Small Airways Disease, Biomarkers and COPD: Where are We?

Chukowry, Priyamvada S; Spittle, Daniella A; Turner, Alice

doi:10.2147/copd.s280157

Cited by 14 publications

(11 citation statements)

References 124 publications

(73 reference statements)

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“… 30 , 33 In mice, overexpression of MMP9 in macrophages results in emphysema. 34 Moreover, MMP12 knockdown attenuated CS-related emphysema in mice. 35 These observations are consistent with our findings that the levels of MMP9 and MMP12 were increased in the lung tissues of COPD patients and CS-exposed mice.…”

Section: Discussionmentioning

confidence: 99%

NCOA4-Mediated Ferroptosis in Bronchial Epithelial Cells Promotes Macrophage M2 Polarization in COPD Emphysema

Liu¹,

Zhang²,

Yang³

et al. 2022

COPD

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Background Macrophage polarization plays an important role in the pathogenesis of COPD emphysema. Changes in macrophage polarization in COPD remain unclear, while polarization and ferroptosis are essential factors in its pathogenesis. Therefore, this study investigated the relationship between macrophage polarization and ferroptosis in COPD emphysema. Methods We measured macrophage polarization and the levels of matrix metalloproteinases (MMPs) in the lung tissues of COPD patients and cigarette smoke (CS)-exposed mice. Flow cytometry was used to determine macrophage (THP-M cell) polarization changes. Ferroptosis was examined by FerroOrange, Perls’ DAB, C11-BODIPY and 4-HNE staining. Nuclear receptor coactivator 4 (NCOA4) was measured in the lung tissues of COPD patients and CS-exposed mice by western blotting. A cell study was performed to confirm the regulatory effect of NCOA4 on macrophage polarization. Results Increased M2 macrophages and MMP9 and MMP12 levels were observed in COPD patients, CS-exposed mice and THP-M cells cocultured with CS extract (CSE)-treated human bronchial epithelial (HBE) cells. Increased NCOA4 levels and ferroptosis were confirmed in COPD. Treatment with NCOA4 siRNA and the ferroptosis inhibitor ferrostatin-1 revealed an association between ferroptosis and M2 macrophages. These findings support a role for NCOA4, which induces an increase in M2 macrophages, in the pathogenesis of COPD emphysema. Conclusion In our study, CS led to the dominance of the M2 phenotype in COPD. We identified NCOA4 as a regulator of M2 macrophages and emphysema by mediating ferroptosis, which offers a new direction for research into COPD diagnostics and treatment.

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Section: Discussionmentioning

confidence: 99%

NCOA4-Mediated Ferroptosis in Bronchial Epithelial Cells Promotes Macrophage M2 Polarization in COPD Emphysema

Liu¹,

Zhang²,

Yang³

et al. 2022

COPD

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“…We next analyzed the balance between expression of remodeling proteases involved in the progression to COPD and their inhibitors. We focused on matrix metalloproteinase (MMP)-9, a gelatinase produced by alveolar macrophages and neutrophils that degrades extracellular matrix proteins and promotes neutrophil chemotaxis, and MMP-12 an elastase mainly produced by alveolar macrophages that contributes to alveolar damages ( 36 ) and their inhibitor tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). MMP-9 and TIMP-1 protein levels ( Figures 2A, B ) in BAL and in lungs ( Figures 2C, D ) were significantly decreased in subchronically CS-exposed Nlrp3 -/- mice as compared to WT mice.…”

Section: Resultsmentioning

confidence: 99%

Cigarette smoke-induced gasdermin D activation in bronchoalveolar macrophages and bronchial epithelial cells dependently on NLRP3

