Novel Treatment of Chronic Graft-Versus-Host Disease in Mice Using the ER Stress Reducer 4-Phenylbutyric Acid.
Novel Treatment of Chronic Graft-Versus-Host Disease in Mice Using the ER Stress Reducer 4-Phenylbutyric Acid.
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DOI：
10.1038/srep41939
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发表时间：
2017-02-06
影响因子：
4.6
通讯作者：
Tsubota K
中科院分区：
文献类型：
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作者：
Mukai S;Ogawa Y;Urano F;Kudo-Saito C;Kawakami Y;Tsubota K
慢性移植物抗宿主病（cGVHD）是异基因造血干细胞移植的一种臭名昭著的并发症，可导致全身性炎症和纤维化。在这项新的研究中，我们专注于内质网（ER）应激和cGVHD之间的关系，旨在创造有效的治疗cGVHD。使用cGVHD的小鼠模型进行一系列实验。我们的数据表明：（1）在cGVHD影响的器官中，ER应激升高;（2）4-苯基丁酸（PBA）可以减轻cGVHD诱导的ER应激，从而减轻全身炎症和纤维化。由于成纤维细胞被认为与cGVHD引起的纤维化有关，并且据报道巨噬细胞在cGVHD的发展中起作用，因此我们研究了成纤维细胞和巨噬细胞中cGVHD触发的ER应激。我们的研究表明：（1）在cGVHD影响的泪腺成纤维细胞中，ER应激指标和成纤维细胞活化标志物升高，（2）PBA可以降低这些指标。我们的工作还表明，PBA给药小鼠的脾巨噬细胞表现出较低水平的ER应激和M2巨噬细胞标志物比cGVHD影响的小鼠。总的来说，这项研究表明，利用PBA减少ER应激可以是治疗系统性cGVHD的临床可转化方法。
Chronic graft-versus-host disease (cGVHD) is a notorious complication of allogeneic hematopoietic stem cell transplantation and causes disabling systemic inflammation and fibrosis. In this novel study, we focused on a relationship between endoplasmic reticulum (ER) stress and cGVHD, and aimed to create effective treatment of cGVHD. A series of experiments were conducted using a mouse model of cGVHD. Our data suggested (1) that ER stress was elevated in organs affected by cGVHD and (2) that 4-phenylbutyric acid (PBA) could reduce cGVHD-induced ER stress and thereby alleviate systemic inflammation and fibrosis. Because fibroblasts are thought to be implicated in cGVHD-elicited fibrosis and because macrophages are reported to play a role in the development of cGVHD, we investigated cGVHD-triggered ER stress in fibroblasts and macrophages. Our investigation demonstrated (1) that indicators for ER stress and activation markers for fibroblasts were elevated in cGVHD-affected lacrimal gland fibroblasts and (2) that they could be reduced by PBA. Our work also indicated that splenic macrophages from PBA-dosed mice exhibited the lower levels of ER stress and M2 macrophage markers than those from cGVHD-affected mice. Collectively, this study suggests that the reduction of ER stress utilizing PBA can be a clinically translatable method to treat systemic cGVHD.