Molecular circuits of resolution: Formation and actions of resolvins and protectins
Molecular circuits of resolution: Formation and actions of resolvins and protectins
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DOI：
10.4049/jimmunol.174.7.4345
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发表时间：
2005-04-01
影响因子：
4.4
通讯作者：
Serhan, CN
中科院分区：
文献类型：
--
作者：
Bannenberg, GL;Chiang, N;Serhan, CN
急性炎症消退背后的细胞事件在分子水平上尚不清楚。为了确定抗炎和促溶解回路，我们使用基于质谱的蛋白质组学和脂质组学研究了自溶解小鼠渗出物的时间和差异变化。关键分辨率组件被定义为分辨率指数，包括 Psi(max)，即炎症反应期间存在的最大中性粒细胞数量； T-max，Psi(max)发生的时间；以及中性粒细胞数量达到 Apm- 一半时从 T-max 到 T-50 的分辨率区间 (R-i)。蛋白质组学分析显示，触珠蛋白和 S100A9 水平达到最大，并且其他渗出蛋白受到动态调节，分辨率开始于 12 小时左右。类二十烷酸和多不饱和脂肪酸在 4 小时内首次出现。有趣的是，二十二碳六烯酸衍生的抗炎脂质介质 10,17S-二十二碳三烯是在 Ri 过程中产生的。施用阿司匹林触发的脂氧素 A、类似物、消解素 E1 或 10,17S-二十二碳三烯均可激活和/或加速消解。例如，阿司匹林触发的脂氧素 A、类似物降低 Psi(max,) resolvin E1 降低 Psi(max) 和 T-max，而 10,17S-二十二碳三烯降低 Psi T-max,(max,) 并缩短 Ri。此外，阿司匹林触发的脂氧素A4类似物在4小时时显着抑制促炎细胞因子和趋化因子（20-50%抑制），而resolvin E1和10,17S-二十二碳三烯的抑制作用在12小时时达到最大（30-80%抑制）。此外，阿司匹林触发的脂氧素 A4 类似物会引起抗炎细胞因子 TGF-β 的释放。这些结果表征了第一个分子解析电路及其主要成分，由特定的新型脂质介质（即解析素El和10,17S-二十二碳三烯）激活以促进解析。
The cellular events underlying the resolution of acute inflammation are not known in molecular terms. To identify anti-inflammatory and proresolving circuits, we investigated the temporal and differential changes in self-resolving murine exudates using mass spectrometry-based proteomics and lipidomics. Key resolution components were defined as resolution indices including Psi(max), the maximal neutrophil numbers that are present during the inflammatory response; T-max, the time when Psi(max) occurs; and the resolution interval (R-i) from T-max to T-50 when neutrophil numbers reach half Apm-. The onset of resolution was at similar to 12 h with proteomic analysis showing both haptoglobin and S100A9 levels were maximal and other exudate proteins were dynamically regulated. Eicosanoids and polyunsaturated fatty acids first appeared within 4 h. Interestingly, the docosahexaenoic acid-derived anti-inflammatory lipid mediator 10,17S-docosatriene was generated during the Ri. Administration of aspirin-triggered lipoxin A, analog, resolvin E1, or 10,17S-docosatriene each either activated and/or accelerated resolution. For example, aspirin-triggered lipoxin A, analog reduced Psi(max,) resolvin E1 decreased both Psi(max) and T-max, whereas 10,17S-docosatriene reduced Psi T-max,(max,) and shortened Ri. Also, aspirin-triggered lipoxin A4 analog markedly inhibited proinflammatory cytokines and chemokines at 4 h (20-50% inhibition), whereas resolvin El and 10,17S-docosatriene's inhibitory actions were maximal at 12 h (30-80% inhibition). Moreover, aspirin-triggered lipoxin A4 analog evoked release of the antiphlogistic cytokine TGF-beta. These results characterize the first molecular resolution circuits and their major components activated by specific novel lipid mediators (i.e., resolvin El and 10,17S-docosatriene) to piromote resolution.