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Endothelial cell-derived MMP19 promotes pulmonary fibrosis by inducing E(nd)MT and monocyte infiltration
Weiming Zhao1, Lan Wang1, Juntang Yang1
1State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China.
Background:
Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which is an MMP, was significantly upregulated in hyperplastic alveolar epithelial cells in IPF lung tissues and promoted epithelial-mesenchymal transition (EMT). Recent studies have demonstrated that endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis. However, the role of MMP19 in pulmonary vascular injury and repair and E(nd)MT remains unclear.
Methods:
To determine the role of MMP19 in E(nd)MT and pulmonary fibrosis. MMP19 expressions were determined in the lung endothelial cells of IPF patients and bleomycin (BLM)-induced mice. The roles of MMP19 in E(nd)MT and endothelial barrier permeability were studied in the MMP19 cDNA-transfected primary human pulmonary microvascular endothelial cells (HPMECs) and MMP19 adenoassociated virus (MMP19-AAV)-infected mice. The regulatory mechanism of MMP19 in pulmonary fibrosis was elucidated by blocking its interacting proteins SDF1 and ET1 with AMD3100 and Bosentan, respectively.
Results:
In this study, we found that MMP19 expression was significantly increased in the lung endothelial cells of IPF patients and BLM-induced mice compared to the control groups. MMP19 promoted E(nd)MT and the migration and permeability of HPMECs in vitro, stimulated monocyte infiltration into the alveolus, and aggravated BLM-induced pulmonary fibrosis in vivo. SDF1 and Endothelin-1 (ET1) were physically associated with MMP19 in HPMECs and colocalized with MMP19 in endothelial cells in IPF patient lung tissues. AMD3100 and bosentan alleviated the fibrosis induced by MMP19 in the BLM mouse model.
Conclusion:
MMP19 promoted E(nd)MT by interacting with ET1 and stimulated monocyte infiltration into lung tissues via the SDF1/CXCR4 axis, thus aggravating BLM-induced pulmonary fibrosis. Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis. Video abstract.
Insights
Matrix metalloproteinase-19 (MMP19) promotes pulmonary fibrosis by driving endothelial-to-mesenchymal transition and vascular injury. Targeting MMP19 interactions with ET1 and SDF1 offers a potential therapeutic strategy for idiopathic pulmonary fibrosis.
Area of Science:
- Pulmonary Medicine
- Vascular Biology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) are implicated in extracellular matrix remodeling and idiopathic pulmonary fibrosis (IPF) pathogenesis.
- MMP19 is upregulated in IPF lung tissues and promotes epithelial-mesenchymal transition (EMT).
- Endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis, but MMP19's role is unclear.
Purpose of the Study:
- To investigate the role of MMP19 in E(nd)MT and pulmonary fibrosis.
- To determine MMP19 expression in lung endothelial cells of IPF patients and a mouse model.
- To elucidate the mechanism by which MMP19 regulates pulmonary fibrosis.
Main Methods:
- MMP19 expression analysis in IPF patient and bleomycin (BLM)-induced mouse lung endothelial cells.
- In vitro studies using transfected human pulmonary microvascular endothelial cells (HPMECs) to assess E(nd)MT and permeability.
- In vivo studies using MMP19-AAV infected mice and blocking agents (AMD3100, Bosentan) to investigate regulatory mechanisms.
Main Results:
- MMP19 expression was significantly increased in lung endothelial cells of IPF patients and BLM-induced mice.
- MMP19 promoted E(nd)MT, migration, and permeability of HPMECs, and aggravated BLM-induced pulmonary fibrosis.
- MMP19 interacted with SDF1 and ET1, which were also found in endothelial cells of IPF lungs; blocking these alleviated fibrosis.
Conclusions:
- MMP19 promotes E(nd)MT and monocyte infiltration via SDF1/CXCR4, exacerbating pulmonary fibrosis.
- Targeting vascular integrity regulated by MMP19 presents a potential therapeutic avenue for pulmonary fibrosis.
- MMP19's interaction with ET1 and SDF1 is crucial in its pro-fibrotic role.
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