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Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis
被引:31
作者:
Chen, Wei-Chih
[1
,2
,3
]
Chen, Nien-Jung
[4
,5
]
Chen, Hsin-Pai
[2
,6
]
Yu, Wen-Kuang
[1
,2
,7
]
Su, Vincent Yi-Fong
[2
,8
]
Chen, Hao
[1
]
Wu, Huai-Hsuan
[1
]
Yang, Kuang-Yao
[1
,2
,3
,5
]
机构:
[1] Taipei Vet Gen Hosp, Dept Chest Med, Taipei 112, Taiwan
[2] Natl Yang Ming Univ, Sch Med, Fac Med, Taipei 112, Taiwan
[3] Natl Yang Ming Univ, Inst Emergency & Crit Care Med, Sch Med, Taipei 112, Taiwan
[4] Natl Yang Ming Univ, Inst Microbiol & Immunol, Sch Life Sci, Taipei 112, Taiwan
[5] Natl Yang Ming Univ, Canc Progress Res Ctr, Taipei 112, Taiwan
[6] Taipei Vet Gen Hosp, Div Infect Dis, Dept Med, Taipei 112, Taiwan
[7] Natl Yang Ming Univ, Inst Physiol, Sch Med, Taipei 112, Taiwan
[8] Taipei City Hosp, Dept Internal Med, 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;
VASCULAR ENDOTHELIAL-CELLS;
ACUTE LUNG INJURY;
ADHESION;
INHIBITOR;
EXPRESSION;
MODELS;
PATHOGENESIS;
INFLAMMATION;
MIGRATION;
DIAGNOSIS;
D O I:
10.3390/ijms21134735
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
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.
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页码:1 / 16
页数:16
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