Regulation of Transforming Growth Factor-β1-driven Lung Fibrosis by Galectin-3
Regulation of Transforming Growth Factor-β1-driven Lung Fibrosis by Galectin-3
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DOI：
10.1164/rccm.201106-0965oc
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发表时间：
2012-03-01
影响因子：
24.7
通讯作者：
Sethi, Tariq
中科院分区：
文献类型：
--
作者：
MacKinnon, Alison C.;Gibbons, Michael A.;Sethi, Tariq
基本原理：特发性肺纤维化（IPF）是一种对肺泡上皮损伤的慢性失调反应，上皮细胞和成纤维细胞分化为分泌基质的肌成纤维细胞，导致肺瘢痕形成。预后差，没有有效的治疗方法或可靠的生物标志物。Galectin-3是一种β-半乳糖苷结合凝集素，在不同病因的纤维化组织中高度表达。Objectives：To examine the role of galectin-3 in pulmonary fibrosis.Methods：We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis.测量和主要结果：转化生长因子（TGF）-β和博莱霉素诱导的肺纤维化在缺乏半乳糖凝集素-3的小鼠中显著减少，表现为TGF-β 1诱导的EMT和肌成纤维细胞活化和胶原蛋白产生减少。Galectin-3降低β-catenin的磷酸化和核转位，但对Smad 2/3磷酸化没有影响。一种新的半乳糖凝集素-3抑制剂TD 139在体外和体内阻断TGF-β诱导的β-连环蛋白激活，并减弱博莱霉素后肺纤维化的晚期进展。与非特异性间质性肺炎和对照组相比，稳定型IPF患者的支气管肺泡灌洗液和血清中半乳糖凝集素-3的表达增加，在急性加重期间急剧上升，表明。半乳糖凝集素-3可能是IPF中活动性纤维化的标志物，阻断半乳糖凝集素-3的策略可能有效治疗IPF的急性纤维化恶化。结论：本研究确定半乳糖凝集素-3作为肺纤维化的重要调节剂，并提供了半乳糖凝集素-3抑制作为IPF潜在的新治疗策略的原则证据。
Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a beta-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies.Objectives: To examine the role of galectin-3 in pulmonary fibrosis.Methods: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF.Measurements and Main Results: Transforming growth factor (TGF)-beta and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-beta 1 induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of beta-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin -3, TD139, blocked TGF-beta-induced beta-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that. galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF.Conclusions: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF.