Prevention of Bleomycin-Induced Pulmonary Fibrosis by a Novel Antifibrotic Peptide with Relaxin-Like Activity
Prevention of Bleomycin-Induced Pulmonary Fibrosis by a Novel Antifibrotic Peptide with Relaxin-Like Activity
复制标题
DOI：
10.1124/jpet.110.170977
复制
发表时间：
2010-12-01
影响因子：
3.5
通讯作者：
Rotman, Galit
中科院分区：
文献类型：
--
作者：
Pini, Alessandro;Shemesh, Ronen;Rotman, Galit
肺纤维化是一种进行性和致命性的肺部疾病，以细胞外基质积聚和肺功能丧失为特征。这种病理状态没有治愈方法，目前的治疗方法往往无法减缓其进展或缓解其症状。松弛素能在体外诱导人肺成纤维细胞的基质降解表型，并在体内抑制肺纤维化。最近，利用我们设计的预测新型G蛋白偶联受体多肽激动剂的计算平台，发现了一种针对松弛蛋白RXFP1/LGR7受体的新肽。在这项研究中，我们在人类细胞试验和博莱霉素诱导的小鼠肺纤维化模型中检测了这种名为CGEN25009的新型多肽的抗纤维化特性。与松弛素相似，CGEN25009对转化生长因子-β1诱导的人真皮成纤维细胞胶原沉积有抑制作用，并能促进基质金属蛋白酶-2的表达。在刺激THP-1人细胞系cAMP、cGMP和NO方面，该肽的生物学活性也与松弛素相似。在体内，预防性或治疗性地给予CGEN25009 2周(即分别在博莱霉素治疗的同时或治疗后7天给予CGEN25009)可显著减少肺部炎症和损伤，并改善不良的气道重塑和支气管周围纤维化。本研究结果表明，CGEN25009具有抗纤维化和抗炎作用，可能为肺纤维化的治疗提供一种新的选择。
Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of extracellular matrix and loss of pulmonary function. No cure exists for this pathologic condition, and current treatments often fail to slow its progression or relieve its symptoms. Relaxin was previously shown to induce a matrix-degrading phenotype in human lung fibroblasts in vitro and to inhibit pulmonary fibrosis in vivo. A novel peptide that targets the relaxin RXFP1/LGR7 receptor was recently identified using our computational platform designed to predict novel G protein-coupled receptor peptide agonists. In this study, we examined the antifibrotic properties of this novel peptide, designated CGEN25009, in human cell-based assays and in a murine model of bleomycin-induced pulmonary fibrosis. Similar to relaxin, CGEN25009 was found to have an inhibitory effect on transforming growth factor-beta 1-induced collagen deposition in human dermal fibroblasts and to enhance MMP-2 expression. The peptide's biological activity was also similar to relaxin in generating cellular stimulation of cAMP, cGMP, and NO in the THP-1 human cell line. In vivo, 2-week administration of CGEN25009 in a preventive or therapeutic mode (i.e., concurrently with or 7 days after bleomycin treatment, respectively) caused a significant reduction in lung inflammation and injury and ameliorated adverse airway remodeling and peribronchial fibrosis. The results of this study indicate that CGEN25009 displays antifibrotic and anti-inflammatory properties and may offer a new therapeutic option for the treatment of pulmonary fibrosis.