Chemotherapy‐induced phlebitis via the GBP5/NLRP3 inflammasome axis and the therapeutic effect of aescin

Abstract

Background and Purpose Intravenous infusion of chemotherapy drugs can cause severe chemotherapy‐induced phlebitis (CIP) in patients. However, the underlying mechanism of CIP development remains unclear. Experimental Approach RNA‐sequencing analysis was used to identify potential disease targets in CIP. Guanylate binding protein‐5 (GBP5) genetic deletion approaches also were used to investigate the role of GBP5 in NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in lipopolysaccharide (LPS) primed murine bone‐marrow‐derived macrophages (BMDMs) induced by vinorelbine (VIN) in vitro and in mouse models of VIN‐induced CIP in vivo. The anti‐CIP effect of aescin was evaluated, both in vivo and in vivo. Key Results Here, we show that the expression of GBP5 was upregulated in human peripheral blood mononuclear cells from CIP patients. Genetic ablation of GBP5 in murine macrophages significantly alleviated VIN‐induced CIP in the experimental mouse model. Mechanistically, GBP5 contributed to the inflammatory responses through activating NLRP3 inflammasome and driving the production of the inflammatory cytokine IL‐1β. Moreover, aescin, a mixture of triterpene saponins extracted from horse chestnut seed, can alleviate CIP by inhibiting the GBP5/NLRP3 axis. Conclusion and Implications These findings suggest that GBP5 is an important regulator of NLRP3 inflammasome in CIP mouse model. Our work further reveals that aescin may serve as a promising candidate in the clinical treatment of CIP.

N-acetylcysteine attenuates the incidence of phlebitis induced by carbomer/vinorelbine gel

“…Phlebitis is caused by the injection of stimulative drugs, such as chemotherapy and hypertonic drugs, through the superficial vein, which damages VECs and causes inflammation of the vein and surrounding tissues [ 8 , 26 ]. Owing to its high incidence, as well as clinical symptoms such as pain and swelling, prevention and treatment strategies for phlebitis are urgently required [ 5 , 6 , 27 ]. Currently, the establishment of phlebitis models is mainly based on intravascular injections in rabbits and mice [ 6 , 11 ].…”

“…Owing to its high incidence, as well as clinical symptoms such as pain and swelling, prevention and treatment strategies for phlebitis are urgently required [ 5 , 6 , 27 ]. Currently, the establishment of phlebitis models is mainly based on intravascular injections in rabbits and mice [ 6 , 11 ]. However, owing to the difficulty of intravascular injection, phlebitis cannot be induced quickly, simply, or efficiently, thus affecting mechanistic studies and the formulation of prevention strategies against this condition.…”

“…Chemotherapeutic drugs circulate throughout the body owing to their fluidity [ 3 ], and their distribution can lead to systemic toxicity [ 4 ]. Patients with phlebitis typically do not exhibit systemic symptoms, but they do present local symptoms such as skin redness, pain, sclerosis, swelling, or venous thrombosis in severe cases [ 5 , 6 ]. Phlebitis severely affects the quality of life of patients and weakens the effects of subsequent chemotherapy [ 7 ].…”

“…Establishing an animal phlebitis model in vivo might help investigate the mechanism and pathological process of infusion phlebitis and aid in formulating effective prevention and treatment measures. The primary method of constructing an animal phlebitis model is the intravenous administration of chemotherapy drugs [ 6 , 8 , 9 ]. Multiple long-term chemotherapy injections at the infusion site are required to effectively induce phlebitis [ 10 ], which increases the difficulty of the procedure and reduces the probability of successful phlebitis induction.…”

The IRF1/GBP5 axis promotes osteoarthritis progression by activating chondrocyte pyroptosis

“…The GBP5 protein is a crucial member of the GTPase family, with its aberrant expression linked to the development of several diseases. The GBP5/NLRP3 inflammasome axis inhibits chemotherapy-induced phlebitis [ 41 ] and exacerbates skin inflammation by inducing M1 macrophage polarization via the NF-KB signaling pathway [ 42 ]. In our study, GBP5 was significantly elevated not only in TNF-α-treated chondrocytes but also in the knee joint cartilage of DMM mice and cartilage tissue of humans with OA.…”