Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis
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...
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MDPI AG
2020-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/13/4735 |
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| author | Wei-Chih Chen Nien-Jung Chen Hsin-Pai Chen Wen-Kuang Yu Vincent Yi-Fong Su Hao Chen Huai-Hsuan Wu Kuang-Yao Yang |
| author_facet | Wei-Chih Chen Nien-Jung Chen Hsin-Pai Chen Wen-Kuang Yu Vincent Yi-Fong Su Hao Chen Huai-Hsuan Wu Kuang-Yao Yang |
| author_sort | Wei-Chih Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T18:42:59Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T18:42:59Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cd688deb4e7b40ce86db7bb65d92a7072023-11-20T05:42:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-07-012113473510.3390/ijms21134735Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary FibrosisWei-Chih Chen0Nien-Jung Chen1Hsin-Pai Chen2Wen-Kuang Yu3Vincent Yi-Fong Su4Hao Chen5Huai-Hsuan Wu6Kuang-Yao Yang7Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, TaiwanInstitute of Microbiology and Immunology, School of Life Sciences, National Yang-Ming University, Taipei 112, TaiwanFaculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, TaiwanDepartment of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, TaiwanFaculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, TaiwanDepartment of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, TaiwanDepartment of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, TaiwanDepartment of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, TaiwanNeutrophils 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.https://www.mdpi.com/1422-0067/21/13/4735nintedanibneutrophilchemokine (C-X-C motif) receptor 2 (CXCR2)G protein-coupled receptor kinase 2 (GRK2)pulmonary fibrosis |
| spellingShingle | Wei-Chih Chen Nien-Jung Chen Hsin-Pai Chen Wen-Kuang Yu Vincent Yi-Fong Su Hao Chen Huai-Hsuan Wu Kuang-Yao Yang Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis International Journal of Molecular Sciences nintedanib neutrophil chemokine (C-X-C motif) receptor 2 (CXCR2) G protein-coupled receptor kinase 2 (GRK2) pulmonary fibrosis |
| title | Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis |
| title_full | Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis |
| title_fullStr | Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis |
| title_full_unstemmed | Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis |
| title_short | Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis |
| title_sort | nintedanib reduces neutrophil chemotaxis via activating grk2 in bleomycin induced pulmonary fibrosis |
| topic | nintedanib neutrophil chemokine (C-X-C motif) receptor 2 (CXCR2) G protein-coupled receptor kinase 2 (GRK2) pulmonary fibrosis |
| url | https://www.mdpi.com/1422-0067/21/13/4735 |
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