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

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.

Protection from Radiation-induced Damage in Rat’s Ileum and Colon by Combined Regimens of Melatonin and Metformin: A Histopathological Study

“…This mechanism may be involved in preserving villi in the intestine, as we have investigated in our study. On the other hand, metformin is a potent inhibitor of mitochondrial derived ROS as well as some other pro-oxidants that may be involved in radiation toxicity [ 22 , 23 ]. The combination of these drugs may be useful for radioprotection of some tissues including colon, whose injuries due to pelvic radiotherapy may lead to severe problems for patients.…”

Association of Metformin Use with Asthma Exacerbation in Patients with Concurrent Asthma and Diabetes: A Systematic Review and Meta-Analysis of Observational Studies

“…Metformin downregulated the expression levels of inflammatory cytokines (IL-1 β , IL-4, and IL-6 and TNF- α ) in intracerebral hemorrhage model rats [ 23 ]. 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 ionizing radiation [ 24 ]. In an animal experiment, metformin increased the ratio of Treg/Th17 cells in mice [ 25 ].…”

“…showed ability to attenuate upregulation of IL-4-DUOX2 pathway and other pathological damages to the lung after exposure to a high dose of ionizing radiation [24]. In an animal experiment, metformin increased the ratio of Treg/ 17 cells in mice [25].…”

Radiation-Induced Lung Fibrosis: Preclinical Animal Models and Therapeutic Strategies

“…Treatment with metformin suppressed upregulation of IR-induced genes and IL-4, which was associated with amelioration of pathological changes. Treatment with metformin attenuated the upregulation of the IL-4–DUOX2 pathway and other pathological damages to the lung after exposure to a high dose of IR [ 102 ]. The heat shock protein 27 (HSP27) was also identified as a candidate target for treating PF in a mouse model of clinical SBRT.…”