S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

Mengyao Hao; Rong Fu; Jun Tai; Zhenhuan Tian; Xia Yuan; Yang Chen; Mingjin Wang; Huimin Jiang; Ming Ji; Fangfang Lai; Nina Xue; Liping Bai; Yizhun Zhu; Xiaoxi Lv; Xiaoguang Chen; Jing Jin

doi:10.1016/j.apsb.2022.10.006

S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

Acta Pharm Sin B. 2023 Mar;13(3):1110-1127. doi: 10.1016/j.apsb.2022.10.006. Epub 2022 Oct 12.

Authors

Mengyao Hao¹, Rong Fu¹, Jun Tai², Zhenhuan Tian³, Xia Yuan⁴, Yang Chen⁵, Mingjin Wang¹, Huimin Jiang¹, Ming Ji¹, Fangfang Lai¹, Nina Xue¹, Liping Bai⁶, Yizhun Zhu⁶, Xiaoxi Lv¹, Xiaoguang Chen¹, Jing Jin¹

Affiliations

¹ 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.
² Department of Otolaryngology, Head and Neck Surgery, Children's Hospital Capital Institute of Pediatrics, Beijing 100020, China.
³ Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Dong Cheng District, Beijing 100730, China.
⁴ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
⁵ Department of Pharmacology, School of Pharmaceutical, Guangzhou University of Chinese Medicine, Guangzhou 510000, China.
⁶ State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau SAR 999078, China.

Abstract

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 S1pr1 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.

Keywords: Endothelial barrier; FTY720; IMMH002; Idiopathic pulmonary fibrosis; Protein stability; Sphingosine-1-phosphate receptor 1; Sphingosine-1-phosphate receptor 1 agonist; Tight junction.