scholarly journals AIM2 Nuclear Exit and Inflammasome Activation in Chronic Obstructive Pulmonary Disease and Response to Cigarette Smoke 

2020 ◽  
Author(s):  
Hai B Tran ◽  
Rhys Hamon ◽  
Hubertus Jersmann ◽  
Miranda P Ween ◽  
Patrick Asare ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Cigarette Smoke ◽  
Nuclear Localization ◽  
Alveolar Macrophages ◽  
Fold Increase ◽  
Cigarette Smoke Extract ◽  
Chronic Obstructive ◽  
Inflammasome Activation ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Abstract IntroductionThe role inflammasomes play in chronic obstructive pulmonary disease (COPD) is unclear. We hypothesised that the AIM2 inflammasome is activated in the airways of COPD patients, and in response to cigarette smoke.Methods Lung tissue, bronchoscopy-derived alveolar macrophages and bronchial epithelial cells from COPD patients and healthy donors; lungs from cigarette smoke-exposed mice; and cigarette smoke extract-stimulated alveolar macrophages from healthy controls and HBEC30KT cell line were investigated. AIM2 inflammasome activation was assessed by multi-fluorescence quantitative confocal microscopy of speck foci positive for AIM2, inflammasome component ASC and cleaved IL-1β. Subcellular AIM2 localization was assessed by confocal microscopy, and immunoblot of fractionated cell lysates. Nuclear localization was supported by in-silico analysis of nuclear localization predicted scores of peptide sequences. Nuclear and cytoplasmic AIM2 was demonstrated by immunoblot in both cellular fractions from HBEC30KT cells.Results Increased cytoplasmic AIM2 speck foci, colocalized with cleaved IL-1β, were demonstrated in COPD lungs (n=9) vs. control (n=5), showing significant positive correlations with GOLD stages. AIM2 nuclear-to-cytoplasmic redistribution was demonstrated in bronchiolar epithelium in cigarette-exposed mice and in HBEC30KT cells post 24 hrs stimulation with 5% cigarette smoke extract. Alveolar macrophages from 8 healthy non-smokers responded to cigarette smoke extract with an >8-fold increase (p<0.05) of cytoplasmic AIM2 and >6-fold increase (p<0.01) of colocalized cleaved IL-1β speck foci, which were also localized with ASC.Conclusion The AIM2 inflammasome is activated in the airway of COPD patients, and in response to cigarette smoke exposure, associated with a nuclear to cytoplasmic shift in the distribution of AIM2.

scholarly journals AIM2 nuclear exit and inflammasome activation in chronic obstructive pulmonary disease and response to cigarette smoke

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Hai B. Tran ◽  
Rhys Hamon ◽  
Hubertus Jersmann ◽  
Miranda P. Ween ◽  
Patrick Asare ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Cigarette Smoke ◽  
Nuclear Localization ◽  
Alveolar Macrophages ◽  
Fold Increase ◽  
Cigarette Smoke Extract ◽  
Chronic Obstructive ◽  
Inflammasome Activation ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Abstract Introduction The role inflammasomes play in chronic obstructive pulmonary disease (COPD) is unclear. We hypothesised that the AIM2 inflammasome is activated in the airways of COPD patients, and in response to cigarette smoke. Methods Lung tissue, bronchoscopy-derived alveolar macrophages and bronchial epithelial cells from COPD patients and healthy donors; lungs from cigarette smoke-exposed mice; and cigarette smoke extract-stimulated alveolar macrophages from healthy controls and HBEC30KT cell line were investigated. AIM2 inflammasome activation was assessed by multi-fluorescence quantitative confocal microscopy of speck foci positive for AIM2, inflammasome component ASC and cleaved IL-1β. Subcellular AIM2 localization was assessed by confocal microscopy, and immunoblot of fractionated cell lysates. Nuclear localization was supported by in-silico analysis of nuclear localization predicted scores of peptide sequences. Nuclear and cytoplasmic AIM2 was demonstrated by immunoblot in both cellular fractions from HBEC30KT cells. Results Increased cytoplasmic AIM2 speck foci, colocalized with cleaved IL-1β, were demonstrated in COPD lungs (n = 9) vs. control (n = 5), showing significant positive correlations with GOLD stages. AIM2 nuclear-to-cytoplasmic redistribution was demonstrated in bronchiolar epithelium in cigarette-exposed mice and in HBEC30KT cells post 24 h stimulation with 5% cigarette smoke extract. Alveolar macrophages from 8 healthy non-smokers responded to cigarette smoke extract with an > 8-fold increase (p < 0.05) of cytoplasmic AIM2 and > 6-fold increase (p < 0.01) of colocalized cleaved IL-1β speck foci, which were also localized with ASC. Conclusion The AIM2 inflammasome is activated in the airway of COPD patients, and in response to cigarette smoke exposure, associated with a nuclear to cytoplasmic shift in the distribution of AIM2.

