Hao Mengyao, Fu Rong, Tai Jun, Tian Zhenhuan, Yuan Xia, Chen Yang, Wang Mingjin, Jiang Huimin, Ji Ming, Lai Fangfang, Xue Nina, Bai Liping, Zhu Yizhun, Lv Xiaoxi, Chen Xiaoguang, Jin Jing
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
Department of Otolaryngology, Head and Neck Surgery, Children's Hospital Capital Institute of Pediatrics, Beijing 100020, China.
Acta Pharm Sin B. 2023 Mar;13(3):1110-1127. doi: 10.1016/j.apsb.2022.10.006. Epub 2022 Oct 12.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.
特发性肺纤维化（IPF）是一种病因不明且治疗选择有限的进行性肺部疾病。IPF患者的中位生存时间约为2至3年，除肺移植外，尚无有效的干预措施来治疗IPF。作为肺组织的重要组成部分，内皮细胞（ECs）与肺部疾病相关。然而，内皮功能障碍在肺纤维化（PF）中的作用尚未完全明确。鞘氨醇-1-磷酸受体1（S1PR1）是一种在肺ECs中高度表达的G蛋白偶联受体。在IPF患者中其表达明显降低。在此，我们构建了一种内皮细胞条件性敲除小鼠模型，该模型在有或没有博来霉素（BLM）攻击的情况下均表现出炎症和纤维化。用S1PR1激动剂IMMH002选择性激活S1PR1，通过保护内皮屏障的完整性，对博来霉素诱导的纤维化小鼠产生了强大的治疗效果。这些结果表明，S1PR1可能是IPF治疗的一个有前景的药物靶点。
