Abstract
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.
Highlights
In end-stage interstitial lung disease (ILD) and in the fibrotic phase of acute respiratory distress syndrome (ARDS), pulmonary fibrosis is commonly observed [1,2]
Lung inflammation and fibrosis induced by the intratracheal injection of bleomycin were evidenced by increased neutrophil infiltration in lung tissue, progressive diffuse alveolar fibrosis, focally dense fibrosis, and epithelial hyperplasia in alveolar ducts with hematoxylin and eosin (HE) staining (Figure 1A)
The histological evaluation of the lungs seven days after bleomycin-induced pulmonary fibrosis showed that lung inflammation and fibrosis were significantly reduced by nintedanib treatment (Figure 1A)
Summary
In end-stage interstitial lung disease (ILD) and in the fibrotic phase of acute respiratory distress syndrome (ARDS), pulmonary fibrosis is commonly observed [1,2]. Bleomycin-induced pulmonary fibrosis has been used for years as a model of fibrotic lung diseases in animal studies. It involves acute inflammation in the alveolar epithelium followed by fibrosis, which is observed in IPF and ARDS [5,6]. Our previous study demonstrated that the early administration of induced pluripotent stem cells might reduce the levels of cytokines and chemokines that mediate inflammation and fibrosis in murine models of bleomycin-induced pulmonary fibrosis [7]. Developing an effective treatment to alleviate lung inflammation during the early stage of fibrosis is important
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