MiR-130a-3p Alleviates Inflammatory and Fibrotic Phases of Pulmonary Fibrosis Through Proinflammatory Factor TNF-alpha and Profibrogenic Receptor TGF-beta RII

Pulmonary fibrosis (PF) is a progressive disease characterized by extracellular matrix (ECM) deposition that destroys the normal structure of the lung parenchyma, which is classified into two successive inflammatory and fibrotic phases. To investigate the anti-inflammatory and anti-fibrotic roles of miR-130a-3p in mice with bleomycin (BLM)-induced PF and the underlying mechanism, we performed single-cell RNA-sequencing analysis, which demonstrated that BLM increased/decreased the percentage of macrophages and fibroblasts/epithelial cells in PF lungs, respectively. The differentially expressed genes were enriched in PPAR signaling pathway and lysosome, ECM-receptor interaction and ribosome, and metabolism reaction. Time-course studies demonstrated that the inflammation-related factors increased significantly at day 7 (inflammatory phase), whereas the fibrosis-related factors increased at day 28 (fibrotic phase) after BLM exposure. Meanwhile, miR-130a-3p could ameliorate pulmonary lesions by downregulating the secretion of inflammatory cytokines (IL-1 beta, IL-6, TNF-alpha, and TGF-beta 1) and the deposition of ECM (alpha-SMA, FN, HYP, and collagen) in the inflammatory and fibrotic phase, respectively. In the LPS-induced inflammatory cell model, the upregulation of miR-130a-3p was mainly achieved by the activation of the NF-kappa B signaling pathway, which suppressed the proinflammatory factor TNF-alpha. Comparatively, the TGF-beta/Smad signaling pathway was inhibited by miR-130a-3p targeting TGF-beta RII in the TGF-beta 1-deduced fibrotic cell model. The evidence supports that miR-130a-3p exerts an anti-inflammatory and anti-fibrotic effect in BLM-induced PF, implying a potential pharmacological agent in the therapy of PF patients.