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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo
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Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo

机译：局部和全身递送稳定的阿司匹林触发的脂蛋白可防止体内嗜中性白细胞募集

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摘要

Aspirin (ASA) triggers a switch in the biosynthesis of lipid mediators, inhibiting prostanoid production and initiating 15-epi-lipoxin generation through the acetylation of cyclooxygenase II. These aspirin-triggered lipoxins (ATL) may mediate some of ASA's beneficial actions and therefore are of interest in the search for novel antiinflammatories that could manifest fewer unwanted side effects. Here, we report that design modifications to native ATL structure prolong its biostability in vivo. In mouse whole blood, ATL analogs protected at carbon 15[15(R/S)-methyl-lipoxin A4 (ATLA1)] and the omega end [15-epi-16-(para-fluoro)-phenoxy-LXA4 (ATLA2)] were recoverable to≈90 and 100 at 3 hr, respectively, compared with a≈40 loss of native lipoxin A4. ATLA2 retains bioactivity and, at levels as low as≈24 nmol/mouse, potently inhibited tumor necrosis factor-α -induced leukocyte recruitment into the dorsal air pouch. Inhibition was evident by either local intra-air pouch delivery (≈77 inhibition) or systemic delivery by intravenous injection (≈85 inhibition) and proved more potent than local delivery of ASA. Rank order for inhibiting polymorphonuclear leukocyte infiltration was: ATLa2 (10μg, local) >ASA (1.0 mg, local). Applied topically to mouse ear skinm, ATLa2, also inhibited polymorphonuclear leukocyte infiltration induced by leukotriene B4(≈78 inhibition) or phorbol
机译：阿司匹林（ASA）触发了脂质介体的生物合成转换，抑制了前列腺素的产生，并通过环加氧酶II的乙酰化而启动了15-表-脂蛋白的产生。这些由阿司匹林触发的脂蛋白（ATL）可能介导ASA的某些有益作用，因此在寻找可以减少不良副作用的新型抗炎药方面引起了人们的兴趣。在这里，我们报告说，对天然ATL结构的设计修饰延长了其在体内的生物稳定性。在小鼠全血中，ATL类似物在碳15 [15（R / S）-甲基-脂蛋白A4（ATLA1）]和欧米茄末端[15-epi-16-（对氟）-苯氧基-LXA4（ATLA2）处受到保护与天然脂蛋白A4损失约40％相比，在3小时时可分别回收到约90和100。 ATLA2保留生物活性，并以低至约24 nmol /小鼠的水平有效抑制肿瘤坏死因子-α诱导的白细胞募集进入背囊。局部气袋内递送（≈77抑制）或静脉内注射全身性递送（≈85抑制）均显示出抑制作用，并且证明比ASA局部递送更有效。抑制多形核白细胞浸润的等级顺序为：ATLa2（10μg，局部）> ASA（1.0mg，局部）。局部应用于小鼠耳皮ATLa2，也抑制白三烯B4或佛波醇诱导的多形核白细胞浸润（≈78抑制）

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