The Role of HMGB1, a Nuclear Damage-Associated Molecular Pattern Molecule, in the Pathogenesis of Lung Diseases

Wang, Mao; Gauthier, Alex; Daley, LeeAnne; Dial, Katelyn; Wu, Jiaqi; Woo, Joanna; Lin, Mo Jun; Ashby, Charles R.; Mantell, Lin L.

doi:10.1089/ars.2019.7818

Cited by 65 publications

(73 citation statements)

References 368 publications

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“…Dying cells are known to release damage-associated molecular pattern molecules (DAMPs), such as high mobility group box 1 (HMGB1). Since apoptotic cells do not produce HMGB1 because it remains tightly attached to the apoptotic chromatin [26], necrotic or necroptotic cells are the primary source of HMGB1 that initiates a cascade of inflammatory responses through the binding to pattern recognition receptors and their activation [27]. Based on the https://doi.org/10.1371/journal.pone.0231267.g003…”

Section: Stress-induced Release Of Hmgb1mentioning

confidence: 99%

“…High mobility group box 1 (HMGB1) is a DAMP that specifically releases from necrotic but not apoptotic cells [49]. Through its binding to pattern recognition receptors, such as Toll Like Receptor 4 (TLR4) and the receptor of advanced glycation end products (RAGE), HMGB1 activates the NfκB pathway and has been shown to play a critical role in the pathogenesis of PAH [27,50]. In this study, we confirmed that the activation of necrotic cell death induced the release of HMGB1 in the culturing media.…”

Section: Plos Onementioning

confidence: 99%

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Sex-specific stress response and HMGB1 release in pulmonary endothelial cells

et al. 2020

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Women are known to be associated with a higher susceptibility to pulmonary arterial hypertension (PAH). In contrast, male PAH patients have a worse survival prognosis. In this study, we investigated whether the contribution of sex goes beyond the effects of sex hormones by comparing the ability of isolated male and female pulmonary endothelial cells to respire, proliferate and tolerate the stress. Mouse lung endothelial cells (MLEC) were isolated from the lungs of male and female 3-week old mice. Male MLEC showed an increased basal mitochondrial respiration rate, elevated maximal respiration, a significantly greater level of mitochondrial polarization, and a higher rate of proliferation. Exposure of cells to hypoxia (2% of O 2 for 24 hours) induced a strong apoptotic response in female but not male MLEC. In contrast, treatment with mitochondrial respiratory Complex III inhibitor Antimycin A (AA, 50μM) mediated severe necrosis specifically in male MLEC, while female cells again responded primarily by apoptosis. The same effect with female cells responding to the stress by apoptosis and male cells responding by necrosis was confirmed in starved pulmonary endothelial cells isolated from human donors. Elevated necrosis seen in male cells was associated with a significant release of damage-associated alarmin, HMGB1. No stimuli induced a significant elevation of HMGB1 secretion in females. We conclude that male cells appear to be protected against mild stress conditions, such as hypoxia, possibly due to increased mitochondrial respiration. In contrast, they are more sensitive to impaired mitochondrial function, to which they respond by necrotic death. Necrosis in male vascular cells releases a significant amount of HMGB1 that could contribute to the pro-inflammatory phenotype known to be associated with the male gender.

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Section: Stress-induced Release Of Hmgb1mentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Sex-specific stress response and HMGB1 release in pulmonary endothelial cells

et al. 2020

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“…Numerous studies have been directed towards elucidating the mechanisms underlying the release of nuclear HMGB1 into the extracellular milieu in order to develop treatments or interventions that attenuate the adverse effects of extracellular HMGB1 (Yang 2005 ; Wang 1999 ). The release of HMGB1 can be partly controlled by the cholinergic anti-inflammatory reflex (Andersson and Tracey 2011 ; Kang et al 2014 ; Wang et al 2019 ). This anti-inflammatory reflex relays the presence of inflammation, danger, and pathogen-associated molecular pattern signals via the afferent vagus nerve to the central nervous system for integration (Andersson and Tracey 2011 ; Kang et al 2014 ; Wang et al 2019 ).…”

Section: Introductionmentioning

confidence: 99%

GTS-21, an α7nAChR agonist, increases pulmonary bacterial clearance in mice by restoring hyperoxia-compromised macrophage function

Sitapara

Gauthier

Patel

et al. 2020

Mol Med

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Background Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. Method GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O2) and subsequently challenged with PA. Results The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA. Conclusions Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.

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“…Furthermore, extracellular HMGB1 levels in the serum of subjects with sepsis is a late mediator of inflammation for septic shock mice [49]. Subsequently, the excessive accumulation of extracellular HMGB1, particularly airway and sputum HMGB1, has been reported in a variety of lung diseases [50].…”

Section: Antioxidants Are Effective In Reducing the Release Of Hmgb1 mentioning

confidence: 99%

“…We have previously shown that the prolonged exposure to hyperoxia induces the accumulation of HMGB1 in mouse airways [6]. Oxidative stress initiates the accumulation of extracellular HMGB1 in a number of lung diseases and highly elevated levels of extracellular HMGB1 are associated with ALI, multiple organ failure and poor clinical outcome in patients [50]. Furthermore, the intratracheal administration of HMGB1 can induce a concentration-dependent increase in the infiltration of interstitial/intra-alveolar neutrophils, alveolar red blood cells, levels of MPO and lung edema, similar to endotoxin-induced ALI [20], suggesting that airway HMGB1 plays a critical role in mediating inflammatory responses in ALI/ARDS [20,52].…”

Section: Antioxidants Are Effective In Reducing the Release Of Hmgb1 mentioning

confidence: 99%

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

Patel

Dial

et al. 2020

IJMS

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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.

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The Role of HMGB1, a Nuclear Damage-Associated Molecular Pattern Molecule, in the Pathogenesis of Lung Diseases

Cited by 65 publications

References 368 publications

Sex-specific stress response and HMGB1 release in pulmonary endothelial cells

Sex-specific stress response and HMGB1 release in pulmonary endothelial cells

GTS-21, an α7nAChR agonist, increases pulmonary bacterial clearance in mice by restoring hyperoxia-compromised macrophage function

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

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