&lt;p&gt;Fine-particulate matter aggravates cigarette smoke extract–induced airway inflammation via Wnt5a–ERK pathway in COPD&lt;/p&gt;

Wang, Zhihua; Zhao, Jianwei; Wang, Ting; Du, Xiaohui; Xie, Jungang

doi:10.2147/copd.s195794

Cited by 25 publications

(17 citation statements)

References 55 publications

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“…The study was approved by the Ethics Review Committee for Human Studies at Shengjing Hospital of China Medical University, and informed written consent was obtained from each patient (2016PS342K). The inclusion criteria for patients with COPD were as follows: 1) 40-80 years of age; 2) history of 10 or more pack-years of smoking; 3) ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) (FEV1/FVC ratio) of 70% or less after bronchodilator use (Wang et al, 2019); and 4) stable clinical pulmonary condition of COPD, with no acute exacerbations for at least 4 weeks prior to enrollment. The severity of airway limitation was graded based on FEV1post%, as described in the GOLD guidelines (Wang et al, 2018).…”

Section: Lung Tissue Sample Collectionmentioning

confidence: 99%

AGR3 Regulates Airway Epithelial Junctions in Patients with Frequent Exacerbations of COPD

Wang

Sun

et al. 2021

Front. Pharmacol.

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Background: The mechanisms underlying differences in the susceptibility to chronic obstructive pulmonary disease (COPD) exacerbations between patients are not well understood. Recent studies have shown that the patients with frequent COPD exacerbations is related to specific protein expression in lung tissue. Anterior gradient 3 (AGR3) is expressed in airway epithelial cells in the lung and proteomic analysis revealed that its expression is decreased in patients with frequent COPD exacerbations. Moreover, the loss of epithelial integrity might facilitate trans-epithelial permeability of pathogens in such patients. This study was performed to determine that AGR3 protein play a role in COPD frequency exacerbators.Methods: Human lung tissues were collected from current-smoking patients (Control; n = 15) as well as patients with infrequent COPD exacerbations (IFCOPD; n = 18) and frequent COPD exacerbations (FCOPD; n = 8). While AGR3 protein expression was measured by immunohistochemistry and western blotting, AGR mRNA expression was determined by real time quantitative polymerase chain reaction (RT-qPCR). Furthermore, adherent junctions (AJs) and tight junctions (TJs) protein expression in human lung tissues were measured by immunohistochemistry. The effects of cigarette smoke extract (CSE) on AJ and TJ protein and mRNA expression in BEAS-2B cells were assessed by western blotting and RT-qPCR. In addition, the effect of AGR3 overexpression and knockdown on AJ and TJ protein expression was determined.Results: AGR3 was mainly expressed in the airway epithelium and AGR3-positive products were localized in the cytoplasm. Western blotting and RT-qPCR results showed that AGR3 protein (p = 0.009) and mRNA (p = 0.04) expression in the FCOPD group was significantly lower than that in the IFCOPD group. Moreover, E-cadherin, occludin, and zonula occludens-1 (ZO-1) expression was lower in the FCOPD group than in the IFCOPD group. The protein and mRNA expression of E-cadherin, occludin, and ZO-1 was decreased within 24 h post-CSE exposure. AGR3 overexpression rescued CSE-induced downregulation of E-cadherin, occludin, and ZO-1.Conclusion: Difference in AGR3 expression in the lung tissue might be correlated with increased susceptibility to COPD exacerbation. AGR3 can prevent CSE-induced downregulation of E-cadherin, occludin, and ZO-1 in airway epithelial cells. Loss of AGR3 might promote viral and bacterial infection and induce immune inflammation to increase COPD exacerbation.

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Section: Lung Tissue Sample Collectionmentioning

confidence: 99%

AGR3 Regulates Airway Epithelial Junctions in Patients with Frequent Exacerbations of COPD

Wang

Sun

et al. 2021

Front. Pharmacol.

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“…Due to its small size and easy transportation, PM2.5 can be inhaled deep into human airway and deposited in lung tissues, especially alveolar regions, causing local damage in the lungs [14]. There have been evidences that PM2.5 has a harmful impact on lung function and alveolar structure, and related mechanisms are focused on inflammatory response, oxidative stress, immune disorders, and genetic alterations [15][16][17][18]. In our previous studies, short-term exposure of healthy rats to high-concentration PM2.5 led to a burst of inflammation and oxidative stress in the lungs, as well as the ciliary dysfunction in the upper airway.…”

Section: Introductionmentioning

confidence: 99%

“…These findings highlighted the potential use of such method to contribute to animal studies on the chronic hazards of air pollutants to human health. And we hypothesize that this exposure method is more realistic than other previous methods, such as intratracheal instillation in the form of PM2.5 suspension liquid with a stable PM2.5 concentration or ultrasonic nebulization in the form of PM2.5 aerosols [17,18,40,41]. However, it is regrettable that the levels of other gas pollutants including ozone, SO 2 , and NO 2 , which have also been demonstrated to contribute to lung injury and COPD development, were ignored to be measured in this study [42].…”

