Blockade of advanced glycation end product formation attenuates bleomycin-induced pulmonary fibrosis in rats
Blockade of advanced glycation end product formation attenuates bleomycin-induced pulmonary fibrosis in rats
复制标题
阻断晚期糖基化终产物形成可减轻博莱霉素诱导的大鼠肺纤维化
DOI：
10.1186/1465-9921-10-55
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发表时间：
2009-06-24
影响因子：
5.8
通讯作者：
Wen, Fu-Qiang
中科院分区：
文献类型：
--
作者：
Chen, Lei;Wang, Tao;Wen, Fu-Qiang
背景晚期糖基化终产物（AGEs）被认为参与了肺纤维化的发生发展，但其在肺纤维化过程中的作用尚未完全清楚。为了探讨AGE形成在肺纤维化中的作用，我们使用了博莱霉素（BLM）刺激的大鼠模型治疗与氨基胍（AG），AGEformation.MethodsRats的交联抑制剂BLM（5 mg/kg）和口服给药AG（40，80，120 mg/kg），每天一次，两周。采用酶联免疫吸附法（ELISA）测定肺组织AGEs水平，Ashcroft评分和羟脯氨酸测定评价肺纤维化程度。用RT-PCR和Western blot检测胶原特异性分子伴侣热休克蛋白47（HSP 47）的表达。结果BLM刺激后大鼠肺组织AGEs含量、肺组织羟脯氨酸含量及Ashcroft评分均显著升高，AG处理后则无此作用。BLM可显著增加肺组织HSP 47 mRNA和蛋白的表达，AG可显著降低BLM诱导的肺组织HSP 47表达，且呈剂量依赖性（p < 0.05）。结论AGE的形成可能参与了BLM诱导的大鼠肺纤维化过程，AG阻断AGE的形成可减轻BLM诱导的大鼠肺纤维化，其机制可能与抑制肺组织中HSP 47的表达和TGFβ/Smads信号通路有关。
BackgroundAdvanced glycation end products (AGEs) have been proposed to be involved in pulmonary fibrosis, but its role in this process has not been fully understood. To investigate the role of AGE formation in pulmonary fibrosis, we used a bleomycin (BLM)-stimulated rat model treated with aminoguanidine (AG), a crosslink inhibitor of AGE formation.MethodsRats were intratracheally instilled with BLM (5 mg/kg) and orally administered with AG (40, 80, 120 mg/kg) once daily for two weeks. AGEs level in lung tissue was determined by ELISA and pulmonary fibrosis was evaluated by Ashcroft score and hydroxyproline assay. The expression of heat shock protein 47 (HSP47), a collagen specific molecular chaperone, was measured with RT-PCR and Western blot. Moreover, TGFβ1 and its downstream Smad proteins were analyzed by Western blot.ResultsAGEs level in rat lungs, as well as lung hydroxyproline content and Ashcroft score, was significantly enhanced by BLM stimulation, which was abrogated by AG treatment. BLM significantly increased the expression of HSP47 mRNA and protein in lung tissues, and AG treatment markedly decreased BLM-induced HSP47 expression in a dose-dependent manner (p < 0.05). In addition, AG dose-dependently downregulated BLM-stimulated overexpressions of TGFβ1, phosphorylated (p)-Smad2 and p-Smad3 protein in lung tissues.ConclusionThese findings suggest AGE formation may participate in the process of BLM-induced pulmonary fibrosis, and blockade of AGE formation by AG treatment attenuates BLM-induced pulmonary fibrosis in rats, which is implicated in inhibition of HSP47 expression and TGFβ/Smads signaling.