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3.
Mol Med ; 26(1): 98, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126860

RESUMO

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.


Assuntos
Compostos de Benzilideno/farmacologia , Hiperóxia/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Infecções por Pseudomonas/tratamento farmacológico , Piridinas/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Proteína HMGB1/metabolismo , Hiperóxia/dietoterapia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Pseudomonas aeruginosa , Células RAW 264.7
4.
Mol Med ; 26(1): 63, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600307

RESUMO

BACKGROUND: Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury. METHODS: Mice were exposed to hyperoxia (≥99% O2) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline. RESULTS: The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology. CONCLUSIONS: Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Compostos de Benzilideno/farmacologia , Proteína HMGB1/metabolismo , Hiperóxia/complicações , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Biomarcadores , Suscetibilidade a Doenças , Proteína HMGB1/sangue , Proteína HMGB1/genética , Imuno-Histoquímica , Masculino , Camundongos , Modelos Biológicos
5.
Mol Med ; 26(1): 16, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013888

RESUMO

The Editors-in-Chief would like to alert readers that this article (Sitapara et al. 2014) is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1.

6.
Am J Respir Cell Mol Biol ; 52(2): 171-82, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24992505

RESUMO

The prolonged exposure to hyperoxia can compromise macrophage functions and contribute to the development of ventilator-associated pneumonia. High levels of extracellular high-mobility group box-1 (HMGB1) in the airways of mice exposed to hyperoxia can directly cause macrophage dysfunction. Hence, inhibition of the release of nuclear HMGB1 into the extracellular milieu may help to maintain macrophage functions under hyperoxic conditions. The present study investigates whether ethacrynic acid (EA) affects hyperoxia-induced HMGB1 release from macrophages and improves their functions. Macrophage-like RAW 264.7 cells and bone marrow-derived macrophages were exposed to different concentrations of EA for 24 hours in the presence of 95% O2. EA significantly decreased the accumulation of extracellular HMGB1 in cultured media. Importantly, the phagocytic activity and migration capability of macrophages were significantly enhanced in EA-treated cells. Interestingly, hyperoxia-induced NF-κB activation was also inhibited in these cells. To determine whether NF-κB plays a role in hyperoxia-induced HMGB1 release, BAY 11-7082, an inhibitor of NF-κB activation, was used. Similar to EA, BAY 11-7082 significantly inhibited the accumulation of extracellular HMGB1 and improved hyperoxia-compromised macrophage migration and phagocytic activity. Furthermore, 24-hour hyperoxic exposure of macrophages caused hyperacetylation of HMGB1 and its subsequent cytoplasmic translocation and release, which were inhibited by EA and BAY 11-7082. Together, these results suggest that EA enhances hyperoxia-compromised macrophage functions by inhibiting HMGB1 hyperacetylation and its release from macrophages, possibly through attenuation of the NF-κB activation. Therefore, the activation of NF-κB could be one of the underlying mechanisms that mediate hyperoxia-compromised macrophage functions.


Assuntos
Ácido Etacrínico/farmacologia , Proteína HMGB1/metabolismo , Hiperóxia/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Células Cultivadas , Lipopolissacarídeos/farmacologia , Camundongos , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia
7.
Mol Med ; 20: 238-47, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24664237

RESUMO

Mechanical ventilation with supraphysiological concentrations of oxygen (hyperoxia) is routinely used to treat patients with respiratory distress. However, prolonged exposure to hyperoxia compromises the ability of the macrophage to phagocytose and clear bacteria. Previously, we showed that the exposure of mice to hyperoxia elicits the release of the nuclear protein high mobility group box-1 (HMGB1) into the airways. 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 dihydrochloride], an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could inhibit hyperoxia-induced HMGB1 release into the airways, enhance macrophage function and improve bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. GTS-21 (0.04, 0.4 and 4 mg/kg) or saline was systemically administered via intraperitoneal injection to mice that were exposed to hyperoxia (≥99% O2) and subsequently challenged with PA. We found that systemic administration of 4 mg/kg GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1. To investigate the cellular mechanism of these observations, RAW 264.7 cells, a macrophagelike 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, hyperoxia-induced hyperacetylation of HMGB1 was significantly reduced in macrophages incubated with GTS-21. Furthermore, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from these macrophages. Our results indicate that GTS-21 is effective in improving bacterial clearance and reducing acute lung injury by enhancing macrophage function via 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.


