Nintedanib regulates GRK2 and CXCR2 to reduce neutrophil recruitment in endotoxin-induced lung injury

Vincent Yi Fong Su, Wei Chih Chen, Wen Kuang Yu, Huai Hsuan Wu, Hao Chen, Kuang Yao Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The role of nintedanib, a multiple tyrosine kinase inhibitor, in the treatment of sepsisinduced acute lung injury (ALI) remains unclear. Lipopolysaccharide (LPS), also known as endotoxin, has been used to induce ALI. The goal of this study was to assess the effect of nintedanib in attenuating the histopathological changes of LPS-induced ALI. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h and 10 min before intratracheal endotoxin instillation. Lung histopathological characteristics, adhesion molecule expression, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed after 24 h. We found that nintedanib significantly reduced histopathological changes and neutrophil recruitment in LPS-induced ALI. The number of neutrophils in bronchoalveolar lavage fluid (BALF) was reduced in nintedanib-treated relative to untreated mice with ALI. Nintedanib mediated the downregulation of the chemotactic response to LPS by reducing the expression of adhesion molecules and the phosphorylated p38:total p38 mitogen-activated protein kinase (MAPK) ratio in the lungs of mice with ALI. Nintedanib also reduced the expression of lymphocyte antigen 6 complex locus G6D (Ly6G) and very late antigen 4 (VLA-4) in BALF neutrophils and mediated the downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in mice with LPS-induced ALI. Nintedanib improved the histopathological changes of LPS-induced ALI by reducing neutrophil chemotaxis. These effects were mediated by the inhibition of adhesion molecules via the activation of GRK2 and the inhibition of p38 MAPK and CXCR2.

Original languageEnglish
Article number9898
JournalInternational Journal Of Molecular Sciences
Issue number18
StatePublished - Sep 2021


  • Acute lung injury
  • Chemotaxis
  • CXCR2
  • GRK2
  • Neutrophil chemotaxis
  • Nintedanib
  • P38 MAPK


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