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.