Metformin Protects Against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression.

Rasoul Azmoonfar,Dheyauldeen Shabeeb,Rasoul Yahyapour,Mohsen Cheki,Ahmed Eleojo Musa,Hana Saffar,Saeed Rezapoor,Ehsan Khodamoradi,Masoud Najafi,Bagher Farhood,Elahe Motevaseli,Farzad Nouruzi,Peyman Amini

doi:10.15171/apb.2018.078

Abstract

Purpose: Lung tissue is one of the most sensitive organs to ionizing radiation (IR). Early and late side effects of exposure to IR can limit the radiation doses delivered to tumors that are within or adjacent to this organ. Pneumonitis and fibrosis are the main side effects of radiotherapy for this organ. IL-4 and IL-13 have a key role in the development of pneumonitis and fibrosis. Metformin is a potent anti-fibrosis and redox modulatory agent that has shown radioprotective effects. In this study, we aimed to evaluate possible upregulation of these cytokines and subsequent cascades such as IL4-R1, IL-13R1, Dual oxidase 1 (DUOX1) and DUOX2. In addition, we examined the potential protective effect of metformin in these cytokines and genes, as well as histopathological changes in rat’s lung tissues.Methods: 20 rats were divided into 4 groups: control; metformin treated; radiation + metformin; and radiation. Irradiation was performed with a 60Co source delivering 15 Gray (Gy) to the chest area. After 10 weeks, rats were sacrificed and their lung tissues were removed for histopathological, real-time PCR and ELISA assays.Results: Irradiation of lung was associated with an increase in IL-4 cytokine level, as well as the expression of IL-4 receptor-a1 (IL4ra1) and DUOX2 genes. However, there was no change in the level of IL-13 and its downstream gene including IL-13 receptor-a2 (IL13ra2). Moreover, histopathological evaluations showed significant infiltration of lymphocytes and macrophages, fibrosis, as well as vascular and alveolar damages. Treatment with metformin caused suppression of upregulated genes and IL-4 cytokine level, associated with amelioration of pathological changes.Conclusion: Results of this study showed remarkable pathological damages, an increase in the levels of IL-4, IL4Ra1 and Duox2, while that of IL-13 decreased. Treatment with metformin showed ability to attenuate upregulation of IL-4–DUOX2 pathway and other pathological damages to the lung after exposure to a high dose of IR.

Highlights

Nowadays, cancer treatment using ionizing radiation (IR), known as radiotherapy, is one of the most common modalities
We examined the protective effect of metformin on development of radiation-induced inflammation and fibrosis associated with other pathological changes such as vascular damage
Studies have shown that IL-4, through its receptor IL-4R1, upregulates the expression of both Dual oxidase 1 (DUOX1) and DUOX2, while IL-13 can upregulate IL13R and DUOX1.31,32 This may continue for a long time after exposure to IR, leading to disruption of normal function of tissues and increased risk of carcinogenesis.[30,33]

Summary

Introduction

Cancer treatment using ionizing radiation (IR), known as radiotherapy, is one of the most common modalities. The aim of radiotherapy is to eradicate all tumor cells with lowest possible damage to the surrounding normal tissues.[1] radiation therapy is associated with some side-effects. And late side effects of exposure to high doses of radiotherapy may limit the radiation doses delivered.[2] a high dose of radiation may affect the long‐term quality of life of cancer patients.[3] lung inflammation and fibrosis is one of the most important late effects of radiotherapy which may appear months or years after

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