Exploration on the regulatory mechanisms of MBD2/miR-301a-5p/CXCL12/CXCR4 on acute exacerbations of chronic obstructive pulmonary disease

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 identified miR-301a-5p was associated with the progression of AE-COPD, but its regulatory mechanism underlying COPD pathogenesis remains uncovered.Methods Serum and peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and patients with COPD in remission (R-COPD) and acute exacerbation (AE-COPD). Human HULEC-5a and HBE cells were transfected with MBD2, sh-MBD2, miR-301a-5p mimics or inhibitor, followed by stimulated with cigarette smoke extract (CSE). The co-culture assays were performed by the addition of the supernatant of medium derived from HULEC-5a cells transfected with miR-301a-5p mimics or inhibitor into si-CXCR4-transfected-lung fibroblast or THP-1 macrophages. Transwell assay was used to analyze cell migration.Results Clinical samples showed that decreased miR-301a-5p level in AE-COPD was significantly positively correlated with the expression level of MBD2, but negatively correlated with CXCL12 expression level. MBD2 overexpression significantly promoted miR-301a-5p, while suppressed CXCL12 in HULEC-5a and HBE cells. CXCL12 was confirmed as a direct target of miR-301a-5p. CXCR4 knockdown significantly the suppressive effect of miR-301a-5p mimics and attenuated the promotional effects of miR-301a-5p inhibitor on the migration of circulating fibroblasts and macrophages, as well as the expression levels of P-MEK and P-AKT.Conclusion In summary, MBD2/miR-301a-5p/CXCL12/CXCR4 appears to be involved in such recruitments of circulating fibroblasts and macrophages during COPD exacerbations.

A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates

“…In summary, we have produced a high-resolution scATACseq data set for the developing human lungs which is highly consistent with our scRNAseq data. Mining this data set provides hypotheses for lineage-determining TFs in lung development, many of which have been reported to be dysregulated in lung disease (Apostolopoulou et al, 2007;Koczulla et al, 2012;Shen et al, 2020). As further scATAC datasets become available for control and diseased adult lungs, our data will provide a resource for comparing normal and aberrant TFs and chromatin regulation.…”