Azilsartan reduced TNF-α and IL-1β levels, increased IL-10 levels and upregulated VEGF, FGF, KGF, and TGF-α in an oral mucositis model.

Caroline Addison Carvalho Xavier de Medeiros,Aurigena Antunes de Araújo,Kênio Costa de Lima,Gerly Anne de Castro Brito,Raimundo Fernandes de Araújo,Hugo Varela,Ligia Moreno de Moura

doi:10.1371/journal.pone.0116799

Abstract

Oral mucositis (OM) is a common complication of treatments for head and neck cancer, particularly radiotherapy with or without chemotherapy. OM is characterised by oral erythema, ulceration, and pain. The aim of this study was to evaluate the effect of azilsartan (AZT), an angiotensin II receptor antagonist, on 5-fluorouracil (5-FU)-induced oral mucositis (OM) in Syrian hamsters. OM was induced by the intraperitoneal administration of 5-FU on experimental days 1 (60mg/Kg) and 2 (40mg/Kg). Animals were pretreated with oral AZT (1, 5, or 10 mg/kg) or vehicle 30 min before 5-FU injection and daily until day 10. Experimental treatment protocols were approved by the Animal Ethics Committee Use/CEUA (Number 28/2012) of the UFRN. Macroscopic analysis and cheek pouch samples were removed for histopathologic analysis. Myeloperoxidase (MPO), Malonyldialdehyde (MDA), interleukin-1 beta (IL-1β), interleukin-10 (IL-10), and tumour necrosis factor-alpha (TNF-α) were analysed by Enzyme Linked Immuno Sorbent Assay (ELISA). Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), and transforming growth factor (TGF)-α were measured by immunohistochemistry. Analysis of variance followed by Bonferroni’s test was used to calculate the means of intergroup differences (p ≤ 0.05). Treatment with 1 mg/kg AZT reduced levels MPO (p<0.01), MDA (p<0.5) and histological inflammatory cell infiltration, and increased the presence of granulation tissue. AZT treatment at 1 mg/kg reduced the TNF-α (p<0.05) and IL-1β (p<0.05) levels, increased the cheek pouch levels of IL-10 (p<0.01), and upregulated VEGF, FGF, KGF, and TGF-α. Administration of AZT at higher doses (5 and 10 mg/kg) did not significantly reverse the OM. AZT at a dose of 1 mg/kg prevented the mucosal damage and inflammation associated with 5-FU-induced OM, increasing granulation and tissue repair.

Highlights

Oral mucositis (OM) is a common complication of treatments for head and neck cancer, radiotherapy with or without chemotherapy
The consequent activation of various enzymes and transcription factors eventually leads to the upregulation of genes coding for inflammatory cytokines, such as tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which target the submucosa and basal epithelium
Studies have shown that AZT exhibits anti-inflammatory activity [18], confirming reports regarding the anti-inflammatory activities of angiotensin receptor blockers (ARBs) [17,28,29]

Summary

Introduction

Oral mucositis (OM) is a common complication of treatments for head and neck cancer, radiotherapy with or without chemotherapy. OM is characterised by oral erythema, ulceration, and pain. The initiation phase involves the initial injury to cells by radiotherapy and/or chemotherapy. This injury may be induced directly via DNA damage or (more commonly) indirectly via reactive oxygen species. The resulting inflammation and tissue damage lead to ulceration and subsequent bacterial colonisation, further feeding a vicious cycle of inflammatory cytokine-mediated damage. The final healing phase involves signalling via the extracellular matrix, resulting in epithelial proliferation, epithelialisation, and reestablishment of the mucosal barrier [3]

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