MiR-15b regulation promoted by Nintedanib in CTD associated progressive pulmonary fibrosis

Pulmonary fibrosis is a progressive respiratory disease. It has a chronic course, led by a fibrous degeneration of the lung parenchyma. It is a common evolution that occurs in rheumatological diseases, which can lead to significant complications and increased mortality. Nintedanib is the most recently developed molecule in IPF treatment, which targets some tyrosine kinase receptors involved in cell growth and regulation of pathogenic processes of fibrosis. We aimed to evaluate epigenetic effect of Nintedanib in patients with pulmonary fibrosis secondary to collagen tissue disease. Patients’ plasma was collected at baseline and after 6 and 12 month of therapy. Levels of miR-15a, miR-15b, let7d, miR-155 and miR-21 were detected at baseline and after 6 and 12 month of treatment by RT-PCR. We also analysed those miRNAs expression levels in PCLS (Precision Cut Lung Slices) model of EMT (Epithelial–Mesenchymal Transition). We assessed that the expression levels of let-7d-5p in plasma are significantly reduced after 6 months of treatment compared to baseline. In addition, we also observed a significant downregulation of miR-15b-5p plasma levels, after 12 months of therapy. NETs (Neutrophil extracellular traps), used to stimulate EMT in PCLS, induced an up-regulation of miR-15b after 48h and a slight decrease when treated with Nintedanib. According to literature data, miR15b can be considered pro-fibrotic since able to regulate Smurf2-HSP27 axis. Thus miR-15b downregulation can be inferred to be protective and suggests another possible target of Nintedanib activity in progressive CTD-ILD.