Mitoquinone ameliorates cigarette smoke-induced airway inflammation and mucus hypersecretion in mice

Yang, Deqing; Xu, Dan; Wang, Tao; Yuan, Zhicheng; Shen, Yongchun; Wen, Fuqiang

doi:10.1016/j.intimp.2020.107149

Cited by 19 publications

(18 citation statements)

References 39 publications

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“…Consistent with our findings, a previous study has also shown that inhibition of the NF-κB signaling pathway through blocking its translocation represses the release of pro-inflammatory proteins ( Ye et al, 2017 ). Notably, accumulating studies have identified that the airway inflammation is ascribed to the activation of the NF-κB signaling pathway ( Girkin et al, 2020 ; Yang H. et al, 2020 ; Yang D. et al, 2021 ). Our study here demonstrated that inhibitor of NF-κB blocked the extracellular ADP-induced release of CXCL10 in alveolar epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Adenosine Diphosphate Stimulates CXCL10-Mediated Mast Cell Infiltration Through P2Y1 Receptor to Aggravate Airway Inflammation in Asthmatic Mice

Gao

2021

Front. Mol. Biosci.

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Asthma is an inflammatory disease associated with variable airflow obstruction and airway inflammation. This study aimed to explore the role and mechanism of extracellular adenosine diphosphate (ADP) in the occurrence of airway inflammation in asthma. The expression of ADP in broncho-alveolar lavage fluid (BALF) of asthmatic patients was determined by enzyme linked immunosorbent assay (ELISA) and the expression of P2Y1 receptor in lung tissues was determined by reverse transcription-quantitative polymerase chain reaction. Asthmatic mouse model was induced using ovalbumin and the mice were treated with ADP to assess its effects on the airway inflammation and infiltration of mast cells (MCs). Additionally, alveolar epithelial cells were stimulated with ADP, and the levels of interleukin-13 (IL-13) and C-X-C motif chemokine ligand 10 (CXCL10) were measured by ELISA. We finally analyzed involvement of NF-κB signaling pathway in the release of CXCL10 in ADP-stimulated alveolar epithelial cells. The extracellular ADP was enriched in BALF of asthmatic patients, and P2Y1 receptor is highly expressed in lung tissues of asthmatic patients. In the OVA-induced asthma model, extracellular ADP aggravated airway inflammation and induced MC infiltration. Furthermore, ADP stimulated alveolar epithelial cells to secrete chemokine CXCL10 by activating P2Y1 receptor, whereby promoting asthma airway inflammation. Additionally, ADP activated the NF-κB signaling pathway to promote CXCL10 release. As a “danger signal” extracellular ADP could trigger and maintain airway inflammation in asthma by activating P2Y1 receptor. This study highlights the extracellular ADP as a promising anti-inflammatory target for the treatment of asthma.

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Section: Discussionmentioning

confidence: 99%

Extracellular Adenosine Diphosphate Stimulates CXCL10-Mediated Mast Cell Infiltration Through P2Y1 Receptor to Aggravate Airway Inflammation in Asthmatic Mice

Gao

2021

Front. Mol. Biosci.

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“…Treatment. Mice were divided into 4 groups: a control group (n = 7) exposed to room air without treatment, and 3 experimental groups exposed to CS for 75 min twice daily, 5 days per week for 4 weeks [13]. One experimental group (CS group, n = 7) received no treatment; the SS-31 (L)+CS group (n = 8) was exposed to CS and treated with a low dose of SS-31 (2.5 mg/kg once daily) refer to the slightly modified dosage [14]; and the SS-31 (H)+CS group (n = 7) was exposed to CS and treated with a high dose of SS-31 (5 mg/kg once daily) [15,16].…”

Section: Cs Exposure and Animalmentioning

confidence: 99%

“…One experimental group (CS group, n = 7) received no treatment; the SS-31 (L)+CS group (n = 8) was exposed to CS and treated with a low dose of SS-31 (2.5 mg/kg once daily) refer to the slightly modified dosage [14]; and the SS-31 (H)+CS group (n = 7) was exposed to CS and treated with a high dose of SS-31 (5 mg/kg once daily) [15,16]. SS-31 (Topscience, Shanghai, China) was intraperitoneally injected 1 h before CS exposure [13,17]. After 4 weeks, all mice were sacrificed by intraperitoneal phenobarbital injection (Sigma-Aldrich, St. Louis, MO, USA) followed by exsanguination from the right ventricle and abdominal aorta.…”

Section: Cs Exposure and Animalmentioning

confidence: 99%

“…Left lungs without lavage were fixed with 4% phosphate-buffered paraformaldehyde under a constant pressure of 25 cm H 2 O and embedded in paraffin; 4 mm thick sections were cut and stained with hematoxylin and eosin. An experienced pathologist who was blinded to the treatments scored lung inflammation based on the severity of lung lesions including peribronchiolar infiltrates, alveolar septal infiltrates, perivascular infiltrates, and combined bronchus-associated lymphoid tissue hyperplasia [13]. Giemsa staining was performed to assess the density of inflammatory cells in alveoli.…”

Section: Balf Collection and Cellmentioning

confidence: 99%

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Mitochondrial‐Targeting Antioxidant SS‐31 Suppresses Airway Inflammation and Oxidative Stress Induced by Cigarette Smoke

