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

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.

Stanniocalcin-1 Alleviates Contrast-Induced Acute Kidney Injury by Regulating Mitochondrial Quality Control via the Nrf2 Pathway

“…Inhibition of the inflammatory mediator HMGB1 along with upregulation of Nrf2/HO-1 has been demonstrated to significantly improve hypoxia-induced cell injury [41,42]. Another study also shows that increased Nrf2 activity can attenuate hyperoxiainduced inflammatory by inhibiting the accumulation of extracellular HMGB1 [43]. Additionally, the protective roles of STC1 in preventing mitochondrial damage, apoptosis, and inflammation response were partly abolished by specific inhibition of Nrf2 activity, demonstrated by Western blot and electron microscope analysis.…”

Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

“…The use of IV Vit-C in 47 sepsis ICU cases was reported and a major reduction in death was possible [129]. Dietary antioxidants (Vit-C and sulforaphane) were helpful to manage oxidative-stress-induced acute inflammatory lung injury that requires mechanical ventilation [130]. Another antioxidant, natural curcumin has also been effective against inflammation that caused during pneumonia [131].…”

Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?

“…Such an experience was reproduced among patients ill with severe influenza [13,14]. Indeed, dietary antioxidants (VC and sulforaphane) were shown to decrease oxidative stress induced acute inflammatory lung injury in patients receiving mechanical ventilation [15]. In addition, oral VC (e.g., 6 g daily) was able to reduce viral infection risk [16] or to improve symptoms [17].…”