Envolvimento de citocinas (TNF-α, IL-1β E IL-10) e óxido nítrico na patogênese da mucosite oral experimental induzida por radioterapia de megavoltagem : efeito protetor da pentoxifilina, inibidor da óxido nítrico sintase induzida e de fitoterápicos

Abstract

INTRODUCTION: The radiation-induced oral mucisitis (OM) is the most important acute toxicity and the most impacting dose-limiting factor in head and neck cancer patients. Despite its major incidence, the pathogenesis is not well known. OBJECTIVES: Evaluate the role of the cytokines and the nitric oxide (NO) in the pathogenesis of the experimental radiation-induced oral mucisitis (OM) as well as indicate possible protector agents. METHODS: The OM was induced with only one fraction of megavoltage radiation (RT) in hamsters. The animals were treated with: cytokines inhibitors (PTX 15 mg/Kg), nitric oxide synthase inhibitor (NOSi), amineguanidine (AG 10, 30 and 90 mg/Kg) or saline solution (0.5 ml) just one hour before RT and daily until the animals’ sacrifice (13th day). Another group of animals were treated with two different phytotherapy using: Myracrodruon urundeava (Aroeira-do-sertao) topical gel 5, 10 and 20% or Aloe barbadensis Miller (Aloe vera) topical gel 25, 50 and 100%. The control group received biologically inert topical gel. The animals were treated just one hour before RT and twice daily until their sacrifice (13th day). For the evaluation of the results, the following parameters were used: histopathology analysis of the oral mucosa (macro and microscopically), MPO and NOSi activity, nitrite and cytokines (TNF-α, IL-1 and IL-10) tissue levels, cytokines and NOSi immunochemistry as well as NOSi expression by Western blot. RESULTS: The animals with radiation-induced OM showed increased inflammatory parameters: on histopathology, myeloperoxidase activity, cytokines and nitrite levels and intense NOSi immune expression when compared to the control group. AG significantly reduced in a dose-dependent effect the macro and microscopically parameters in animals with OM as well as the neutrophil infiltration and nitrite and cytokines (TNF-α, IL-1) levels. AG also reduced the NOSi activity and the cytokines and NOSi immune expression. The PTX treatment significantly reduced the inflammatory parameters (on histopathology, MPO activity, and cytokines tissue levels) and the cytokines and NOSi immune expression. The Aroeira, despite of inhibiting the nitrite and tissue TNF-α production, did not reduce the micro and macroscopically parameters of OM. On the other hand, the Aloe vera 100%, significantly inhibited the inflammatory parameters (on histopathology, MPO activity, tissue cytokines, TNF-α, IL-1 and nitrite levels). CONCLUSIONS: The data suggested that TNF-α and IL-1 by NOSi activation and consequently NO production seem to play an important role in the pathogenesis of the experimental radiation-induced OM. PTX, AG and Aloe vera 100% were able to significantly reduce the OM.