Pirfenidone ameliorates paraquat-induced pulmonary EMT by regulating miR-9-8974-5p/RGS2 expression

Irreversible and extensive pulmonary fibrosis is the leading cause of death from paraquat (PQ) poisoning, particularly in developing countries. A key pathological process contributing to this fibrosis is epithelial-mesenchymal transition (EMT), where epithelial cells acquire a mesenchymal phenotype, promoting extracellular matrix deposition. Current treatments for paraquat poisoning are limited, and understanding the molecular mechanisms driving EMT is crucial for developing effective therapies. MicroRNAs (miRNAs) are known regulators of EMT progression, and identifying specific miRNA-target axes could reveal novel therapeutic targets for PQ-induced pulmonary fibrosis.

Researchers established EMT models in mouse lung tissue and MLE-12 cells induced by paraquat (PQ). They investigated the expression levels of Regulator of G-protein signaling 2 (RGS2) and miR-9-8974-5p in these models. The study then evaluated the therapeutic effects of Pirfenidone (PFD) on PQ-induced EMT in both in vivo and in vitro settings. Additionally, they manipulated miR-9-8974-5p expression (over-expression/inhibition) to assess its impact on RGS2 levels and the severity of EMT, aiming to elucidate the underlying molecular pathway.

In both paraquat-induced mouse lung tissue and MLE-12 cells, the expression of Regulator of G-protein signaling 2 (RGS2) was significantly decreased. Conversely, manipulating miR-9-8974-5p directly influenced RGS2 levels: over-expressing miR-9-8974-5p decreased RGS2, while inhibiting it increased RGS2 expression. Pirfenidone (PFD) treatment effectively relieved PQ-induced EMT in both mouse lung tissue and MLE-12 cells.

Notably, the PFD treatment group exhibited high expression of RGS2, suggesting a direct link between PFD's therapeutic action and RGS2 upregulation. Further experiments showed that mimicking miR-9-8974-5p aggravated EMT by decreasing RGS2 levels, whereas inhibiting miR-9-8974-5p relieved EMT by increasing RGS2 levels. These findings collectively indicate that miR-9-8974-5p mediates PQ-induced pulmonary EMT by regulating RGS2 expression.