Mefunidone Hydrochloride

Inflammation, oxidative stress, and epithelial-mesenchymal transition (EMT) play crucial roles in forming posterior capsular opacification (PCO), particularly in fibrotic PCO. Here we investigated the protective effects of mefunidone (MFD), a novel compound with potent antifibrotic properties, which could be useful in preventing PCO.

We utilized an extracapsular lens extraction (ECLE) surgery in mice to simulate the development of PCO in vivo. Treatment was performed immediately postsurgery through the intracameral injection of MFD solution. Expression levels of EMT and inflammatory markers were analyzed using Western blot, qRT-PCR, immunofluorescence, and hematoxylin and eosin staining. Additionally, the oxidative stress indicator malondialdehyde and glutathione expression were monitored to assess the oxidative stress response. In vitro experiments, TGF-β2, and H2O2 were used to treat lens epithelial cells to induce EMT and oxidative stress models, respectively. These models were employed to explore the effects of MFD and investigate its underlying mechanisms.

Compared to the model group, the group treated with anterior chamber MFD injection effectively suppressed inflammation, oxidative stress, and fibrotic responses within the capsular bag after ECLE and partially inhibited the downregulation of the epithelial marker E-cadherin. To further elucidate the underlying mechanisms, we discovered that MFD treatment in vitro remarkably reduced inflammation, decreased the production of reactive oxygen species, and suppressed the phosphorylation of TGF-β/SMAD as well as MAPK/ERK, thereby inhibiting the occurrence of EMT.

Our findings substantiate the efficacy of MFD in treating PCO and provide insights into its potential mechanisms of action.

Silicosis is the most common and severe type of pneumoconiosis, imposing a substantial disease burden and economic loss on patients and society. The pathogenesis and key targets of silicosis are not yet clear, and there are currently no effective treatments available. Therefore, we conducted research on mefunidone (MFD), a novel antifibrotic drug, to explore its efficacy and mechanism of action in murine silicosis.

Acute 7-day and chronic 28-day silicosis models were constructed in C57BL/6J mice by the intratracheal instillation of silica and subsequently treated with MFD to assess its therapeutic potential. The effects of MFD on silica-induced inflammation, pyroptosis, and fibrosis were further investigated using immortalized mouse bone marrow-derived macrophages (iBMDMs).

In the 7-day silica-exposed mouse models, MFD treatment significantly alleviated pulmonary inflammation and notably reduced macrophage infiltration into the lung tissue. RNA-sequencing analysis of silica-induced iBMDMs followed by gene set enrichment analysis revealed that MFD profoundly influenced cytokine-cytokine receptor interactions, chemokine signaling, and the toll-like receptor signaling pathways. MFD treatment also markedly reduced the secretion of inflammatory cytokines and chemokines from silica-exposed iBMDMs. Moreover, MFD effectively downregulated the activation of the TLR4-NF-κB/MAPK signaling pathway induced by silica and mitigated the upregulation of pyroptosis markers. Additionally, MFD treatment significantly suppressed the activation of fibroblasts and alveolar epithelial cells co-cultured with silica-exposed mouse macrophages. Ultimately, in the 28-day silica-exposed mouse models, MFD administration led to a substantial reduction in the severity of pulmonary fibrosis.

MFD mitigates silica-induced pulmonary inflammation and fibrosis in mice by suppressing the TLR4-NF-κB/MAPK signaling pathway and reducing pyroptotic responses in macrophages. MFD could potentially emerge as a novel therapeutic agent for the treatment of silicosis.