L-PGDS-derived PGD2 attenuates acute lung injury by enhancing endothelial barrier formation
L-PGDS-derived PGD2 attenuates acute lung injury by enhancing endothelial barrier formation
复制标题
DOI：
10.1002/path.5253
复制
发表时间：
2019-07-01
影响因子：
7.3
通讯作者：
Murata, Takahisa
中科院分区：
文献类型：
--
作者：
Horikami, Daiki;Toya, Naoki;Murata, Takahisa
急性肺损伤(ALI)是由酸吸入、感染等多种刺激因素引起的，临床转归严重，病死率高。前列腺素D-2(PGD(2))是ALI患者肺部产生的一种脂质介质。前列腺素D合成酶(PGDS)有两种，即脂钙素型前列腺素D合成酶(L-PGDS)和造血型前列腺素D合成酶(H-PGDS)。我们先前报道了H-PGDS衍生的PGD(2)在内毒素诱导的小鼠ALI模型中的抗炎作用。因此，在本研究中，我们比较了L-PGDS来源的PGD(2)和H-PGDS来源的PGD(2)在ALI中的作用。气管内注射盐酸可引起小鼠肺部炎症，并伴有肺组织水肿和中性粒细胞聚集。L-PGDS和H-PGDS的缺乏性加重了盐酸所致的肺功能障碍。此外，详细的研究表明，L-前列腺素DS衍生的PGD(2)可抑制肺水肿，而H-PGDS衍生的PGD(2)可抑制中性粒细胞的浸润。免疫组织化学染色显示炎症内皮细胞表达L-PGDS，巨噬细胞和中性粒细胞表达H-PGDS。WT骨髓造血重建不能挽救L-PGDS缺陷小鼠加重的肺水肿，提示非造血型内皮细胞/上皮细胞表达的L-PGDS对ALI的保护作用。改良的Miles法显示，L-前列腺素DS缺乏可加速炎症肺的血管高通透性，这种高通透性可被前列腺素D(2)受体D前列腺素(DP)受体抑制。在体外，DP激动剂可增强内皮细胞的屏障功能，但不能增强上皮细胞的屏障功能。综上所述，我们的结果表明，在盐酸诱导的小鼠ALI模型中，炎症的内皮细胞和上皮L-PGDS局部产生了PGD(2)，这通过DP受体增强了内皮屏障。版权所有(C)2019年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Acute lung injury (ALI) is caused by various stimuli such as acid aspiration and infection, resulting in severe clinical outcomes with high mortality. Prostaglandin D-2 (PGD(2)) is a lipid mediator produced in the lungs of patients with ALI. There are two prostaglandin D synthases (PGDS), namely, lipocalin-type PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS). We previously reported the anti-inflammatory role of H-PGDS-derived PGD(2) in an endotoxin-induced murine ALI model. Therefore, in this study, we investigated the role of L-PGDS-derived PGD(2) in ALI in comparison to H-PGDS-derived PGD(2). Intratracheal administration of HCl caused lung inflammation accompanied by tissue edema and neutrophil accumulation in mouse lungs. The deficiency of both L-PGDS and H-PGDS exacerbated HCl-induced lung dysfunction to a similar extent. Furthermore, a detailed investigation revealed that L-PGDS-derived PGD(2) inhibited lung edema, while H-PGDS-derived PGD(2) inhibited neutrophil infiltration. Immunostaining showed that inflamed endothelial/epithelial cells express L-PGDS, while macrophages and neutrophils express H-PGDS. Hematopoietic reconstitution with WT bone marrow did not rescue the exacerbated lung edema in L-PGDS deficient mice, indicating the importance of nonhematopoietic endothelial/epithelial cell-expressing L-PGDS for protection against ALI. A modified Miles assay showed that L-PGDS deficiency accelerated vascular hyper-permeability in the inflamed lung, which was suppressed by the stimulation of D prostanoid (DP) receptor, a PGD(2) receptor. In vitro, DP agonism enhanced the barrier function of endothelial cells but not epithelial cells. Taken together, our results suggest that in the HCl-induced murine ALI model PGD(2) was produced locally by inflamed endothelial and epithelial L-PGDS and this enhanced the endothelial barrier through the DP receptor. Copyright (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.