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      Hydrogen therapy promotes macrophage polarization to the M2 subtype in radiation lung injury by inhibiting the NF-κB signalling pathway

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          Abstract

          Background

          Radiotherapy has become a standard treatment for chest tumors, but a common complication of radiotherapy is radiation lung injury. Currently, there is still a lack of effective treatment for radiation lung injury.

          Methods

          A mouse model of radioactive lung injury (RILI) was constructed and then treated with different cycles of hydrogen inhalation. Lung function tests were performed to detect changes in lung function.HE staining was used to detect pathological changes in lung tissue. Immunofluorescence staining was used to detect the polarization of macrophages in lung tissue. Immunohistochemistry was used to detect changes in cytokine expression in lung tissues. Western Blot was used to detect the expression of proteins related to the NF-κB signalling pathway.

          Results

          Lung function test results showed that lung function decreased in the model group and improved in the treatment group.HE staining showed that inflammatory response was evident in the model group and decreased in the treatment group. Immunohistochemistry results showed that the expression of pro-inflammatory factors was significantly higher in the model group, and the expression of pro-inflammatory factors was significantly higher in the treatment group. The expression of pro-inflammatory factors in the treatment group was significantly lower than that in the model group, and the expression of anti-inflammatory factors in the treatment group was higher than that in the model group. Immunofluorescence showed that the expression of M1 subtype macrophages was up-regulated in the model group and down-regulated in the treatment group. The expression of M2 subtype macrophages was up-regulated in the treatment group relative to the model group. Western Blot showed that P–NF-κB p65/NF-κB p65 was significantly increased in the model group, and P–NF-κB p65/NF-κB p65 was decreased in the treatment group.

          Conclusion

          Hydrogen therapy promotes macrophage polarization from M1 to M2 subtypes by inhibiting the NF-κB signalling pathway, thereby attenuating the inflammatory response to radiation lung injury.

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          Most cited references44

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          The chemokine system in diverse forms of macrophage activation and polarization.

          Plasticity and functional polarization are hallmarks of the mononuclear phagocyte system. Here we review emerging key properties of different forms of macrophage activation and polarization (M1, M2a, M2b, M2c), which represent extremes of a continuum. In particular, recent evidence suggests that differential modulation of the chemokine system integrates polarized macrophages in pathways of resistance to, or promotion of, microbial pathogens and tumors, or immunoregulation, tissue repair and remodeling.
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            The Metabolic Signature of Macrophage Responses

            Macrophages are a heterogeneous population of immune cells playing several and diverse functions in homeostatic and immune responses. The broad spectrum of macrophage functions depends on both heterogeneity and plasticity of these cells, which are highly specialized in sensing the microenvironment and modify their properties accordingly. Although it is clear that macrophage phenotypes are difficult to categorize and should be seen as plastic and adaptable, they can be simplified into two extremes: a pro-inflammatory (M1) and an anti-inflammatory/pro-resolving (M2) profile. Based on this definition, M1 macrophages are able to start and sustain inflammatory responses, secreting pro-inflammatory cytokines, activating endothelial cells, and inducing the recruitment of other immune cells into the inflamed tissue; on the other hand, M2 macrophages promote the resolution of inflammation, phagocytose apoptotic cells, drive collagen deposition, coordinate tissue integrity, and release anti-inflammatory mediators. Dramatic switches in cell metabolism accompany these phenotypic and functional changes of macrophages. In particular, M1 macrophages rely mainly on glycolysis and present two breaks on the TCA cycle that result in accumulation of itaconate (a microbicide compound) and succinate. Excess of succinate leads to Hypoxia Inducible Factor 1α (HIF1α) stabilization that, in turn, activates the transcription of glycolytic genes, thus sustaining the glycolytic metabolism of M1 macrophages. On the contrary, M2 cells are more dependent on oxidative phosphorylation (OXPHOS), their TCA cycle is intact and provides the substrates for the complexes of the electron transport chain (ETC). Moreover, pro- and anti-inflammatory macrophages are characterized by specific pathways that regulate the metabolism of lipids and amino acids and affect their responses. All these metabolic adaptations are functional to support macrophage activities as well as to sustain their polarization in specific contexts. The aim of this review is to discuss recent findings linking macrophage functions and metabolism.
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              Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.

              Acute oxidative stress induced by ischemia-reperfusion or inflammation causes serious damage to tissues, and persistent oxidative stress is accepted as one of the causes of many common diseases including cancer. We show here that hydrogen (H(2)) has potential as an antioxidant in preventive and therapeutic applications. We induced acute oxidative stress in cultured cells by three independent methods. H(2) selectively reduced the hydroxyl radical, the most cytotoxic of reactive oxygen species (ROS), and effectively protected cells; however, H(2) did not react with other ROS, which possess physiological roles. We used an acute rat model in which oxidative stress damage was induced in the brain by focal ischemia and reperfusion. The inhalation of H(2) gas markedly suppressed brain injury by buffering the effects of oxidative stress. Thus H(2) can be used as an effective antioxidant therapy; owing to its ability to rapidly diffuse across membranes, it can reach and react with cytotoxic ROS and thus protect against oxidative damage.
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                Author and article information

                Journal
                Heliyon
                Heliyon
                Heliyon
                Elsevier
                2405-8440
                11 May 2024
                30 May 2024
                11 May 2024
                : 10
                : 10
                : e30902
                Affiliations
                [a ]Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
                [b ]Department of Pathology, The First Affiliated Hospital of Shandong First Medical University, China
                [c ]Department of Pathology, Linfen Central Hospital, China
                [d ]Department of Oncology, Affiliated Central Hospital of Shandong First Medical University, China
                [e ]Department of Pathology, Liaocheng Infectious Disease Hospital, China
                Author notes
                [* ]Corresponding author. Tumor Pathology, Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, China.
                [** ]Corresponding author. Department of Pathophysiology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, China.
                Article
                S2405-8440(24)06933-0 e30902
                10.1016/j.heliyon.2024.e30902
                11141264
                7caf7424-1139-46c8-b3ce-63130210b89c
                © 2024 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 14 January 2024
                : 4 May 2024
                : 7 May 2024
                Categories
                Research Article

                hydrogen,radiation lung injury,macrophage polarization,toxic injury,pathological mechanism

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