Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.
Highlights
Idiopathic pulmonary fibrosis (IPF) belongs to the family of interstitial lung diseases and is a chronic, progressive, fibrotic interstitial lung disease of unknown cause that occurs primarily in the elderly [1,2]
We firstly explored the cytotoxicity and animal toxicity of RG, our experiments revealed that RG had not toxic effect on Mouse lung fibroblast (Mlg) and NaCl-primary pulmonary fibroblast (PPF) cells and C57BL/6j mice (Figure S1)
RG promoted mouse lung function in the BLM-induced pulmonary fibrosis model. These findings indicate that RG improves lung fibrosis mainly by inhibiting myofibroblast activation and extracellular matrix (ECM) production and promoting autophagy, suggesting that this drug can prevent fibrotic progression
Summary
Idiopathic pulmonary fibrosis (IPF) belongs to the family of interstitial lung diseases and is a chronic, progressive, fibrotic interstitial lung disease of unknown cause that occurs primarily in the elderly [1,2]. The main pathological features of IPF are the massive accumulation of myofibroblasts and the excessive deposition of extracellular matrix in the lung interstitium, leading to the destruction of alveolar structure and interruption of gas exchange, after which patients have died of respiratory failure [3]. Its frequency is similar to that of gastric, brain, and testicular cancers, and the median survival time from diagnosis is 2.8 years [4]. The incidence of IPF has increased over time [5]. The estimated cases are 2.8 and 18.0 per 100,000 people per year, respectively [6,7]. Nintedanib and pirfenidone, have been approved for the treatment of IPF, and can increase the mandatory vital capacity of patients to a certain extent; they have limited efficacy [8]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.