Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis
Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis
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DOI：
10.1016/s0002-9440(10)64282-4
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发表时间：
2003-05-01
影响因子：
6
通讯作者：
Doglioni, C
中科院分区：
文献类型：
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作者：
Chilosi, M;Poletti, V;Doglioni, C
为了研究可能支持特发性肺纤维化/普通型间质性肺炎（IPF/UIP）特征性功能障碍修复过程的分子事件，我们分析了20例IPF/UIP肺样本中β-连环蛋白的表达模式，以及Wnt信号传导的两个下游靶基因，细胞周期蛋白D1和基质溶解素。在连续切片研究的20例IPF/UIP病例中，18例在增殖性细支气管病变（基底细胞增生、鳞状化生、细支气管化、蜂窝样变）中显示细胞核β-连环蛋白免疫反应性和细胞周期蛋白D1和基质溶解素水平异常。使用特异性标记物（DeltaN-p63、表面活性蛋白-A、细胞角蛋白-5）精确定义这些病变的性质。有趣的是，在大多数（16/20）IPF/UIP样本的成纤维细胞灶中也发现了细胞核β-连环蛋白蓄积，通常与细支气管病变相关。在正常肺和其他纤维化肺病（弥漫性肺泡损伤、机化性肺炎、非特异性间质性肺炎、脱屑性间质性肺炎）中未观察到类似特征。对从3份IPF/UIP样本中提取的DNA进行的序列分析未发现影响β-连环蛋白基因的异常。基于这些发现，可以假设IPF/UIP发病机制的新模型，其中心是Wnt/β-连环蛋白信号传导的异常激活，最终触发细支气管-肺泡连接处的分化上皮再生和上皮-间充质转化，导致肺组织的严重和不可逆重塑。
To investigate the molecular events that may underpin dysfunctional repair processes that characterize idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), we analyzed the expression patterns of beta-catenin on 20 IPF/UIP lung samples, together with two downstream target genes of Wnt signaling, cyclin-D1, and matrilysin. In 18 of 20 cases of IPF/UIP investigated on serial sections, nuclear beta-catenin immunoreactivity and abnormal levels of cyclin-D1 and matrilysin were demonstrated in proliferative bronchiolar lesions (basal-cell hyperplasia, squamous metaplasia, bronchiolization, honeycombing). The nature of these lesions was precisely defined using specific markers (DeltaN-p63, surfactant-protein-A, cytokeratin-5). Interestingly, nuclear beta-catenin accumulation was also demonstrated in fibroblast foci in most (16 of 20) IPF/UIP samples, often associated with bronchiolar lesions. Similar features were not observed in normal lung and other fibrosing pulmonary diseases (diffuse alveolar damage, organizing pneumonia, nonspecific interstitial pneumonia, desquamative interstitial pneumonia). Sequence analysis performed on DNA extracted from three samples of IPF/UIP did not reveal abnormalities affecting the beta-catenin gene. On the basis of these findings new models for IPF/UIP pathogenesis can be hypothesized, centered on the aberrant activation of Wnt/beta-catenin signaling, with eventual triggering of divergent epithelial regeneration at bronchiolo-alveolar junctions and epithelial-mesenchymal-transitions, leading to severe and irreversible remodeling of the pulmonary tissue.