Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
PLoS One. 2013 Jun 6;8(6):e64724. doi: 10.1371/journal.pone.0064724. Print 2013.
Chronic graft-versus-host disease (cGVHD), a serious complication following allogeneic HSCT (hematopoietic stem cell transplantation), is characterized by systemic fibrosis. The tissue renin-angiotensin system (RAS) is involved in the fibrotic pathogenesis, and an angiotensin II type 1 receptor (AT1R) antagonist can attenuate fibrosis. Tissue RAS is present in the lacrimal gland, lung, and liver, and is known to be involved in the fibrotic pathogenesis of the lung and liver. This study aimed to determine whether RAS is involved in fibrotic pathogenesis in the lacrimal gland and to assess the effect of an AT1R antagonist on preventing lacrimal gland, lung, and liver fibrosis in cGVHD model mice. We used the B10.D2→BALB/c (H-2(d)) MHC-compatible, multiple minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD. First, we examined the localization and expression of RAS components in the lacrimal glands using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). Next, we administered an AT1R antagonist (valsartan; 10 mg/kg) or angiotensin II type 2 receptor (AT2R) antagonist (PD123319; 10 mg/kg) intraperitoneally into cGVHD model mice and assessed the fibrotic change in the lacrimal gland, lung, and liver. We demonstrated that fibroblasts expressed angiotensin II, AT1R, and AT2R, and that the mRNA expression of angiotensinogen was greater in the lacrimal glands of cGVHD model mice than in controls generated by syngeneic-HSCT. The inhibition experiment revealed that fibrosis of the lacrimal gland, lung, and liver was suppressed in mice treated with the AT1R antagonist, but not the AT2R antagonist. We conclude that RAS is involved in fibrotic pathogenesis in the lacrimal gland and that AT1R antagonist has a therapeutic effect on lacrimal gland, lung, and liver fibrosis in cGVHD model mice. Our findings point to AT1R antagonist as a possible target for therapeutic intervention in cGVHD.
慢性移植物抗宿主病（cGVHD）是异基因造血干细胞移植（HSCT）后的一种严重并发症，其特征为全身纤维化。组织肾素-血管紧张素系统（RAS）参与纤维化发病机制，血管紧张素 II 型 1 型受体（AT1R）拮抗剂可减轻纤维化。RAS 存在于泪腺、肺和肝中，已知其参与肺和肝纤维化的发病机制。本研究旨在确定 RAS 是否参与了 cGVHD 模型小鼠泪腺纤维化的发病机制，并评估 AT1R 拮抗剂对预防 cGVHD 模型小鼠泪腺、肺和肝纤维化的作用。我们使用 B10.D2→BALB/c（H-2(d)）MHC 相容、多个次要组织相容性抗原不匹配的模型，该模型反映了人类 cGVHD 的临床和病理症状。首先，我们通过免疫组织化学和实时定量聚合酶链反应（PCR）检测 RAS 成分在泪腺中的定位和表达。接下来，我们给 cGVHD 模型小鼠腹腔内注射 AT1R 拮抗剂（缬沙坦；10mg/kg）或血管紧张素 II 型 2 型受体（AT2R）拮抗剂（PD123319；10mg/kg），并评估泪腺、肺和肝的纤维化变化。我们证明了成纤维细胞表达血管紧张素 II、AT1R 和 AT2R，并且 cGVHD 模型小鼠的泪腺中血管紧张素原的 mRNA 表达高于同基因 HSCT 产生的对照。抑制实验表明，在接受 AT1R 拮抗剂治疗的小鼠中，泪腺、肺和肝的纤维化得到抑制，但接受 AT2R 拮抗剂治疗的小鼠则没有。我们得出结论，RAS 参与了泪腺纤维化的发病机制，AT1R 拮抗剂对 cGVHD 模型小鼠的泪腺、肺和肝纤维化具有治疗作用。我们的研究结果表明，AT1R 拮抗剂可能是治疗 cGVHD 的潜在靶点。
