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

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...

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Autores principales: Azmoonfar, Rasoul, Amini, Peyman, Saffar, Hana, Rezapoor, Saeed, Motevaseli, Elahe, Cheki, Mohsen, Yahyapour, Rasoul, farhood, Bagher, Nouruzi, Farzad, Khodamoradi, Ehsan, Shabeeb, Dheyauldeen, Eleojo Musa, Ahmed, Najafi, Masoud
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Tabriz University of Medical Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311649/
https://www.ncbi.nlm.nih.gov/pubmed/30607342
http://dx.doi.org/10.15171/apb.2018.078
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author Azmoonfar, Rasoul
Amini, Peyman
Saffar, Hana
Rezapoor, Saeed
Motevaseli, Elahe
Cheki, Mohsen
Yahyapour, Rasoul
farhood, Bagher
Nouruzi, Farzad
Khodamoradi, Ehsan
Shabeeb, Dheyauldeen
Eleojo Musa, Ahmed
Najafi, Masoud
author_facet Azmoonfar, Rasoul
Amini, Peyman
Saffar, Hana
Rezapoor, Saeed
Motevaseli, Elahe
Cheki, Mohsen
Yahyapour, Rasoul
farhood, Bagher
Nouruzi, Farzad
Khodamoradi, Ehsan
Shabeeb, Dheyauldeen
Eleojo Musa, Ahmed
Najafi, Masoud
author_sort Azmoonfar, Rasoul
collection PubMed
description 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 (60)Co 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.
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spelling pubmed-63116492019-01-03 Metformin Protects Against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression Azmoonfar, Rasoul Amini, Peyman Saffar, Hana Rezapoor, Saeed Motevaseli, Elahe Cheki, Mohsen Yahyapour, Rasoul farhood, Bagher Nouruzi, Farzad Khodamoradi, Ehsan Shabeeb, Dheyauldeen Eleojo Musa, Ahmed Najafi, Masoud Adv Pharm Bull Research Article 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 (60)Co 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. Tabriz University of Medical Sciences 2018-11 2018-11-29 /pmc/articles/PMC6311649/ /pubmed/30607342 http://dx.doi.org/10.15171/apb.2018.078 Text en ©2018 The Authors. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from the authors or the publishers.
spellingShingle Research Article
Azmoonfar, Rasoul
Amini, Peyman
Saffar, Hana
Rezapoor, Saeed
Motevaseli, Elahe
Cheki, Mohsen
Yahyapour, Rasoul
farhood, Bagher
Nouruzi, Farzad
Khodamoradi, Ehsan
Shabeeb, Dheyauldeen
Eleojo Musa, Ahmed
Najafi, Masoud
Metformin Protects Against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression
title Metformin Protects Against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression
title_full Metformin Protects Against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression
title_fullStr Metformin Protects Against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression
title_full_unstemmed Metformin Protects Against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression
title_short Metformin Protects Against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression
title_sort metformin protects against radiation-induced pneumonitis and fibrosis and attenuates upregulation of dual oxidase genes expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311649/
https://www.ncbi.nlm.nih.gov/pubmed/30607342
http://dx.doi.org/10.15171/apb.2018.078
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