Macrophage Influence on COPD Development by Regulating CAVIN2+ Airway Basal Stem Cells

Background: Airway wall thickening is the major cause of decreased lung function in chronic obstructive pulmonary disease (COPD). Recent studies suggest that interleukin (IL)-17A has been implicated in the pathogenesis of COPD.However, its role in airway remodeling in COPD has not beenfully elucidated. Aims and objectives: We aimed to determine whether IL-17A plays a functional role in airway remodeling of COPD, and the possible underlying mechanisms. Methods: We examined the expression of IL-17A in small airways from smokers with COPD and controls by immunohistochemistry, and then the association between IL-17A expression and airway remodeling was analyzed. In parallel, IL-17Adeficiency (IL-17A -/- ) mice and wild-type (WT) mice were exposed to cigarette smoke (CS) or room air for 3 months, and the airway inflammation and remodeling were assessed. In vitro , primary human lung fibroblasts were exposed to IL-17A, and the proliferation and collagen synthesis of fibroblasts were evaluated. Results: IL-17A immunoreactivity was significantly elevated in smokers with COPD compared with controls, andwas positively correlated with collagen deposition. CS-exposed IL-17A -/- mice exhibited reduced airway inflammation, smooth muscle area, and lung collagen content as compared with WT mice. IL-17A induced proliferation and collagen synthesis of human primary lung fibroblasts, which was TGF-β1 mediated. Conclusions: IL-17A is critical for the development of airway remodeling in CS-induced COPD. Targeting IL-17A inhibition may thus be beneficial to attenuate airway remodeling in COPD by suppressing airway inflammation and decreasing lung fibroblast activation.

Airway remodeling is a significant pathological characteristic of chronic obstructive pulmonary disease (COPD). In recent years, hypoxia-inducible factor 1-α (HIF-1α), a member of the hypoxia-inducible factor protein family, has gained attention. However, the potential correlation between HIF-1α and COPD airway remodeling remains unclear. This study explored the expression patterns of HIF-1α in patients with COPD and its association with airway remodelling. This investigation aims to furnish novel insights for the clinical identification of prospective therapeutic targets for ameliorating COPD-related airway remodelling. A total of 88 subjects were included, consisting of 28 controls and 60 COPD patients. Various staining methods were employed to observe the pathological changes in airway tissues. Immunohistochemistry was utilized to detect the expression of HIF-1α and MMP9 (matrix metalloproteinase 9) in airway tissues. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration in serum of HIF-1α and MMP9. Computed tomography (CT) airway parameters were measured in all participants to assess airway remodeling. The relationship between serum HIF-1α and MMP9 concentrations and airway parameters was analyzed. Staining of airway structures in COPD patients revealed significant pathological changes associated with airway remodelling, including mixed cilia and subepithelial fibrosis. The expression of HIF-1α and MMP9 was significantly higher in both human airway tissue and serum compared to controls. Chest CT scans exhibited typical imaging features of airway remodeling and increased airway parameters. The findings suggest a correlation between increased HIF-1α expression and COPD airway remodelling. This study provides novel evidence that HIF-1α may be a potential biomarker for airway remodelling in COPD patients.

Airway basal stem cell changes in COPD including hyperplasia, squamous cell metaplasia, epithel-mesenchymal transision, impairment of cillia and secretoric non mucosal cell differentiation, and junctional barrier integrity disturbances that lead to histological changes. There are also molecular changes such as disturbances in gene expresion, cytokines, inflamation factor and dysregulation of basal cell transcriptome in locus 19q13.2. This article is aimed to review airway basal cell changes in COPD. By understanding initial changes of airway basal stem cell in COPD, hopefully can help to develop stem cell therapy in COPD treatment. The research aims to explore molecular and histological changes in airway basal stem cells on chronic obstructive pulmonary disease. The researchers used literature review as the way to verify their arguments on the issue discussed by analyzing the results of scientific sources, especially from trusted sources such as Google Scholar and Science Direct. The study continues by stating that regenerative therapy using stem cells has started to evolve with the advancement of stem cell technology and is anticipated to improve and treat this illness. Only preclinical and phase 2 clinical trials have seen recent advancements in the use of stem cells for treating COPD.

