Abstract

BACKGROUND: Diabetes causes damage to the soft tissue and bone structure of the foot, referred to as “diabetic foot”. Ibrutinib is a Bruton tyrosine kinase (Btk) inhibitor, and the role and mechanism of ibrutinib on the diabetic foot have not been elucidated.

MATERIAL AND METHODS: Male Wister rats were randomly divided into 3 groups: control group, model group, and ibrutinib group. After 14 days, the ulcer wound size of each group was measured, and the ulcer healing rate was calculated. The level of inflammatory factors interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 was detected by enzyme-linked immunosorbent assay (ELISA). Real-time polymerase chain reaction (PCR) was used to analyze the changes of Toll-like receptor 2 (TLR2) and TLR4. The expression of vascular endothelial growth factor (VEGF) and the RAGE (receptor for advanced glycation end product/NF-κB (nuclear factor-kappa B) pathway was detected by western blot.

RESULTS: Blood glucose, blood lipids, serum creatinine, and urea nitrogen (BUN) levels were increased in the model group, together with increased levels of IL-1β, TNF-α, IL-6, as well as TLR2 and TLR4 expression, and there were significant differences compared with the control group (P<0.05). Meanwhile, the model group showed decreased VEGF expression and increased expression of RAGE and NF-κB. However, ibrutinib reduced blood sugar, blood lipids, creatinine, and urea nitrogen levels, inhibited the secretion of inflammatory factors, promoted ulcer healing, improved ulcer healing rate, decreased the expression of TLR2, TLR4, RAGE, and NF-κB, and increased VEGF expression; there were significant differences in the ibrutinib group compared with the model group (P<0.05).

CONCLUSIONS: The Btk inhibitor ibrutinib can upregulate VEGF expression, inhibit the expression of TLRs, inhibit the secretion of inflammatory factors, and promote the healing of diabetic foot ulcer possibly by regulating the RAGE/NF-κB pathway.

Keywords: Rage, Vascular Endothelial Growth Factor A, Adenine, Agammaglobulinaemia Tyrosine Kinase, Cytokines, Diabetes Mellitus, Diabetic Foot, Piperidines, Pyrazoles, Pyrimidines, Rats, Wistar, Receptor for Advanced Glycation End Products, Toll-Like Receptors