Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis

International Journal of Molecular Sciences

Huai-Hsuan Wu¹  Kuang-Yao Yang¹  Wei-Chih Chen¹  Hao Chen¹  Wen-Kuang Yu¹  Hsin-Pai Chen²  VincentYi-Fong Su²  Nien-Jung Chen³ 

[1] Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan;Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan;Institute of Microbiology and Immunology, School of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan;

关键词: nintedanib;    neutrophil;    chemokine (C-X-C motif) receptor 2 (CXCR2);    G protein-coupled receptor kinase 2 (GRK2);    pulmonary fibrosis;   

DOI  :  10.3390/ijms21134735

来源: DOAJ

【 摘 要 】

Neutrophils are involved in the alveolitis of idiopathic pulmonary fibrosis (IPF). However, their pathogenic mechanisms are still poorly understood. Nintedanib has antifibrotic and anti-inflammatory activity in IPF. This study aimed to investigate the regulatory mechanism of nintedanib on neutrophil chemotaxis in bleomycin (BLM)-induced pulmonary fibrosis. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h after a bleomycin intratracheal injection (1.5 U/kg). Lung histopathological findings, the expression of cytokines, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed. The effect of nintedanib was also investigated in a mouse model with adoptive neutrophil transfer in vivo. Nintedanib significantly decreased the histopathological changes and neutrophil recruitment in BLM-induced pulmonary fibrosis. Nintedanib mediated a downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and very late antigen 4 (VLA-4) expression, as well as an upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in BLM-induced pulmonary fibrosis. Nintedanib also decreased the activation of endothelial cells by the decreased expression of vascular cell adhesion molecule 1 (VCAM-1). The effect of nintedanib on regulating neutrophil chemotaxis was also confirmed by a mouse model with adoptive neutrophil transfer in vivo. In conclusion, nintedanib reduces neutrophil chemotaxis and endothelial cell activation to regulate the severity of BLM-induced pulmonary fibrosis. These effects are associated with an enhancement of GRK2 activity and a reduction in CXCR2 and VLA-4 expression on neutrophils and a decrease in VCAM-1 expression on endothelial cells.

【 授权许可】

Unknown