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confidence: 99%

Exposure to Air Pollution Exacerbates Inflammation in Rats with Preexisting COPD

Wang

Zhao

et al. 2020

Mediators of Inflammation

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Particulate matter with an aerodynamic diameter equal or less than 2.5 micrometers (PM2.5) is associated with the development of chronic obstructive pulmonary disease (COPD). The mechanisms by which PM2.5 accelerates disease progression in COPD are poorly understood. In this study, we aimed to investigate the effect of PM2.5 on lung injury in rats with hallmark features of COPD. Cardinal features of human COPD were induced in a rat model by repeated cigarette smoke inhalation and bacterial infection for 8 weeks. Then, from week 9 to week 16, some of these rats with COPD were subjected to real-time concentrated atmospheric PM2.5. Lung function, pathology, inflammatory cytokines, oxidative stress, and mucus and collagen production were measured. As expected, the COPD rats had developed emphysema, inflammation, and deterioration in lung function. PM2.5 exposure resulted in greater lung function decline and histopathological changes, as reflected by increased Mucin (MUC) 5ac, MUC5b, Collagen I, Collagen III, and the profibrotic cytokine α-smooth muscle-actin (SMA), transforming growth factor- (TGF-) β1 in lung tissues. PM2.5 also aggravated inflammation, increasing neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF) and cytokines including Interleukin- (IL-) 1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-4. The likely mechanism is through oxidative stress as antioxidants levels were decreased, whereas oxidants were increased, indicating a detrimental shift in the oxidant-antioxidant balance. Altogether, these results suggest that PM2.5 exposure could promote the development of COPD by impairing lung function and exacerbating pulmonary injury, and the potential mechanisms are related to inflammatory response and oxidative stress.

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“…HBSMCs were stimulated with different doses of BOX5 (100–300 μM) for 48 h with reference to the relevant literature. 21 No significant changes in cell activity were observed after the treatment with 100 μM BOX5 ( Figure 6D ); therefore, 100 μM BOX5 was subsequently selected as the experimental dose in combination with a literature review. As expected, compared with the PM2.5 group, the levels of PCNA and α-SMA were downregulated in the BOX5 + PM2.5 group ( Figure 6A – C ), indicating that BOX5 inhibited PM2.5-induced HBSMC proliferation.…”

Section: Resultsmentioning

confidence: 99%

PM2.5 Induces Airway Remodeling in Chronic Obstructive Pulmonary Diseases via the Wnt5a/β-Catenin Pathway

Zou¹,

Wang²,

Sun³

et al. 2021

COPD

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Background Fine-particulate matter ≤2.5 μm in diameter (PM2.5)-associated airway remodeling has recently been recognized as a central feature of COPD. Activation of the Wnt/β-catenin pathway is closely related to the occurrence of airway remodeling. Accordingly, the goal of this study was to determine whether the Wnt5a/β-Catenin pathway is involved in PM2.5-induced smooth muscle proliferation in vivo and in vitro, which promotes the development of airway remodeling in subjects with COPD. Methods The effect of Wnt5a on β-Catenin-mediated airway remodeling was assessed using an in vivo model of PM2.5-induced COPD and PM2.5-exposed human bronchial smooth muscle cells (HBSMCs) in vitro. Small animal spirometry was used to measure lung function in mice. H&E staining and immunohistochemistry were performed to inspect emphysema and airway remodeling indices. Real-time PCR was used to detect Wnt5a, β-Catenin, TGF-β1, CyclinD1 and c-myc mRNA expression. The CCK8 assay was performed to detect cellular activity. Western blotting was performed to assess PCNA, α-SMA, Wnt5a, β-Catenin, PDGFRβ and TenascinC protein expression. β-Catenin expression was detected using cellular immunofluorescence. Results Exposure to PM2.5 led to emphysema, airway wall thickening, an increased smooth muscle layer thickness, decreased lung function and increased expression of the Wnt5a, β-Catenin, PDGFRβ and Tenascin C proteins in the mouse lung tissue. BOX5 (a Wnt5a antagonist) alleviated these PM2.5-induced outcomes in mice. Moreover, PM2.5 induced the expression of the Wnt5a, β-Catenin, TGF-β1, CyclinD1 and c-myc mRNAs in HBSMCs. BOX5 also inhibited the PM2.5-induced increases in PCNA, α-SMA, Wnt5a, β-Catenin, PDGFRβ and Tenascin C protein expression in HBSMCs. Conclusion Our findings suggest that PM2.5 exposure induces HBSMC proliferation, contributing to airway remodeling via the Wnt5a/β-Catenin signaling pathway in vivo and in vitro, which might be a target for COPD treatment.

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<p>Fine-particulate matter aggravates cigarette smoke extract–induced airway inflammation via Wnt5a–ERK pathway in COPD</p>

Cited by 25 publications

References 55 publications

AGR3 Regulates Airway Epithelial Junctions in Patients with Frequent Exacerbations of COPD

AGR3 Regulates Airway Epithelial Junctions in Patients with Frequent Exacerbations of COPD

Exposure to Air Pollution Exacerbates Inflammation in Rats with Preexisting COPD

PM2.5 Induces Airway Remodeling in Chronic Obstructive Pulmonary Diseases via the Wnt5a/β-Catenin Pathway

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