Regorafenib prevents the development of emphysema in a murine elastase model

Abstract

Emphysema is a chronic obstructive lung disease characterized by inflammation and enlargement of the air spaces. Regorafenib, a potential senomorphic drug, exhibited a therapeutic effect in porcine pancreatic elastase (PPE)-induced emphysema in mice. In the current study we examined the preventive role of regorafenib in development of emphysema. Lung function tests and morphometry showed that oral administration of regorafenib (5 mg/kg/day) for seven days after instillation of PPE resulted in attenuation of emphysema. Mechanistically, regorafenib reduced the recruitment of inflammatory cells, particularly macrophages and neutrophils, in bronchoalveolar lavage fluid. In agreement with these findings, measurements using a cytokine array and ELISA showed that expression of inflammatory mediators including interleukin (IL)-1β, IL-6, and CXCL1/KC, and tissue inhibitor of matrix metalloprotease-1 (TIMP-1), was downregulated. The results of immunohistochemical analysis confirmed that expression of IL-6, CXCL1/KC, and TIMP-1 was reduced in the lung parenchyma. Collectively, the results support the preventive role of regorafenib in development of emphysema in mice and provide mechanistic insights into prevention strategies.

Regorafenib Attenuates Osteoclasts Differentiation by Inhibiting the NF-κB, NFAT, ERK, and p38 Signaling Pathways

“…Regorafenib, as a multitargeted tyrosine kinase inhibitor, is gradually being discovered to have potential curative effects in animal models of pulmonary emphysema, pulmonary hypertension, autoimmune arthritis, and Alzheimer’s disease . Given its established antitumor properties, exploring regorafenib’s utility in noncancerous diseases is of significant scientific interest.…”

“…5 The high prevalence and serious complications of this condition underscore the urgent necessity for innovative therapeutic strategies aimed at managing osteoclast-related osteolytic diseases. Regorafenib, as a multitargeted tyrosine kinase inhibitor, is gradually being discovered to have potential curative effects in animal models of pulmonary emphysema, 53 pulmonary hypertension, 54 autoimmune arthritis, 55 and Alzheimer's disease. 56 Given its established antitumor properties, exploring regorafenib's utility in noncancerous diseases is of significant scientific interest.…”

Targeting accelerated pulmonary ageing to treat chronic obstructive pulmonary disease‐induced neuropathological comorbidities

“…In complementary studies, the potential of regorafenib was shown in a porcine pancreatic elastase (PPE)‐induced model of emphysema. Treatment with regorafenib (5 mg·kg −1 ) attenuated the senescence profile with reduced SA‐β‐Gal staining and p16 INK4a expression and improved PPE‐induced emphysema in mice (Oh et al, 2023 ; Park et al, 2023 ). To the best of our knowledge, there is no experimental data on the effects of regorafenib on the circadian rhythm in a disease setting.…”