Role of heat shock protein 47, a collagen-binding chaperone, in lacrimal gland pathology in patients with cGVHD
Role of heat shock protein 47, a collagen-binding chaperone, in lacrimal gland pathology in patients with cGVHD
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DOI：
10.1167/iovs.06-0601
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Kuwana, Masataka
中科院分区：
文献类型：
--
作者：
Ogawa, Yoko;Razzaque, Mohammed S.;Kuwana, Masataka
目的.由于细胞外基质蛋白在慢性移植物抗宿主病（cGVHD）患者泪腺中的过度积累而导致的不受控制的纤维化已被充分记录。热休克蛋白47（HSP 47）参与胶原的分子成熟，并已被证明在各种纤维化疾病中具有纤维化作用。本研究旨在探讨热休克蛋白47（HSP 47）在cGVHD患者泪腺病变中的作用。在从患有cGVHD（n = 8）和Sjogren综合征（SS; n = 7）的患者的泪腺获得的成纤维细胞的组织切片和原代培养物中检查HSP 47、Ki 67（增殖标记物）、I型和III型胶原和α-平滑肌肌动蛋白（α-SMA）的表达。结果cGVHD患者泪腺组织切片显示，与SS患者相比，中等大小导管周围的成纤维细胞中HSP 47的表达显著增加。cGVHD患者中HSP 47的表达升高主要在Ki 67阳性成纤维细胞中检测到，并且与纤维化区域中和周围的I型和III型胶原的积累增加相关。RT-PCR检测cGVHD泪腺成纤维细胞HSP 47 mRNA表达水平高于SS活检组织成纤维细胞（P < 0.05）。与此相反，α-SMA在SS中的表达水平高于cGVHD，且SS中α-SMA阳性的泪腺成纤维细胞多于cGVHD（P <0. 01）。在cGVHD中，HSP 47的表达增加可能促进导管周围区域中和周围的过度胶原组装，其中成纤维细胞大多处于活性状态。cGVHD泪腺成纤维细胞中较少的α-SMA表明相对缺乏肌纤维母细胞转化。可能的是，不能成肌纤维细胞转化的成纤维细胞是HSP 47和胶原蛋白产生的主要来源，并且所产生的效果是在患有cGVHD的患者的泪腺中观察到的导管周围纤维化变化。
PURPOSE. Uncontrolled fibrosis due to excessive accumulation of extracellular matrix proteins in the lacrimal glands of patients with chronic graft-versus-host disease (cGVHD) is well documented. Heat-shock protein 47 (HSP47) is involved in the molecular maturation of Collagen and has been shown to have a fibrogenic role in various fibrotic diseases. In this study, the role of HSP47 in the pathogenesis of lacrimal gland of patients with cGVHD was investigated.METHODS. The expression of HSP47, Ki67 (a proliferation marker), types I and III collagen, and alpha-smooth muscle actin (alpha-SMA) was examined in tissue sections and in primary cultures of fibroblasts obtained from the lacrimal glands of patients with cGVHD (n = 8) and Sjogren's syndrome (SS; n = 7). RESULTS. Tissue sections of the lacrimal glands of patients with cGVHD showed markedly increased expression of HSP47 in fibroblasts around the medium-sized ducts than did those from patients with SS. The elevated expression of HSP47 in patients with cGVHD was mostly detected in Ki67-positive fibroblasts and was associated with increased accumulation of types I and III Collagen in and around the fibrotic areas. Primary fibroblast cultures generated from cGVHD lacrimal gland showed higher HSP47 mRNA expression than did fibroblasts isolated from SS biopsy tissue, as determined by RT-PCR (P < 0.05). In contrast, alpha-SMA was higher in the SS than cGVHD fibroblasts at both mRNA and protein levels, and more lacrimal gland fibroblasts in the SS were positive for alpha-SMA than cGVHD (P < 0.01).CONCLUSIONS. In cGVHD, increased expression of HSP47 may promote excessive Collagen assembly in and around the periductal areas where fibroblasts are mostly in an active state. The less alpha-SMA in the cGVHD lacrimal gland fibroblasts suggests a relative lack of myofibroblastic transformation. It is likely that fibroblasts incapable of myofibroblastic transformation are the main source of HSP47 and Collagen production, and the resultant effect is the periductal fibrotic changes seen in lacrimal glands of patients with cGVHD.