et al. 2022

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Chronic pulmonary inflammation and chronic obstructive pulmonary disease (COPD) are major health issues largely due to air pollution and cigarette smoke (CS) exposure. The role of the innate receptor NLRP3 (nucleotide-binding domain and leucine-rich repeat containing protein 3) orchestrating inflammation through formation of an inflammasome complex in CS-induced inflammation or COPD remains controversial. Using acute and subchronic CS exposure models, we found that Nlrp3-deficient mice or wild-type mice treated with the NLRP3 inhibitor MCC950 presented an important reduction of inflammatory cells recruited into the bronchoalveolar space and of pulmonary inflammation with decreased chemokines and cytokines production, in particular IL-1β demonstrating the key role of NLRP3. Furthermore, mice deficient for Caspase-1/Caspase-11 presented also decreased inflammation parameters, suggesting a role for the NLRP3 inflammasome. Importantly we showed that acute CS-exposure promotes NLRP3-dependent cleavage of gasdermin D in macrophages present in the bronchoalveolar space and in bronchial airway epithelial cells. Finally, Gsdmd-deficiency reduced acute CS-induced lung and bronchoalveolar space inflammation and IL-1β secretion. Thus, we demonstrated in our model that NLRP3 and gasdermin D are key players in CS-induced pulmonary inflammation and IL-1β release potentially through gasdermin D forming-pore and/or pyroptoctic cell death.

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“…From a cellular perspective, cells of the small airway epithelium, ciliated cells and goblet cells undergo various morphological and/or functional alterations, eventually resulting in airway remodeling. Moreover, increased immune cell infiltration in the small airways, including macrophages, neutrophils and T lymphocytes, correlates with the degree of airflow obstruction and contributes to lung damage in chronic airway diseases ( 19 – 21 ). More importantly, SAD occurs earlier than tissue destruction, as well as clinically detectable airflow limitation.…”

Section: Discussionmentioning

confidence: 99%

Exposure to second-hand smoke is an independent risk factor of small airway dysfunction in non-smokers with chronic cough: A retrospective case-control study

Zhao

Bai

Wan

et al. 2022

Front. Public Health

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ObjectivesThis study aimed to identify the potential risk factors for small airway dysfunction (SAD) in non-smokers with chronic cough.MethodsNon-smokers with chronic cough who underwent lung function tests at Xiangya Hospital from May 2019 to May 2020 were enrolled, and divided into the derivation and validation cohorts based on their hospital admission time. SAD was determined based on the presence of at least two of the following three indicators of lung function being less than 65% of predicted: maximal mid-expiratory flow, forced expiratory flow at 50% of forced vital capacity (FVC), and forced expiratory flow at 75% of FVC. Clinical data of these patients were collected. Risk factors for SAD were identified by logistic regression analysis in the derivation cohort and further confirmed in the validation cohort.ResultsIn total, 316 patients (152 in the non-SAD group and 164 in the SAD group) were included in the derivation cohort. Compared with the non-SAD group, the SAD group had a higher proportion of female patients (82.3 vs. 59.2%, P < 0.001), was more commonly exposed to second-hand smoke (SHS) (61.6 vs. 27.6%, P < 0.001), and tended to be older (median age, 45.5 vs. 40.0 years old, P = 0.004). The median FVC, forced expiratory volume in one second (FEV1) % pred, FEV1/FVC ratio, and peak expiratory flow (PEF) % pred were slightly lower in the SAD group. Multivariable logistic analysis showed that exposure to SHS was an independent risk factor (OR 4.166 [95% CI 2.090–8.302], P < 0.001) for SAD in non-smokers with chronic cough after adjusting for related variables. In the validation cohort (n = 146), patients with SHS exposure had a relative risk of 1.976 (95% CI 1.246–3.135, P = 0.004) for SAD compared to those without SHS exposure. Multivariable logistic analysis consistently confirmed that exposure to SHS was an independent risk factor (OR 3.041 [95% CI 1.458–6.344], P = 0.003) for SAD in non-smokers.ConclusionsExposure to SHS is independently associated with a higher risk of SAD in non-smokers with chronic cough. Reduction in SHS exposure may ameliorate lung function, thus lowering the risk of irreversible airway obstruction.

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Small Airways Disease, Biomarkers and COPD: Where are We?

Cited by 14 publications

References 124 publications

NCOA4-Mediated Ferroptosis in Bronchial Epithelial Cells Promotes Macrophage M2 Polarization in COPD Emphysema

NCOA4-Mediated Ferroptosis in Bronchial Epithelial Cells Promotes Macrophage M2 Polarization in COPD Emphysema

Cigarette smoke-induced gasdermin D activation in bronchoalveolar macrophages and bronchial epithelial cells dependently on NLRP3

Exposure to second-hand smoke is an independent risk factor of small airway dysfunction in non-smokers with chronic cough: A retrospective case-control study

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