BackgroundAirway basal cells from patients with chronic obstructive pulmonary disease (COPD) regenerate abnormal airway epithelium and this was associated with reduced expression of several genes involved in epithelial repair. Quercetin reduces goblet cell metaplasia and the expression of pro-inflammatory cytokines in COPD models. This study assessed whether quercetin improves epithelial regeneration from COPD airway basal cells.MethodsCOPD airway basal cells were treated with DMSO or 1 μM quercetin for three days. The cells were then cultured at air/liquid interface (ALI) for up to 4 weeks. Basal cells from healthy donors cultured at air/liquid interface were used as controls. Polarization of cells was determined at 8 days of ALI. The cell types and IL-8 expression in differentiated cell cultures were quantified by flow cytometry and ELISA. Microarray analysis was conducted on DMSO or quercetin-treated COPD basal cells to identify differentially regulated genes (DEG) and the enriched biological pathways. Bronchial brushings from COPD patients treated with either placebo or quercetin for 6 months were used to confirm the effects of quercetin on gene expression.ResultsCompared to DMSO, quercetin-treated COPD basal cells showed an increase in TER and regenerated the airway epithelium with more ciliated cells, and less goblet cells and IL-8. Comparison of DMSO- and quercetin-treated COPD basal cell transcriptomic profiles indicated that quercetin upregulated genes associated with tissue and epithelial development and differentiation. COPD patients treated with quercetin, but not placebo showed significantly increased expression of two developmental genes HOXB2 and ELF3, which were also increased in quercetin-treated COPD basal cells. Bronchial brushings from active smokers showed significantly increased mRNA expression of TGF-β and IL-8, and it was reduced after quercetin treatment.ConclusionsThese results indicate that quercetin may improve airway epithelial regeneration by increasing the expression of genes involved in epithelial development/differentiation in COPD.Trial registrationThis study was registered at ClinicalTrials.gov on 6–18–2019. The study number is NCT03989271.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by irreversible airway remodeling and is a global burden on the healthcare system. The World Health Organization predicts it will be the third leading cause of death by 2030. The causes of airway remodeling in COPD are complex. Several elements, such as the lung parenchyma and interstitium, as well as endothelium, mesenchymal cells, and a range of bioactive chemicals, work together to either encourage or impede the alteration of the airway’s structure during the remodeling process. Airway remodeling is an important factor in the irreversible limitation of ventilatory function. To reduce airway remodeling, significant efforts are being directed to find effective therapeutic ways that inhibit airway remodeling. In China, many patients use traditional Chinese medicine (TCM). Some TCM can improve the symptoms and lung function of COPD patients. Here, we describe the molecular mechanisms and key cellular players of airway remodeling in COPD patients and review the Chinese herbal medicines that may effectively inhibit airway remodeling.

Airway basal cells (BCs) are adult stem cells in the airways, playing a crucial role in airway renewal and post-injury regeneration and repair. Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and remodeling leading to incompletely reversible airflow limitation, significantly impairing patients' quality of life. COPD-related pathogenic factors can influence the genetic expression, proliferation, differentiation, and inflammatory regulation of BCs by altering their gene expression and molecular phenotypes, ultimately contributing to COPD-associated pathological changes. This article systematically reviews the changes in BCs during COPD progression and explores the potential and prospects of targeting BCs as a therapeutic approach for COPD from the perspective of regenerative medicine.

