MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom.
Am J Respir Crit Care Med. 2012 Mar 1;185(5):537-46. doi: 10.1164/rccm.201106-0965OC. Epub 2011 Nov 17.
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 β-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies.
To examine the role of galectin-3 in pulmonary fibrosis.
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.
Transforming growth factor (TGF)-β and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-β1-induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of β-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin-3, TD139, blocked TGF-β-induced β-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.
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.
特发性肺纤维化（IPF）是一种慢性、失调的肺泡上皮损伤反应，其特征为上皮细胞和成纤维细胞向分泌细胞外基质的肌成纤维细胞分化，导致肺纤维化。预后较差，目前尚无有效的治疗方法或可靠的生物标志物。半乳糖凝集素-3 是一种β-半乳糖苷结合凝集素，在多种病因的纤维化组织中高度表达。
研究半乳糖凝集素-3 在肺纤维化中的作用。
我们使用遗传缺失和药理学抑制方法，在经过充分验证的肺纤维化小鼠模型中进行了研究。进一步的机制研究在体外和 IPF 患者的样本中进行。
缺乏半乳糖凝集素-3 的小鼠，转化生长因子（TGF）-β和博来霉素诱导的肺纤维化明显减少，表现为 TGF-β1 诱导的 EMT 和肌成纤维细胞激活以及胶原产生减少。半乳糖凝集素-3 降低了 β-连环蛋白的磷酸化和核易位，但对半胱氨酸磷酸化没有影响。一种新型半乳糖凝集素-3 抑制剂 TD139，可阻断 TGF-β 诱导的β-连环蛋白在体外和体内的激活，并减轻博来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，稳定的特发性肺纤维化患者的支气管肺泡灌洗液和血清中的半乳糖凝集素-3 表达增加，在急性加重期间急剧上升，提示半乳糖凝集素-3 可能是特发性肺纤维化中活跃纤维化的标志物，阻断半乳糖凝集素-3 的策略可能对特发性肺纤维化的急性纤维化加重有效。
本研究确定半乳糖凝集素-3 是肺纤维化的一个重要调节因子，并为半乳糖凝集素-3 抑制作为特发性肺纤维化的一种潜在新型治疗策略提供了原理证明。
