Suppression of Laser-Induced Choroidal Neovascularization by the Oral Medicine Targeting Histamine Receptor H4 in Mice
Suppression of Laser-Induced Choroidal Neovascularization by the Oral Medicine Targeting Histamine Receptor H4 in Mice
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DOI：
10.1167/tvst.4.2.6
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发表时间：
2015-03-01
影响因子：
3
通讯作者：
Terasaki, Hiroko
中科院分区：
文献类型：
--
作者：
Ijima, Ryo;Kaneko, Hiroki;Terasaki, Hiroko
目的：探讨组胺受体H4(HRH4)与激光诱导的脉络膜新生血管形成的关系，以及口服HRH4拮抗剂对激光诱导的小鼠脉络膜新生血管的抑制作用。玻璃体内注射组胺，测量CNV体积。采用激光光凝和玻璃体内注射HRH4拮抗剂JNJ7777120，耗尽循环中单核细胞来源的巨噬细胞，并与对照组(二甲基亚砜/PBS)进行比较。激光CNV后3天，用流式细胞仪对野生型和HHH4(-/-)小鼠视网膜色素上皮(RPE)/脉络膜复合体中F4/80(+)CD11b(+)巨噬细胞群进行定量。用长效HRH4拮抗剂JNJ28307474行玻璃体腔注射，并与对照组进行比较。注射JNJ7777120的小鼠眼部激光CNV与注射DMSO/PBS的小鼠相当。激光-CNV诱导后的流式细胞术显示，HHH4(-/-)小鼠的RPE/脉络膜复合体中的F4/80(+)CD11b(+)巨噬细胞数比野生型小鼠少。口服JNJ28307474可显著减少野生型小鼠的激光新生血管体积。结论：HRH4阳性巨噬细胞在激光新生血管的发病机制中起重要作用，它们需要不同于组胺的配体。口服HRH4拮抗剂成功地减少了激光-CNV。翻译相关性：我们的结果表明，针对HRH4的药物可能是治疗老年性黄斑变性的一种新的口服治疗方法。
Purpose: This study aimed to examine relationship of histamine receptor H4 (HRH4) and the pathogenesis of laser-induced choroidal neovascularization (laser-CNV) and to determine whether oral administration of HRH4 antagonists suppressed laser-CNV in mice.Methods: Laser photocoagulation was performed in mice to induce the laser-CNV. Histamine was administered intravitreously, and CNV volume was measured. Laser photocoagulation and intravitreous injection of HRH4 antagonist JNJ7777120 were performed after intraperitoneal injection of clodronate liposome, which depletes circulating monocyte-derived macrophages; CNV volume was compared with that in mice injected with control (dimethyl sulfoxide [DMSO]/PBS). Three days after laser-CNV, the F4/80(+)CD11b(+) macrophage population in retinal pigment epithelium (RPE)/choroid complex was quantified with flow cytometry in wild-type and Hrh4(-/-) mice. The long-acting HRH4 antagonist JNJ28307474 was then administrated periorally, and the laser-CNV volume was compared with controls.Results: Intravitreous injection of histamine did not affect laser-CNV volume. The laser-CNV from the eye injected with JNJ7777120 was equivalent to that injected with the DMSO/PBS in mice that had intraperitoneally received clodronate liposome. Flow cytometry after laser-CNV induction revealed a smaller F4/80(+)CD11b(+) macrophage population in the RPE/choroid complex of Hrh4(-/-) mice than in wild-type mice. Oral administration of JNJ28307474 significantly reduced laser-CNV volume in wild-type mice.Conclusions: Our results suggested that HRH4-positive macrophages played an important role in the pathogenesis of laser-CNV and that they require a different ligand from that of histamine. The oral administration of an HRH4 antagonist successfully reduced laser-CNV.Translational Relevance: Our results indicate that drugs targeting HRH4 are potentially a novel oral treatment for age-related macular degeneration.