immune disorders.