Yang

Zuo

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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This study investigated whether the mitochondrial-targeted peptide SS-31 can protect against cigarette smoke- (CS-) induced airway inflammation and oxidative stress in vitro and in vivo. Mice were exposed to CS for 4 weeks to establish a CS-induced airway inflammation model, and those in the experimental group were pretreated with SS-31 1 h before CS exposure. Pathologic changes and oxidative stress in lung tissue, inflammatory cell counts, and proinflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. The mechanistic basis for the effects of SS-31 on CS extract- (CSE-) induced airway inflammation and oxidative stress was investigated using BEAS-2B bronchial epithelial cells and by RNA sequencing and western blot analysis of lung tissues. SS-31 attenuated CS-induced inflammatory injury of the airway and reduced total cell, neutrophil, and macrophage counts and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, and matrix metalloproteinase (MMP) 9 levels in BALF. SS-31 also attenuated CS-induced oxidative stress by decreasing malondialdehyde (MDA) and myeloperoxidase (MPO) activities and increasing that of superoxide dismutase (SOD). It also reversed CS-induced changes in the expression of mitochondrial fission protein (MFF) and optic atrophy (OPA) 1 and reduced the amount of cytochrome c released into the cytosol. Pretreatment with SS-31 normalized TNF-α, IL-6, and MMP9 expression, MDA and SOD activities, and ROS generation in CSE-treated BEAS-2B cells and reversed the changes in MFF and OPA1 expression. RNA sequencing and western blot analysis showed that SS-31 inhibited CS-induced activation of the mitogen-activated protein kinase (MAPK) signaling pathway in vitro and in vivo. Thus, SS-31 alleviates CS-induced airway inflammation and oxidative stress via modulation of mitochondrial function and regulation of MAPK signaling and thus has therapeutic potential for the treatment of airway disorders caused by smoking.

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“…Wild-type (Rhot1 fl/fl ) and lung epithelial cell-specific Rhot1 KO mice (Rhot1 CreCC10 ) models were exposed to CS for 3 days duration (acute -Rhot1flp CreCC10)) and 4 months (chronic -Rhot1Flox CreCC10) (Both flp and flox techniques are based on the LoxP/Cre-mediated conditional gene KO and are widely used for studying gene specific functions), using Baumgartner-Jaeger CSM2082i (cigarette smoke generating machine; CH Technologies, Westwood, NJ, USA) (J. Chen et al, 2019;Sundar et al, 2010;Yang et al, 2021). All the air group mice were exposed to filtered room air and the same time duration was maintained as for the CS exposure.…”

Section: Animal Model and Exposurementioning

confidence: 99%

Epithelial Ablation of Miro1/Rhot1 GTPase Leads to Mitochondrial Dysfunction and Lung Inflammation by Cigarette Smoke

Sharma¹,

Wang²,

Muthumalage³

et al. 2021

Preprint

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Cigarette smoke (CS) exposure results in lung damage and inflammation through mitochondrial dysfunction. Mitochondria quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase by its interaction with PINK1/Parkin during mitophagy. However, the exact mechanism that operates this interaction of mitophagy machinery in Miro1 degradation and CS-induced mitochondrial dysfunction that results in lung inflammation remains unclear. We hypothesized that mitochondrial Miro1 plays an important role in regulating mitophagy machinery and resulting lung inflammation by CS in mouse lung. We showed a role of Miro1 in CS-induced mitochondrial dysfunction and quality control mechanisms. The Rhot1Fl/Fl (WT) and lung epithelial cell-specific Rhot1 KO were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). The cellular infiltration, cytokines, and lung histopathology were studied for the inflammatory response in the lungs. Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils associated with inflammatory mediators and Miro1 associated mitochondrial quality control proteins Parkin and OPA1. Chronic exposure showed an increase infiltration of total inflammatory cells and neutrophils versus air controls. Histopathological changes, such as pulmonary macrophages and neutrophils were increased in CS exposed mice. The epithelial Miro1 ablation led to augmentation of inflammatory cell infiltration with alteration in the levels of pro-inflammatory cytokines and histopathological changes. Thus, CS induces disruption of mitochondrial quality control mechanisms, and Rhot1/Miro1 mediates the process of CS-induced mitochondrial dysfunction ensuing lung inflammatory responses.

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Mitoquinone ameliorates cigarette smoke-induced airway inflammation and mucus hypersecretion in mice

Cited by 19 publications

References 39 publications

Extracellular Adenosine Diphosphate Stimulates CXCL10-Mediated Mast Cell Infiltration Through P2Y1 Receptor to Aggravate Airway Inflammation in Asthmatic Mice

Extracellular Adenosine Diphosphate Stimulates CXCL10-Mediated Mast Cell Infiltration Through P2Y1 Receptor to Aggravate Airway Inflammation in Asthmatic Mice

Mitochondrial‐Targeting Antioxidant SS‐31 Suppresses Airway Inflammation and Oxidative Stress Induced by Cigarette Smoke

Epithelial Ablation of Miro1/Rhot1 GTPase Leads to Mitochondrial Dysfunction and Lung Inflammation by Cigarette Smoke

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