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S1pr1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung
  • +13
  • Jing Jin,
  • Mengyao Hao,
  • Rong Fu,
  • Juan Tai,
  • Xia Yuan,
  • Mingjin Wang,
  • Huimin Jiang,
  • Ming Ji,
  • Fangfang Lai,
  • Nina Xue,
  • Yang Chen,
  • Shuan Rao,
  • Liping Bai,
  • zhu yizhun,
  • Xiaoguang Chen,
  • Xiao-Xi Lv
Jing Jin
Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Materia Medica

Corresponding Author:[email protected]

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Mengyao Hao
Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Materia Medica
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Rong Fu
Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Materia Medica
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Juan Tai
Department of Otolaryngology, Head and Neck Surgery, Children's Hospital Capital Institute of Pediatrics, Beijing 100020, China.
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Xia Yuan
Peking University School of Pharmaceutical Sciences
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Mingjin Wang
Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Materia Medica
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Huimin Jiang
Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Materia Medica
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Ming Ji
Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Materia Medica
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Fangfang Lai
Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Materia Medica
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Nina Xue
Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Materia Medica
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Yang Chen
Guangzhou University of Chinese Medicine
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Shuan Rao
Southern Medical University Nanfang Hospital
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Liping Bai
Macau University of Science and Technology
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zhu yizhun
Macau University of Science and Technology
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Xiaoguang Chen
Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Materia Medica
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Xiao-Xi Lv
Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Materia Medica
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Abstract

Background and Purpose:As important components of lung tissue, endothelial cells (ECs) are associated with many lung diseases. The role of ECs dysfunction in idiopathic pulmonary fibrosis (IPF) and how to improve alveolar capillary barrier (ACB) to treat IPF is incompletely understood. Therefore we investigated the involvment of endothelial Sphingosine-1-phosphate receptor 1 (S1pr1) in PF and therapeutic effect of selective S1pr1 agonist IMMH002. Experimental approach:Databases of IPF patients and individuals without fibrosis were mined by Seurat. We generated an endothelial-conditional S1pr1 knockout (S1pr1+/−) mice and we also examined a bleomycin-induced model of pulmonary fibrosis (PF). We performed qRT-PCR,Western blot, Immunofluorescence staining and EC permeability experiments. Key results:Expression of S1pr1 in ECs was reduced markedly in IPF patients. Mice with endothelial-specific S1pr1 deficiency exhibited severer inflammation and fibrosis upon challenge with bleomycin. Significant accumulation of alpha-smooth muscle actin (α-SMA) was observed near vessels after S1pr1 deficiency, which indicated a potential connection between ACB injury and fibrosis. S1pr1 activation by a selective agonist IMMH002 could ameliorate PF by improving tight junctions in ECs and protects the ACB. Conclusion and Implications: Our results suggest that S1pr1 plays a significant role in ACB and it could be a potential target for IPF. Activation of S1pr1 with IMMH002 elicits a potent therapeutic effect in bleomycin-induced fibrosis by increasing tight junctions in endothelial cells and protecting the integrity of ACB therefore improve survial rate and lung function.