{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:45:55Z","timestamp":1792007155418,"version":"4.4.0"},"reference-count":27,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T00:00:00Z","timestamp":1631491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The role of nintedanib, a multiple tyrosine kinase inhibitor, in the treatment of sepsis-induced 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.<\/jats:p>","DOI":"10.3390\/ijms22189898","type":"journal-article","created":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T21:37:12Z","timestamp":1631569032000},"page":"9898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Nintedanib Regulates GRK2 and CXCR2 to Reduce Neutrophil Recruitment in Endotoxin-Induced Lung Injury"],"prefix":"10.3390","volume":"22","author":[{"given":"Vincent Yi-Fong","family":"Su","sequence":"first","affiliation":[{"name":"School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St, Taipei 11221, Taiwan"},{"name":"Department of Internal Medicine, Taipei City Hospital, Taipei City Government, Taipei 10364, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4172-5529","authenticated-orcid":false,"given":"Wei-Chih","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St, Taipei 11221, Taiwan"},{"name":"Department of Chest Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shi-Pai Road, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Kuang","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St, Taipei 11221, Taiwan"},{"name":"Department of Chest Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shi-Pai Road, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huai-Hsuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chest Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shi-Pai Road, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chest Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shi-Pai Road, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2803-980X","authenticated-orcid":false,"given":"Kuang-Yao","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St, Taipei 11221, Taiwan"},{"name":"Department of Chest Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shi-Pai Road, Taipei 11217, Taiwan"},{"name":"Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2119\/molmed.2010.00138","article-title":"Contribution of neutrophils to acute lung injury","volume":"17","author":"Grommes","year":"2011","journal-title":"Mol. 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