Ding Hui, Ji XiuHai, Chen Ruhua, Ma Tieliang, Tang Zhiwei, Fen Yan, Cai Hourong
Department of Pulmonary Medicine, Affiliated Yixing People Hospital, Jiangsu University, 214200, China.
Department of Oncology, Affiliated Taicang Hospital of Traditional Chinese Medicine, Suzhou, China.
Pulm Pharmacol Ther. 2015 Dec;35:34-41. doi: 10.1016/j.pupt.2015.10.010. Epub 2015 Nov 3.
Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease with poor survival. Previous reports suggested the contributory effect of receptor for advanced glycation end products (RAGE) to the pathogenesis of IPF. But the findings are controversial. The present in vivo study with RAGE null mice, we further confirmed the evidence that lack of RAGE evolves worse bleomycin-induced pulmonary fibrosis compared with control mice. Moreover, RAGE null mice spontaneously developed similar pathogenesis of lung fibrosis via immunohistochemical staining. In addition, we investigated the negative roles of RAGE on epithelial-mesenchymal transition (EMT) indicated by elevated α-smooth muscle actin (α-SMA) and collagen-I (Col-I) deposition in A549 cell treated with transforming growth factor-β (TGF-β), all of which were blocked by sRAGE, a decoy receptor. Furthermore, interacting with the specific ligand as AGE, RAGE blocked TGF-β-induced activation of Smad2, ERK and JNK signals in A549 cells, which were also challenged by sRAGE administration. This present study confirmed an important role of RAGE in vivo and vitro models of pulmonary fibrosis and suggested the therapeutic possibility for pulmonary fibrosis via RAGE regulation.
特发性肺纤维化（IPF）是一种进展性慢性间质性肺疾病，生存率低。既往报道提示晚期糖基化终末产物受体（RAGE）在IPF发病机制中起作用。但这些发现存在争议。在本项对RAGE基因敲除小鼠的体内研究中，我们进一步证实，与对照小鼠相比，缺乏RAGE会使博来霉素诱导的肺纤维化更严重。此外，通过免疫组织化学染色发现，RAGE基因敲除小鼠自发出现了类似肺纤维化的发病机制。此外，我们研究了RAGE对上皮-间质转化（EMT）的负性作用，转化生长因子-β（TGF-β）处理的A549细胞中α平滑肌肌动蛋白（α-SMA）升高和I型胶原蛋白（Col-I）沉积表明了这种负性作用，而这一切均被诱饵受体sRAGE阻断。此外，RAGE与AGE这种特异性配体相互作用，阻断了TGF-β诱导的A549细胞中Smad2、ERK和JNK信号的激活，给予sRAGE也对这些信号产生了挑战。本研究证实了RAGE在肺纤维化体内和体外模型中的重要作用，并提示了通过调节RAGE治疗肺纤维化的可能性。