scholarly journals Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke

2021 ◽  
Vol 15 ◽  
pp. 175346662110397
Author(s):  
Patrick F. Asare ◽  
Hai B. Tran ◽  
Plinio R. Hurtado ◽  
Griffith B. Perkins ◽  
Phan Nguyen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cigarette Smoke ◽  
Alveolar Macrophages ◽  
Therapeutic Potential ◽  
Lung Resection ◽  
Cigarette Smoke Extract ◽  
Chronic Obstructive ◽  
Strong Positive Correlation ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Introduction/Rationale: In chronic obstructive pulmonary disease (COPD), defective macrophage phagocytic clearance of cells undergoing apoptosis by efferocytosis may lead to secondary necrosis of the uncleared cells and contribute to airway inflammation. The precise mechanisms for this phenomenon remain unknown. LC3-associated phagocytosis (LAP) is indispensable for effective efferocytosis. We hypothesized that cigarette smoke inhibits the regulators of LAP pathway, potentially contributing to the chronic airways inflammation associated with COPD. Methods: Bronchoalveolar (BAL)-derived alveolar macrophages, lung tissue macrophages obtained from lung resection surgery, and monocyte-derived macrophages (MDM) were prepared from COPD patients and control participants. Lung/airway samples from mice chronically exposed to cigarette smoke were also investigated. Differentiated THP-1 cells were exposed to cigarette smoke extract (CSE). The LAP pathway including Rubicon, as an essential regulator of LAP, efferocytosis and inflammation was examined using western blot, ELISA, flow cytometry, and/or immunofluorescence. Results: Rubicon was significantly depleted in COPD alveolar macrophages compared with non-COPD control macrophages. Rubicon protein in alveolar macrophages of cigarette smoke-exposed mice and cigarette smoke-exposed MDM and THP-1 was decreased with a concomitant impairment of efferocytosis. We also noted increased expression of LC3 which is critical for LAP pathway in COPD and THP-1 macrophages. Furthermore, THP-1 macrophages exposed to cigarette smoke extract exhibited higher levels of other key components of LAP pathway including Atg5 and TIM-4. There was a strong positive correlation between Rubicon protein expression and efferocytosis. Conclusion: LAP is a requisite for effective efferocytosis and an appropriate inflammatory response, which is impaired by Rubicon deficiency. Our findings suggest dysregulated LAP due to reduced Rubicon as a result of CSE exposure. This phenomenon could lead to a failure of macrophages to effectively process phagosomes containing apoptotic cells during efferocytosis. Restoring Rubicon protein expression has unrecognized therapeutic potential in the context of disease-related modifications caused by exposure to cigarette smoke.

scholarly journals Identification of MMP-9 as a biomarker for detecting progression of chronic obstructive pulmonary disease

2015 ◽  
Vol 93 (6) ◽  
pp. 541-547 ◽  
Author(s):  
Marwa F. Abd El-Fatah ◽  
Mohamed A. Ghazy ◽  
Mohamed S. Mostafa ◽  
May M. El-Attar ◽  
Ahmed Osman
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Fold Increase ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Mrna Levels ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Metalloproteinase 9 ◽  
Severe Copd

Chronic obstructive pulmonary disease (COPD) is a complex immunological disease with multiple pathological features that is primarily induced by smoking together with additional genetic risk factors. COPD is frequently underdiagnosed; forced expiratory volume in the first second (FEV1) is considered to be the main diagnostic measure for COPD, yet it is insufficiently sensitive to monitor disease progression. Biomarkers capable of monitoring COPD progression and severity are needed. In this report, we evaluated matrix metalloproteinase-9 (MMP-9) as an early marker for the detection and staging of COPD, by assessing the mRNA levels of MMP-9 in peripheral blood samples collected from 22 COPD patients, 6 asymptomatic smokers, and 5 healthy controls. Our results demonstrate that the mRNA levels of MMP-9 increased more than two-fold in severe COPD relative to non-COPD smokers or moderate COPD groups. Moreover, in the very severe COPD group, MMP-9 mRNA levels showed a 4-fold increase relative to the non-COPD smokers or the moderate COPD groups, while there was a mild increase (∼40%) when compared to the severe COPD group. Taken together, our results suggest that MMP-9 serves as a biomarker for the grade and severity of COPD.

scholarly journals Sensitivity to glucocorticosteroids and heterogeneity of in vitro cell response in patients with chronic obstructive pulmonary disease

2018 ◽  
Vol 28 (5) ◽  
pp. 558-566 ◽  
Author(s):  
A. G. Kadushkin ◽  
A. D. Taganovich ◽  
A. A. Arabey ◽  
L. M. Shishlo ◽  
A. P. Lyubetskaya ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Fluorescence Intensity ◽  
Alveolar Macrophages ◽  
Cell Response ◽  
Blood Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Tnf Α

