Extracellular superoxide dismutase (EC-SOD) R213G variant reduces mitochondrial ROS and preserves mitochondrial function in bleomycin-induced lung injury

Elajaili, Hanan; Hernandez-Lagunas, Laura; Harris, Peter; Sparagna, Genevieve C.; Jonscher, Raleigh; Ohlstrom, Denis; Sucharov, Carmen C.; Bowler, Russell P.; Suliman, Hagir B.; Fritz, Kristofer S.; Roede, James R.; Nozik, Eva S.

doi:10.1016/j.arres.2022.100035

Cited by 3 publications

(1 citation statement)

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“…While we did not differentiate between extracellular and intracellular superoxide with CPH, our results show that changing the extracellular redox environment changes intracellular and mitochondrial superoxide levels. This finding is consistent with our recently published study in bleomycin-induced lung injury, where altered EC-SOD content impacts mitochondrial superoxide production and metabolism [ 46 ]. This does not indicate that EC-SOD directly lowers superoxide in other compartments, but more likely demonstrates the protection against intracellular or mitochondrial processes indirectly.…”

Section: Discussionsupporting

confidence: 93%

Use of Electron Paramagnetic Resonance (EPR) to Evaluate Redox Status in a Preclinical Model of Acute Lung Injury

et al. 2023

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Purpose Patients with hyper- vs. hypo-inflammatory subphenotypes of acute respiratory distress syndrome (ARDS) exhibit different clinical outcomes. Inflammation increases the production of reactive oxygen species (ROS) and increased ROS contributes to the severity of illness. Our long-term goal is to develop electron paramagnetic resonance (EPR) imaging of lungs in vivo to precisely measure superoxide production in ARDS in real time. As a first step, this requires the development of in vivo EPR methods for quantifying superoxide generation in the lung during injury, and testing if such superoxide measurements can differentiate between susceptible and protected mouse strains. Procedures In WT mice, mice lacking total body extracellular superoxide dismutase (EC-SOD) (KO), or mice overexpressing lung EC-SOD (Tg), lung injury was induced with intraperitoneal (IP) lipopolysaccharide (LPS) (10 mg/kg). At 24 h after LPS treatment, mice were injected with the cyclic hydroxylamines 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine hydrochloride (CPH) or 4-acetoxymethoxycarbonyl-1-hydroxy-2,2,5,5-tetramethylpyrrolidine-3-carboxylic acid (DCP-AM-H) probes to detect, respectively, cellular and mitochondrial ROS – specifically superoxide. Several probe delivery strategies were tested. Lung tissue was collected up to one hour after probe administration and assayed by EPR. Results As measured by X-band EPR, cellular and mitochondrial superoxide increased in the lungs of LPS-treated mice compared to control. Lung cellular superoxide was increased in EC-SOD KO mice and decreased in EC-SOD Tg mice compared to WT. We also validated an intratracheal (IT) delivery method, which enhanced the lung signal for both spin probes compared to IP administration. Conclusions We have developed protocols for delivering EPR spin probes in vivo , allowing detection of cellular and mitochondrial superoxide in lung injury by EPR. Superoxide measurements by EPR could differentiate mice with and without lung injury, as well as mouse strains with different disease susceptibilities. We expect these protocols to capture real-time superoxide production and enable evaluation of lung EPR imaging as a potential clinical tool for subphenotyping ARDS patients based on redox status. Supplementary Information The online version contains supplementary material available at 10.1007/s11307-023-01826-5.

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Section: Discussionsupporting

confidence: 93%

Use of Electron Paramagnetic Resonance (EPR) to Evaluate Redox Status in a Preclinical Model of Acute Lung Injury

et al. 2023

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Mechanisms of Bleomycin-induced Lung Fibrosis: A Review of Therapeutic Targets and Approaches

Mohammed,

Al-Saedi,

Mohammed

et al. 2024

Cell Biochem Biophys

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Lung EC-SOD Overexpression Prevents Hypoxia-Induced Platelet Activation and Lung Platelet Accumulation

Colon Hidalgo,

Jordan,

Posey

et al. 2024

Antioxidants

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Pulmonary hypertension (PH) is a progressive disease marked by pulmonary vascular remodeling and right ventricular failure. Inflammation and oxidative stress are critical in PH pathogenesis, with early pulmonary vascular inflammation preceding vascular remodeling. Extracellular superoxide dismutase (EC-SOD), a key vascular antioxidant enzyme, mitigates oxidative stress and protects against inflammation and fibrosis in diverse lung and vascular disease models. This study utilizes a murine hypobaric hypoxia model to investigate the role of lung EC-SOD on hypoxia-induced platelet activation and platelet lung accumulation, a critical factor in PH-related inflammation. We found that lung EC-SOD overexpression blocked hypoxia-induced platelet activation and platelet accumulation in the lung. Though lung EC-SOD overexpression increased lung EC-SOD content, it did not impact plasma extracellular SOD activity. However, ex vivo, exogenous extracellular SOD treatment specifically blunted convulxin-induced platelet activation but did not blunt platelet activation with thrombin or ADP. Our data identify platelets as a novel target of EC-SOD in response to hypoxia, providing a foundation to advance the understanding of dysregulated redox signaling and platelet activation in PH and other chronic hypoxic lung diseases.

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Extracellular superoxide dismutase (EC-SOD) R213G variant reduces mitochondrial ROS and preserves mitochondrial function in bleomycin-induced lung injury

Cited by 3 publications

References 56 publications

Use of Electron Paramagnetic Resonance (EPR) to Evaluate Redox Status in a Preclinical Model of Acute Lung Injury

Use of Electron Paramagnetic Resonance (EPR) to Evaluate Redox Status in a Preclinical Model of Acute Lung Injury

Mechanisms of Bleomycin-induced Lung Fibrosis: A Review of Therapeutic Targets and Approaches

Lung EC-SOD Overexpression Prevents Hypoxia-Induced Platelet Activation and Lung Platelet Accumulation

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