Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1.

Vivek Patel,Jiaqi Wu,Wenjun Wu,Mosi Lin,Lin L Mantell,Charles R Ashby,Alex G Gauthier,Katelyn Dial,Douglas D Thomas,Michael G Espey

doi:10.3390/ijms21030977

Abstract

Mechanical ventilation with hyperoxia is the major supportive measure to treat patients with acute lung injury and acute respiratory distress syndrome (ARDS). However, prolonged exposure to hyperoxia can induce oxidative inflammatory lung injury. Previously, we have shown that high levels of airway high-mobility group box 1 protein (HMGB1) mediate hyperoxia-induced acute lung injury (HALI). Using both ascorbic acid (AA, also known as vitamin C) and sulforaphane (SFN), an inducer of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), we tested the hypothesis that dietary antioxidants can mitigate HALI by ameliorating HMGB1-compromised macrophage function in phagocytosis by attenuating hyperoxia-induced extracellular HMGB1 accumulation. Our results indicated that SFN, which has been shown to attenute HALI in mice exposed to hyperoxia, dose-dependently restored hyperoxia-compromised macrophage function in phagocytosis (75.9 ± 3.5% in 0.33 µM SFN versus 50.7 ± 1.8% in dimethyl sulfoxide (DMSO) control, p < 0.05) by reducing oxidative stress and HMGB1 release from cultured macrophages (47.7 ± 14.7% in 0.33 µM SFN versus 93.1 ± 14.6% in DMSO control, p < 0.05). Previously, we have shown that AA enhances hyperoxic macrophage functions by reducing hyperoxia-induced HMGB1 release. Using a mouse model of HALI, we determined the effects of AA on hyperoxia-induced inflammatory lung injury. The i.p. administration of 50 mg/kg of AA to mice exposed to 72 h of ≥98% O2 significantly decreased hyperoxia-induced oxidative and nitrosative stress in mouse lungs. There was a significant decrease in the levels of airway HMGB1 (43.3 ± 12.2% in 50 mg/kg AA versus 96.7 ± 9.39% in hyperoxic control, p < 0.05), leukocyte infiltration (60.39 ± 4.137% leukocytes numbers in 50 mg/kg AA versus 100 ± 5.82% in hyperoxic control, p < 0.05) and improved lung integrity in mice treated with AA. Our study is the first to report that the dietary antioxidants, ascorbic acid and sulforaphane, ameliorate HALI and attenuate hyperoxia-induced macrophage dysfunction through an HMGB1-mediated pathway. Thus, dietary antioxidants could be used as potential treatments for oxidative-stress-induced acute inflammatory lung injury in patients receiving mechanical ventilation.

Highlights

Acute respiratory distress syndrome (ARDS) accounts for 10% of intensive care unit admissions and results in 3 million deaths annually [1]
The prolonged exposure of bone-marrow derived macrophages (BMDMs) to hyperoxia in the presence of SFN (0.11, 0.33 or 1 μM) significantly increased macrophage phagocytic function in a concentration-dependent manner (65.3 ± 1.3% in the 0.11 μM group, 75.9 ± 2.8% in the 0.33 μM group, and 83.9 ± 2.7% in the 1 μM group compared to 56.6 ± 1.7% in the vehicle control group, p < 0.05, Figure 2B)
We report that SFN, a dietary nuclear factor (erythroid-derived 2)-like 2 (Nrf2) inducer, effectively mitigates some characteristics associated with the pathogenesis of hyperoxia-induced acute lung injury (HALI) such as restoring hyperoxia-impaired macrophage phagocytosis and reducing hyperoxia-induced high-mobility group box 1 protein (HMGB1) accumulation in the extracellular milieu

Summary

Introduction

Acute respiratory distress syndrome (ARDS) accounts for 10% of intensive care unit admissions and results in 3 million deaths annually [1]. Mechanical ventilation is a life-saving intervention for patients with respiratory distress or failure, it can exacerbate injury in previously damaged lungs [2,3], resulting in significantly high morbidity and mortality rates in patients on ventilation [4,5]. Prolonged exposure to hyperoxia can cause hyperoxia-induced acute lung injury (HALI). The prolonged exposure to hyperoxia can induce excessive generation of reactive oxygen species (ROS), superoxide, by both the mitochondrial electron transport chain and NADPH oxidases [2,9,11]. We reported that hyperoxia-impaired macrophage function in phagocytosis is at least partially due to actin oxidation, causing cytoskeleton disorganization, and the antioxidants, superoxide dismutase (SOD) and procysteine, attenuate this damage [14]. The goal of this study is to determine if dietary antioxidants can reduce HALI via enhancing the macrophage functions compromised by prolonged exposure to hyperoxia

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Discussion

Conclusion