Inhaled corticosteroids are widely used for the treatment of chronic obstructive pulmonary disease (COPD), but their efficacy significantly varies between patients. The aim of the study was to establish approaches to reveal steroid-sensitive and steroid-resistant patients with COPD using the blood and lung cells. Methods. Forty five patients with COPD undergoing bronchoscopy were recruited for the study of cytokine secretion by alveolar macrophages under the influence of glucocorticoids. Alveolar macrophages isolated from bronchoalveolar lavage fluid were cultured with lipopolysaccharide (LPS) and different concentrations of dexamethasone (0.01 – 1000 nM) for 24 h. Then, supernatants were removed and analyzed for concentrations of interleukin 6 (IL-6), IL-8 and tumor necrosis factor α (TNF-α). Binding of the glucocorticoid with its receptors was investigated in 24 patients with COPD, 20 healthy smokers and 20 healthy non-smokers. Blood cells were cultured with fluorescein isothiocyanate (FITC)-labelled dexamethasone and monoclonal antibodies against surface antigens of lymphocyte and monocyte populations. Fluorescence intensity of FITC-labelled dexamethasone was analyzed in blood cells using flow cytometry. Results. Dexamethasone significantly inhibited IL-6, IL-8, and TNF-α production in alveolar macrophages in a dose dependent manner. The maximal inhibition of cytokine production was observed at dexamethasone concentration of 100 nM, and the maximal cell response variability was found at 10 nM. IL-8 was less sensitive to the corticosteroid compared to IL-6 and TNF-α. Dexamethasone at any concentration failed to reach >50% inhibition of LPS-induced production of IL-8, IL-6 and TNF-α in alveolar macrophages of 40.0%; 11.1% and 8.9% of COPD patients, respectively. The fluorescence intensity of FITC-labelled dexamethasone in blood lymphocytes and monocytes was lower in smokers with COPD compared to healthy smokers and healthy non-smokers. The binding of dexamethasone with its receptors in the blood cells was higher in healthy non-smokers compared to healthy smokers. Conclusion. In vitro response of alveolar macrophages to glucocorticoids in COPD patients is characterized by significant inter-individual variability. The weak corticosteroid-related inhibition of IL-8 production can contribute to neutrophilic inflammation in COPD. The capacity of glucocorticoid receptors to bind with their ligands in blood lymphocytes and monocytes is decreased in COPD patients.

scholarly journals WITHDRAWN: LncRNA TUG1 knockdown mitigates inflammatory injury induced by cigarette smoke extract in chronic obstructive pulmonary disease via miR-34c/BRD4 axis

2020 ◽  
Author(s):  
Beibei Song ◽  
Siyu Wu ◽  
Liyun Ye ◽  
Zeng Jing ◽  
Jing Cao
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Cigarette Smoke ◽  
Cigarette Smoke Extract ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Inflammatory Injury ◽  
Data Validity ◽  
Lncrna Tug1

The Accepted Manuscript version of this article (published on 19 August 2020) was withdrawn on 3 December 2020 due to concerns over data validity.

Oral and Oropharyngeal Sensory Function in Adults With Chronic Obstructive Pulmonary Disease

2020 ◽  
Vol 29 (2) ◽  
pp. 864-872
Author(s):  
Fernanda Borowsky da Rosa ◽  
Adriane Schmidt Pasqualoto ◽  
Catriona M. Steele ◽  
Renata Mancopes
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Oral Cavity ◽  
Pulmonary Disease ◽  
Thermal Sensation ◽  
Sensory Function ◽  
Control Group ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Age Related ◽  
Copd Patients

Introduction The oral cavity and pharynx have a rich sensory system composed of specialized receptors. The integrity of oropharyngeal sensation is thought to be fundamental for safe and efficient swallowing. Chronic obstructive pulmonary disease (COPD) patients are at risk for oropharyngeal sensory impairment due to frequent use of inhaled medications and comorbidities including gastroesophageal reflux disease. Objective This study aimed to describe and compare oral and oropharyngeal sensory function measured using noninstrumental clinical methods in adults with COPD and healthy controls. Method Participants included 27 adults (18 men, nine women) with a diagnosis of COPD and a mean age of 66.56 years ( SD = 8.68). The control group comprised 11 healthy adults (five men, six women) with a mean age of 60.09 years ( SD = 11.57). Spirometry measures confirmed reduced functional expiratory volumes (% predicted) in the COPD patients compared to the control participants. All participants completed a case history interview and underwent clinical evaluation of oral and oropharyngeal sensation by a speech-language pathologist. The sensory evaluation explored the detection of tactile and temperature stimuli delivered by cotton swab to six locations in the oral cavity and two in the oropharynx as well as identification of the taste of stimuli administered in 5-ml boluses to the mouth. Analyses explored the frequencies of accurate responses regarding stimulus location, temperature and taste between groups, and between age groups (“≤ 65 years” and “> 65 years”) within the COPD cohort. Results We found significantly higher frequencies of reported use of inhaled medications ( p < .001) and xerostomia ( p = .003) in the COPD cohort. Oral cavity thermal sensation ( p = .009) was reduced in the COPD participants, and a significant age-related decline in gustatory sensation was found in the COPD group ( p = .018). Conclusion This study found that most of the measures of oral and oropharyngeal sensation remained intact in the COPD group. Oral thermal sensation was impaired in individuals with COPD, and reduced gustatory sensation was observed in the older COPD participants. Possible links between these results and the use of inhaled medication by individuals with COPD are discussed.

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