Abstract
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.
Highlights
Acute lung injury (ALI), and its most severe form, acute respiratory distress syndrome (ARDS), are life-threatening diseases in critically ill patients
Since neutrophil chemotaxis has been implicated in acute lung injury (ALI) induced by LPS, we examined the protective effect of nintedanib on ALI induced by LPS
Nintedanib significantly reduced neutrophil accumulation (Ly6G staining: 38.4% vs. 71.6%, p < 0.05) after LPS injection (Figure 2A)
Summary
Acute lung injury (ALI), and its most severe form, acute respiratory distress syndrome (ARDS), are life-threatening diseases in critically ill patients. CXCR2 belongs to the CXCR family and is the major receptor of chemotactic factors that mediate migration [2]. In models of sepsis-induced ALI, CXCR2 mediates the migration of neutrophils into the lung. Macrophage-inflammatory protein 2 (MIP-2), a cytokine belonging to the CXC chemokine family and among the most common chemotactic factors, responds to lipopolysaccharides (LPSs) by activating neutrophil migration to sites of inflammation or infection, including the lung in patients with sepsis-induced ALI [3]. GRK2 is highly expressed on neutrophils and appears to be an important regulator of the migratory response during inflammation [5,6]. Recent data indicate that the inhibition of GRK2 can increase CXCR2 activity and decrease CXCR2 resistance to phosphorylation, desensitization, and internalization [7]
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