Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
Respir Res. 2012 Dec 2;13(1):110. doi: 10.1186/1465-9921-13-110.
Docosahexaenoic acid (DHA) and DHA-derived lipid mediators have recently been shown to possess anti-inflammatory and pro-resolving properties. In fact, DHA can down-regulate lipolysaccharide (LPS)-induced activation of NF-κB via a PPARγ-dependent pathway. We sought to investigate the effects of the novel DHA-derived mediator resolvin D1 (RvD1) on LPS-induced acute lung injury and to determine whether these effects occur via a PPARγ-dependent pathway.
BALB/c mice aged 6-8 weeks were randomly divided into seven groups: two control groups receiving saline or RvD1 (600 ng) without LPS; a control group receiving LPS only; an experimental group receiving RvD1 (300 ng) or RvD1 (600 ng), followed by LPS; a group receiving the PPARγ antagonist GW9662; and a group receiving GW9662, then RvD1 (600 ng) and finally LPS. LPS (50 μM) and saline were administered intratracheally. RvD1 was injected intravenously 24 h and 30 min before LPS, while GW9662 was injected intravenously 30 min before RvD1. Mice were killed at 6, 12, and 24 h. Samples of bronchoalveolar lavage fluid (BALF) were analyzed for cell counts and cytokine analysis. Lung tissues were collected for histology, Western blotting and electrophoretic mobility shift assays (EMSAs).
At all three time points, groups receiving either dose of RvD1 followed by LPS had significantly lower total leukocyte counts and levels of TNF-α and IL-6 levels in BALF than did the group given only LPS. RvD1 markedly attenuated LPS-induced lung inflammation at 24 h, based on hematoxylin-eosin staining of histology sections. RvD1 activated PPARγ and suppressed IκBα degradation and NF-κB p65 nuclear translocation, based on Western blots and EMSAs. The PPARγ inhibitor GW9662 partially reversed RvD1-induced suppression of IκBα degradation and p65 nuclear translocation.
These results suggest that RvD1 may attenuate lung inflammation of LPS-induced acute lung injury by suppressing NF-κB activation through a mechanism partly dependent on PPARγ activation.
二十二碳六烯酸（DHA）和 DHA 衍生的脂质介质最近被证明具有抗炎和促解决的特性。事实上，DHA 可以通过 PPARγ 依赖性途径下调脂多糖（LPS）诱导的 NF-κB 的激活。我们试图研究新型 DHA 衍生介质分辨率 D1（RvD1）对 LPS 诱导的急性肺损伤的影响，并确定这些作用是否通过 PPARγ 依赖性途径发生。
6-8 周龄 BALB/c 小鼠随机分为 7 组：两组生理盐水或无 LPS 的 RvD1（600ng）对照组；仅 LPS 对照组；接受 RvD1（300ng）或 RvD1（600ng）后再接受 LPS 的实验组；给予 PPARγ 拮抗剂 GW9662 的组；以及先给予 GW9662，然后再给予 RvD1（600ng），最后给予 LPS 的组。LPS（50μM）和生理盐水经气管内给药。RvD1 在 LPS 前 24 小时和 30 分钟静脉注射，而 GW9662 在 RvD1 前 30 分钟静脉注射。在 6、12 和 24 小时处死小鼠。分析支气管肺泡灌洗液（BALF）中的细胞计数和细胞因子分析。收集肺组织进行组织学、Western 印迹和电泳迁移率变动分析（EMSA）。
在所有三个时间点，给予 RvD1 后再给予 LPS 的两组 BALF 中的总白细胞计数和 TNF-α和 IL-6 水平均明显低于仅给予 LPS 的组。根据苏木精-伊红染色的组织学切片，RvD1 在 24 小时显着减轻 LPS 诱导的肺炎症。RvD1 通过 Western 印迹和 EMSA 激活 PPARγ并抑制 IκBα降解和 NF-κB p65 核易位。PPARγ 抑制剂 GW9662 部分逆转了 RvD1 诱导的 IκBα降解和 p65 核易位的抑制。
这些结果表明，RvD1 可能通过抑制 NF-κB 激活来减轻 LPS 诱导的急性肺损伤的肺炎症，其机制部分依赖于 PPARγ 激活。
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