Cepharanthine Ameliorates Pulmonary Fibrosis by Inhibiting the NF-κB/NLRP3 Pathway, Fibroblast-to-Myofibroblast Transition and Inflammation

Abstract

Pulmonary fibrosis (PF) is one of the sequelae of Corona Virus Disease 2019 (COVID-19), and currently, lung transplantation is the only viable treatment option. Hence, other effective treatments are urgently required. We investigated the therapeutic effects of an approved botanical drug, cepharanthine (CEP), in a cell culture model of transforming growth factor-β1 (TGF-β1) and bleomycin (BLM)-induced pulmonary fibrosis rat models both in vitro and in vivo. In this study, CEP and pirfenidone (PFD) suppressed BLM-induced lung tissue inflammation, proliferation of blue collagen fibers, and damage to lung structures in vivo. Furthermore, we also found increased collagen deposition marked by α-smooth muscle actin (α-SMA) and Collagen Type I Alpha 1 (COL1A1), which was significantly alleviated by the addition of PFD and CEP. Moreover, we elucidated the underlying mechanism of CEP against PF in vitro. Various assays confirmed that CEP reduced the viability and migration and promoted apoptosis of myofibroblasts. The expression levels of myofibroblast markers, including COL1A1, vimentin, α-SMA, and Matrix Metallopeptidase 2 (MMP2), were also suppressed by CEP. Simultaneously, CEP significantly suppressed the elevated Phospho-NF-κB p65 (p-p65)/NF-κB p65 (p65) ratio, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels, and elevated inhibitor of NF-κB Alpha (IκBα) degradation and reversed the progression of PF. Hence, our study demonstrated that CEP prevented myofibroblast activation and treated BLM-induced pulmonary fibrosis in a dose-dependent manner by regulating nuclear factor kappa-B (NF-κB)/ NLRP3 signaling, thereby suggesting that CEP has potential clinical application in pulmonary fibrosis in the future.

The mitigating effect of para‐hydroxycinnamic acid in bleomycin‐induced pulmonary fibrosis in mice through targeting oxidative, inflammatory and fibrotic pathways

“…Nevertheless, a significant degree of diversity in the level of fibrosis was observed among individual animals following a single OP administration of BLM at a dose of 5 mg/kg. The administration of BLM has been observed to induce an elevation in inflammation and the deposition of collagen in pulmonary tissue 39 . A marked elevation in lung tissue pro‐inflammatory and pro‐fibrotic cytokines was observed in mice induced with BLM after 3 weeks; this was determined through the use of H&E and MT staining techniques, which revealed the presence of increased collagen fibres and structural damage to the lungs.…”

“…The administration of BLM has been observed to induce an elevation in inflammation and the deposition of collagen in pulmonary tissue. 39 A marked elevation in lung tissue pro-inflammatory and profibrotic cytokines was observed in mice induced with BLM after 3 weeks; this was determined through the use of H&E and MT staining techniques, which revealed the presence of increased collagen fibres and structural damage to the lungs. Furthermore, elevated collagen deposition was demonstrated by the increased expression levels of α-SMA in immunostained lung sections and tissue homogenate HYP.…”

Phytochemicals for mitigating the COVID-19 crisis: evidence from pre-clinical and clinical studies

“…Mathematical modelling of combination treatment of NFV (oral administration) and cepharanthine (intravenous injection) is predicted to downregulate the viral RNA load 6.15 days faster than the untreated group and 1.23 days earlier than NFV treatment alone [138]. There is an ongoing randomized phase 2, double-blind clinical trial to assess the efficacy and safety of orally administered cepharanthine in non-hospitalized asymptomatic or mild adult participants with COVID-19 to reduce viral clearance time and SARS-CoV-2 viral load [139].…”

Nintedanib Mitigates Radiation-Induced Pulmonary Fibrosis by Suppressing Epithelial Cell Inflammatory Response and Inhibiting Fibroblast-to-Myofibroblast Transition

“…Research has indicated that the occurrence of RIPF is a dynamic response process influenced by multiple factors 6 , 7 . Specifically, radiation-induced epithelial cell damage and fibroblast activation play pivotal roles in mediating the development of RIPF 8 , 9 . The primary mechanisms initiating the process involve direct DNA damage and the generation of reactive oxygen species within epithelial cells 10 , 11 .…”