Assuntos
Compostos de Benzilideno/farmacologia , Hiperóxia/metabolismo , Macrófagos/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Pneumonia Associada à Ventilação Mecânica/metabolismo , Piridinas/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Carga Bacteriana , Líquido da Lavagem Broncoalveolar/química , Linhagem Celular , Proteína HMGB1/metabolismo , Pulmão/metabolismo , Pulmão/microbiologia , Macrófagos/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fagocitose/efeitos dos fármacos , Pneumonia Associada à Ventilação Mecânica/microbiologia , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
8.
Redox Biol ; 2: 314-22, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24563849

RESUMO

Prolonged exposure to hyperoxia results in acute lung injury (ALI), accompanied by a significant elevation in the levels of proinflammatory cytokines and leukocyte infiltration in the lungs. However, the mechanisms underlying hyperoxia-induced proinflammatory ALI remain to be elucidated. In this study, we investigated the role of the proinflammatory cytokine high mobility group box protein 1 (HMGB1) in hyperoxic inflammatory lung injury, using an adult mouse model. The exposure of C57BL/6 mice to ≥99% O2 (hyperoxia) significantly increased the accumulation of HMGB1 in the bronchoalveolar lavage fluids (BALF) prior to the onset of severe inflammatory lung injury. In the airways of hyperoxic mice, HMGB1 was hyperacetylated and existed in various redox forms. Intratracheal administration of recombinant HMGB1 (rHMGB1) caused a significant increase in leukocyte infiltration into the lungs compared to animal treated with a non-specific peptide. Neutralizing anti-HMGB1 antibodies, administrated before hyperoxia significantly attenuated pulmonary edema and inflammatory responses, as indicated by decreased total protein content, wet/dry weight ratio, and numbers of leukocytes in the airways. This protection was also observed when HMGB1 inhibitors were administered after the onset of the hyperoxic exposure. The aliphatic antioxidant, ethyl pyruvate (EP), inhibited HMGB1 secretion from hyperoxic macrophages and attenuated hyperoxic lung injury. Overall, our data suggest that HMGB1 plays a critical role in mediating hyperoxic ALI through the recruitment of leukocytes into the lungs. If these results can be translated to humans, they suggest that HMGB1 inhibitors provide treatment regimens for oxidative inflammatory lung injury in patients receiving hyperoxia through mechanical ventilation.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Anticorpos/administração & dosagem , Líquido da Lavagem Broncoalveolar/imunologia , Proteína HMGB1/metabolismo , Piruvatos/administração & dosagem , Acetilação , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/terapia , Animais , Hipóxia Celular , Linhagem Celular , Modelos Animais de Doenças , Proteína HMGB1/antagonistas & inibidores , Injeções Espinhais , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo
9.
Am J Respir Cell Mol Biol ; 48(3): 280-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23087050

RESUMO

Mechanical ventilation with supraphysiological concentrations of oxygen (hyperoxia) is routinely used to treat patients with respiratory distress. However, a significant number of patients on ventilators exhibit enhanced susceptibility to infections and develop ventilator-associated pneumonia (VAP). Pseudomonas aeruginosa (PA) is one of the most common species of bacteria found in these patients. Previously, we demonstrated that prolonged exposure to hyperoxia can compromise the ability of alveolar macrophages (AMs), an essential part of the innate immunity, to phagocytose PA. This study sought to investigate the potential molecular mechanisms underlying hyperoxia-compromised innate immunity against bacterial infection in a murine model of PA pneumonia. Here, we show that exposure to hyperoxia (≥ 99% O2) led to a significant elevation in concentrations of airway high mobility group box-1 (HMGB1) and increased mortality in C57BL/6 mice infected with PA. Treatment of these mice with a neutralizing anti-HMGB1 monoclonal antibody (mAb) resulted in a reduction in bacterial counts, injury, and numbers of neutrophils in the lungs, and an increase in leukocyte phagocytic activity compared with mice receiving control mAb. This improved phagocytic function was associated with reduced concentrations of airway HMGB1. The correlation between phagocytic activity and concentrations of extracellular HMGB1 was also observed in cultured macrophages. These results indicate a pathogenic role for HMGB1 in hyperoxia-induced impairment with regard to a host's ability to clear bacteria and inflammatory lung injury. Thus, HMGB1 may provide a novel molecular target for improving hyperoxia-compromised innate immunity in patients with VAP.


Assuntos
Proteína HMGB1/metabolismo , Hiperóxia/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar/microbiologia , Pneumonia Bacteriana/metabolismo , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Proteína HMGB1/imunologia , Hiperóxia/imunologia , Hiperóxia/patologia , Imunidade Inata/imunologia , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Fagocitose/imunologia , Fagocitose/fisiologia , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Pneumonia Associada à Ventilação Mecânica/imunologia , Pneumonia Associada à Ventilação Mecânica/metabolismo , Pneumonia Associada à Ventilação Mecânica/microbiologia , Pneumonia Associada à Ventilação Mecânica/patologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/imunologia , Respiração Artificial/efeitos adversos
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