Blockade of the Wnt/β-Catenin Pathway Attenuates Bleomycin-Induced Pulmonary Fibrosis
Blockade of the Wnt/β-Catenin Pathway Attenuates Bleomycin-Induced Pulmonary Fibrosis
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DOI：
10.1620/tjem.223.45
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发表时间：
2011-01-01
影响因子：
2.2
通讯作者：
Sohn, Jang Won
中科院分区：
文献类型：
--
作者：
Kim, Tae Hyung;Kim, Sang-Heon;Sohn, Jang Won
特发性肺纤维化（IPF）是一种进行性肺纤维化疾病，以成纤维细胞异常生长和肺瘢痕形成为特征。虽然IPF的发病机制尚不清楚，但转化生长因子- β (tgf - β)的激活和肺泡基底膜的破坏似乎在导致基质的过度破坏中起重要作用，这与活化的基质金属蛋白酶（MMP）和肌成纤维细胞的异常增殖有关。Wnt/ β -catenin通路是细胞增殖和分化的重要调节因子，在IPF中观察到Wnt/ β -catenin信号的异常激活。在博莱霉素诱导的小鼠肺纤维化模型中，我们检测了抑制Wnt/ β -连环蛋白通路是否可以减轻肺纤维化。气管内灌注博来霉素诱导C57BL/6N小鼠肺纤维化。为了抑制Wnt/ β -catenin通路，在博莱霉素滴注前2 h和之后每48 h向气管内注入β -catenin小干扰RNA (siRNA)，直至第14天牺牲。博莱霉素给药小鼠上皮细胞中β -连环蛋白表达水平升高。与对照组相比，气管内用β -catenin siRNA治疗可显著降低β -catenin表达、肺纤维化和胶原合成，但对炎症反应无显著影响。β -连环蛋白靶向siRNA也显著降低肺组织中MMP-2和tgf - β的表达水平（P < 0.01）。在小鼠模型中，β -catenin siRNA阻断Wnt/ β -catenin通路可减少博莱霉素诱导的肺纤维化。这些发现表明，靶向Wnt/ β -连环蛋白信号可能是治疗IPF的有效方法。
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease and characterized by abnormal growth of fibroblasts and lung scarring. While the pathogenesis of IPF is not clearly understood, activation of transforming growth factor-beta (TGF-beta) and disruption of alveolar basement membrane seem to play important roles in leading to excess disruption of the matrix, which is associated with activated matrix metalloproteinase (MMP) and aberrant proliferation of myofibroblasts. The Wnt/beta-catenin pathway is an important regulator of cellular proliferation and differentiation and abnormal activation of Wnt/beta-catenin signal was observed in IPF. We examined whether inhibition of the Wnt/beta-catenin pathway could attenuate pulmonary fibrosis in a bleomycin-induced murine model of pulmonary fibrosis. Pulmonary fibrosis was induced in C57BL/6N mice by intratracheal instillation of bleomycin. To inhibit the Wnt/beta-catenin pathway, small interfering RNA (siRNA) for beta-catenin was administered into trachea 2 h before bleomycin instillation and every 48 h afterward until sacrifice on day 14. The level of beta-catenin expression was increased in the epithelial cells of bleomycin-administered mice. Intratracheal treatment with beta-catenin siRNA significantly reduced beta-catenin expression, pulmonary fibrosis and collagen synthesis in bleomycin-administered mice compared with controls, with no significant effect on the inflammatory response. The beta-catenin-targeted siRNA also significantly decreased the levels of MMP-2 (P < 0.01) and TGF-beta (P < 0.01) expression in the lung tissue. Blockade of the Wnt/beta-catenin pathway by beta-catenin siRNA decreased bleomycin-induced pulmonary fibrosis in the murine model. These findings suggest that targeting Wnt/beta-catenin signaling may be an effective therapeutic approach in the treatment of IPF.