The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis
The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis
复制标题
DOI：
10.1007/s00109-020-02001-x
复制
发表时间：
2020-11-09
影响因子：
4.7
通讯作者：
Sakaguchi, Masakiyo
中科院分区：
文献类型：
--
作者：
Araki, Kota;Kinoshita, Rie;Sakaguchi, Masakiyo
在间质性肺炎患者中，肺纤维化是一种不可逆的疾病，可导致呼吸衰竭。肺纤维化的新疗法是必要的。炎症被认为激活肺成纤维细胞，导致肺纤维化。在已知的炎性分子中，我们重点关注了S100 A8/A9从炎症发作到随后的炎症进展。我们的研究结果证实了S100 A8/A9在肺纤维化患者标本中的高表达。S100 A8/A9不仅在成纤维细胞的增殖中，而且在成纤维细胞向肌成纤维细胞（成纤维细胞的活性形式）的分化中表现出积极的作用。S100 A8/A9还迫使成纤维细胞上调胶原蛋白的产生。这些作用通过S100 A8/A9的受体诱导，即，成纤维细胞上的晚期糖基化终末产物受体（AGEs）。抗S100 A8/A9中和抗体抑制S100 A8/A9对成纤维细胞的作用，并抑制博莱霉素（BLM）诱导的肺纤维化小鼠模型中的纤维化进展。我们的研究结果强烈表明S100 A8/A9在肺纤维化中的关键作用以及S100 A8/A9靶向治疗纤维化间质性肺炎的有用性。
In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia.