Anti-inflammatory role of PGD2 in acute lung inflammation and therapeutic application of its signal enhancement
Anti-inflammatory role of PGD2 in acute lung inflammation and therapeutic application of its signal enhancement
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DOI：
10.1073/pnas.1218091110
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发表时间：
2013-03-26
影响因子：
11.1
通讯作者：
Ozaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Murata, Takahisa;Aritake, Kosuke;Ozaki, Hiroshi
我们研究了前列腺素D-2（PGD（2））信号在急性肺损伤（ALI）中的作用，重点是其在体内的生产者-效应器相互作用。内毒素给药增加了WT小鼠肺中的水肿和中性粒细胞浸润。造血PGD合酶（H-PGDS）基因的破坏加重了所有症状。涉及WT和H-PGDS缺陷小鼠之间骨髓移植的实验表明，来自肺泡非造血谱系细胞的PGD（2）（即，内皮细胞和上皮细胞）在ALI的早期阶段（第1天）促进血管屏障功能，而嗜酸性粒细胞衍生的PGD（2）在ALI的晚期阶段（第3天）减弱其自身的浸润和细胞因子表达。用PGD（2）受体激动剂DP或PGD（2）降解产物15-deoxy-Delta（12，14）-PGJ（2）治疗，对ALI具有治疗作用。从WT和DP缺陷小鼠之间的骨髓移植获得的数据表明，肺泡内皮细胞中的DP信号对于PGD的抗炎反应至关重要（2）。在体外，DP激动直接增强内皮屏障形成，15-deoxy-Delta（12，14）-PGJ（2）减弱中性粒细胞迁移和细胞因子表达。这些观察结果表明，肺泡内皮/上皮细胞和浸润中性粒细胞之间的PGD（2）信号在ALI中提供抗炎作用，并提示这些信号增强的治疗潜力。
We investigated the role of prostaglandin D-2 (PGD(2)) signaling in acute lung injury (ALI), focusing on its producer-effector interaction in vivo. Administration of endotoxin increased edema and neutrophil infiltration in the WT mouse lung. Gene disruption of hematopoietic PGD synthase (H-PGDS) aggravated all of the symptoms. Experiments involving bone marrow transplantation between WT and H-PGDS-deficient mice showed that PGD(2) derived from alveolar nonhematopoietic lineage cells (i.e., endothelial cells and epithelial cells) promotes vascular barrier function during the early phase (day 1), whereas neutrophil-derived PGD(2) attenuates its own infiltration and cytokine expression during the later phase (day 3) of ALI. Treatment with either an agonist to the PGD(2) receptor, DP, or a degradation product of PGD(2), 15-deoxy-Delta(12,14)-PGJ(2), exerted a therapeutic action against ALI. Data obtained from bone marrow transplantation between WT and DP-deficient mice suggest that the DP signal in alveolar endothelial cells is crucial for the anti-inflammatory reactions of PGD(2). In vitro, DP agonism directly enhanced endothelial barrier formation, and 15-deoxy-Delta(12,14)-PGJ(2) attenuated both neutrophil migration and cytokine expression. These observations indicate that the PGD(2) signaling between alveolar endothelial/epithelial cells and infiltrating neutrophils provides anti-inflammatory effects in ALI, and suggest the therapeutic potential of these signaling enhancements.