Abstract | Background:
Chronic obstructive pulmonary disease ( COPD) is characterized by irreversible expiratory airflow obstruction, and its chronic course is worsened by recurrent acute exacerbations. Our previous microarray assay identified microRNA (miR)-301a-5p as being associated with progression of acute exacerbation of COPD (AE- COPD); however, the mechanism underlying COPD pathogenesis remains unknown. Methods: Samples of serum and peripheral blood mononuclear cells (PBMCs) were isolated from healthy control subjects and patients with stable COPD (R- COPD) or with an acute exacerbation of COPD (AE- COPD). Human HULEC-5a and human bronchial epithelial (HBE) cells were transfected with methyl-CpG-binding domain protein 2 (MBD2), sh-MBD2, miR-301a-5p mimics or an inhibitor, and then stimulated with cigarette smoke extract (CSE). Conditioned medium co-culture assays were performed by adding the supernatant of medium derived from HULEC-5a cells transfected with miR-301a-5p mimics or inhibitor into wells containing si-c-x-c motif chemokine receptor 4 (CXCR4)-transfected-lung fibroblasts or human leukemic THP-1 cell line macrophages. Transwell assays were performed to analyze cell migration. Results: Our analysis of clinical samples showed that decreased miR-301a-5p levels in patients with AE- COPD were positively correlated with levels of MBD2 expression, but negatively correlated with levels of chemokine ligand C-X-C motif chemokine ligand 12 (CXCL12) expression. MBD2 overexpression significantly promoted miR-301a-5p production, but suppressed CXCL12 production in HULEC-5a and HBE cells. CXCL12 was confirmed to be a direct target of miR-301a-5p. CXCR4 knockdown significantly enhanced the suppressive effect of miR-301a-5p mimics and attenuated the promotional effects of the miR-301a-5p inhibitor on the migration of circulating fibroblasts and macrophages, as well as the expression levels of phospho- mitogen-activated protein kinase (p- MEK) and phospho- protein kinase B (p-AKT). Conclusion: In summary, the MBD2/miR-301a-5p/CXCL12/CXCR4 pathway was shown to affect the migration of lung fibroblasts and monocyte-derived macrophages, which may play an important role during COPD exacerbations.
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Authors | Wen Shen, Zhiyin Weng, Minjuan Fan, Shukun Wang, Ruili Wang, Yang Zhang, Hong Tian, Xi Wang, Xin Wu, Xiaolei Yang, Wei Wei, Kaifen Yuan |
Journal | International journal of chronic obstructive pulmonary disease
(Int J Chron Obstruct Pulmon Dis)
Vol. 15
Pg. 2561-2572
( 2020)
ISSN: 1178-2005 [Electronic] New Zealand |
PMID | 33116473
(Publication Type: Journal Article)
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Copyright | © 2020 Shen et al. |
Chemical References |
- CXCL12 protein, human
- CXCR4 protein, human
- Chemokine CXCL12
- DNA-Binding Proteins
- MBD2 protein, human
- MIRN301A microRNA, human
- MicroRNAs
- Receptors, CXCR4
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Topics |
- Chemokine CXCL12
(genetics)
- DNA-Binding Proteins
(metabolism)
- Humans
- Leukocytes, Mononuclear
(metabolism)
- Lung
(metabolism)
- MicroRNAs
(genetics)
- Pulmonary Disease, Chronic Obstructive
(diagnosis, genetics)
- Receptors, CXCR4
(genetics)
- Signal Transduction
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