Pulmongene (Beijing) Ltd., Beijing 102206, China.
National Institute of Biological Sciences, Beijing 102206, China.
Cell Stem Cell. 2024 Sep 5;31(9):1344-1358.e6. doi: 10.1016/j.stem.2024.07.004. Epub 2024 Aug 2.
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Recent studies have highlighted the persistence of an intermediate state of alveolar stem cells in IPF lungs. In this study, we discovered a close correlation between the distribution pattern of intermediate alveolar stem cells and the progression of fibrotic changes. We showed that amphiregulin (AREG) expression is significantly elevated in intermediate alveolar stem cells of mouse fibrotic lungs and IPF patients. High levels of serum AREG correlate significantly with profound deteriorations in lung function in IPF patients. We demonstrated that AREG in alveolar stem cells is both required and sufficient for activating EGFR in fibroblasts, thereby driving lung fibrosis. Moreover, pharmacological inhibition of AREG using a neutralizing antibody effectively blocked the initiation and progression of lung fibrosis in mice. Our study underscores the therapeutic potential of anti-AREG antibodies in attenuating IPF progression, offering a promising strategy for treating fibrotic diseases.
特发性肺纤维化（IPF）是一种进行性和致命性的纤维化疾病。最近的研究强调了肺泡干细胞在 IPF 肺部的中间状态的持续存在。在这项研究中，我们发现中间肺泡干细胞的分布模式与纤维化变化的进展密切相关。我们表明，表皮生长因子受体（EGFR）配体 Amphiregulin（AREG）在小鼠纤维化肺和 IPF 患者的中间肺泡干细胞中的表达显著升高。高水平的血清 AREG 与 IPF 患者肺功能的严重恶化显著相关。我们证明，肺泡干细胞中的 AREG 对于激活成纤维细胞中的 EGFR 是必需和充分的，从而驱动肺纤维化。此外，使用中和抗体抑制 AREG 的药理学作用可有效阻止小鼠肺纤维化的发生和进展。我们的研究强调了抗 AREG 抗体在减轻 IPF 进展方面的治疗潜力，为治疗纤维化疾病提供了一种有前途的策略。
