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From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity

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      Beyond oxidative stress: an immunologist's guide to reactive oxygen species.

       Carl Nathan,  A Bussel (2013)
      Reactive oxygen species (ROS) react preferentially with certain atoms to modulate functions ranging from cell homeostasis to cell death. Molecular actions include both inhibition and activation of proteins, mutagenesis of DNA and activation of gene transcription. Cellular actions include promotion or suppression of inflammation, immunity and carcinogenesis. ROS help the host to compete against microorganisms and are also involved in intermicrobial competition. ROS chemistry and their pleiotropy make them difficult to localize, to quantify and to manipulate - challenges we must overcome to translate ROS biology into medical advances.
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        Linking oxidative stress to inflammation: Toll-like receptors.

        Injury caused by oxidative stress occurs in many clinical scenarios involving ischemia and reperfusion such as organ transplantation, hemorrhagic shock (HS), myocardial infarction, and cerebral vascular accidents. Activation of the immune system as a result of disturbances in the redox state of cells seems to contribute to tissue and organ damage in these conditions. The link between oxidative stress and inflammatory pathways is poorly understood. Recently, Toll-like receptors (TLRs) have been shown to mediate the inflammatory response seen in experimental ischemia and reperfusion (I/R). The TLR family of receptors involved in alerting the innate immune system of danger seems to be activated by damage-associated molecular pattern molecules (DAMPs) that are released during conditions of oxidative stress. In this review, we examine the role of TLRs in various experimental models of oxidative stress such as HS and I/R. We also report on potential DAMPs that may interact with TLRs in mediating injury. Finally, potential mechanisms by which reactive oxygen species from NADPH oxidase can signal the commencement of inflammatory pathways through TLRs are explored. (c) 2009 Elsevier Inc. All rights reserved.
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          Mitochondrial reactive oxygen species regulate transforming growth factor-β signaling.

          TGF-β signaling is required for normal tissue repair; however, excessive TGF-β signaling can lead to robust profibrotic gene expression in fibroblasts, resulting in tissue fibrosis. TGF-β binds to cell-surface receptors, resulting in the phosphorylation of the Smad family of transcription factors to initiate gene expression. TGF-β also initiates Smad-independent pathways, which augment gene expression. Here, we report that mitochondrial reactive oxygen species (ROS) generated at complex III are required for TGF-β-induced gene expression in primary normal human lung fibroblasts. TGF-β-induced ROS could be detected in both the mitochondrial matrix and cytosol. Mitochondrially targeted antioxidants markedly attenuated TGF-β-induced gene expression without affecting Smad phosphorylation or nuclear translocation. Genetically disrupting mitochondrial complex III-generated ROS production attenuated TGF-β-induced profibrotic gene expression. Furthermore, inhibiting mitochondrial ROS generation attenuated NOX4 (NADPH oxidase 4) expression, which is required for TGF-β induced myofibroblast differentiation. Lung fibroblasts from patients with pulmonary fibrosis generated more mitochondrial ROS than normal human lung fibroblasts, and mitochondrially targeted antioxidants attenuated profibrotic gene expression in both normal and fibrotic lung fibroblasts. Collectively, our results indicate that mitochondrial ROS are essential for normal TGF-β-mediated gene expression and that targeting mitochondrial ROS might be beneficial in diseases associated with excessive fibrosis.
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            Author and article information

            Journal
            Toxicological Sciences
            Toxicol. Sci.
            Oxford University Press (OUP)
            1096-6080
            1096-0929
            December 05 2016
            December 07 2016
            : 154
            : 2
            : 341-353
            10.1093/toxsci/kfw170
            © 2016

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