Chronic obstructive pulmonary disease (COPD) is common in patients with aortic aneurysms. Severe COPD is associated with an increased risk of aneurysm rupture and perioperative complications. This study assesses the outcomes of COPD and non-COPD patients after fenestrated-branched endovascular aortic aneurysm repair (FBEVAR). A single institution, retrospective study of FBEVAR patients between 2011 and 2020 compared outcomes between COPD and non-COPD patients. COPD patients were stratified by Global Initiative for Chronic Obstructive Lung Disease criteria and oxygen dependence. Outcome measures included 30-day mortality, pulmonary complications, major adverse events (MAE), and mid-term survival. 387 patients (71% male, age 72 years, interquartile range [68-79]) underwent FBEVAR. 181 patients (47%) had COPD. Smoking history was more frequent in COPD patients (P = .022). Among COPD patients, 20.4% were oxygen-dependent. Technical success, defined as successful delivery of the main aortic endograft and all intended side branches, was 98.4%. 30-day mortality (P = .83) and MAE rates (P = .87) were similar between groups. While not statistically significant, COPD patients had more frequent pulmonary complications (6.1% vs. 2.4%, P = .13) and were more frequently discharged on oxygen (P = .002). There were no differences in intensive care unit or hospital length of stay between groups (P = .29; P = .85, respectively). 5-year survival was similar between groups (P = .10). Oxygen-dependent COPD and severe-very severe COPD were associated with decreased mid-term survival (Hazard Ratio 2.39, P = .048). FBEVAR is safe and effective for treating complex aortic pathology in COPD patients, including oxygen-dependent patients. Patients with more severe COPD were more frequently discharged on oxygen. Mid-term survival was slightly reduced in patients with oxygen-dependent and severe-very severe COPD. Level 3, non-randomized controlled cohort/follow-up study.

To investigate the correlations between lipid ratio/oxidative stress status in chronic obstructive pulmonary disease (COPD) patients and pulmonary hypertension as well as the prognosis. Methods: A total of 120 patients with COPD were randomly selected and served as the COPD group and 30 healthy persons were selected as the control group. The ratios of low density lipoprotein (LDL)/high-density lipoprotein (HDL), triglyceride (TG)/HDL and total cholesterol (TC)/HDL were measured. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) level in the control group and COPD patients were detected. Pulmonary hypertension incidence and 3-year survival rate for COPD patients were statistically analyzed. Spearman rank correlation method was used to analyze relationship between lipid ratio /oxidative stress status and pulmonary hypertension. Results: Compared with control group, the ratios of LDL/HDL, TG/HDL and TC/HDL, and the serum MDA level in the COPD group were increased, while the serum SOD and T-AOC level in the COPD group were decreased; compared with stable period, lipid ratios and MDA levels in the acute period were elevated, while serum SOD and T-AOC levels were reduced (P<0.05). Pulmonary hypertension incidence and 3-year survival rates in the COPD group were 56.67% and 81.67% respectively; the lipid ratios and serum MDA levels in COPD patients with pulmonary hypertension were elevated compared with that in COPD patients without pulmonary hypertension; the serum SOD and T-AOC levels in COPD patients with pulmonary hypertension were reduced compared with that in patients without pulmonary hypertension (P<0.05). Spearman rank correlation analysis showed that ratios of LDL/HDL, TG/HDL and TC/HDL, and the serum MDA levels in COPD patients were positively correlated with 3-years pulmonary hypertension incidence (r=0.752, 0.748, 0.752, 0.748; P<0.05), and negatively correlated with 3-years survival rate (r=-0.722, -0.751, -0.736, -0.748; P<0.05); serum SOD and T-AOC levels in COPD patients were negatively correlated with 3-years pulmonary hypertension (r=-0.711, -0.734; P<0.05), and positively correlated with 3-year survival rate (r=0.726, 0.733; P<0.05). Conclusion: Blood lipid ratio and oxidative stress levels in COPD patients are elevated while antioxidant abilities were attenuated. The lipid ratio and oxidative stress status in COPD patients is closely related to the prognosis of pulmonary hypertension. Therefore, blood lipid ratio and oxidative stress status may be used in evaluation of pulmonary hypertension and prognosis for COPD patients.

Background: Identifying comorbidities in chronic obstructive pulmonary disease (COPD) may lead to improved disease management, survival and costs. Objective: To compare comorbidities and associated healthcare use between COPD and non-COPD patients. Methods: COPD patients9 medical records data from primary care in Sweden were linked to primary and secondary care national registries information. Data included prescriptions, mortality, income/social characteristics, and pre- and post-COPD diagnosis comorbidities. Comorbidity prevalence was compared between COPD patients and an age-, gender- and calendar year-matched reference population. Healthcare costs were categorized as COPD- and non-COPD related, and comprised drug costs and primary and secondary care visits. Results: There were 17,545 COPD and 84,514 reference group patients. A higher pre-COPD diagnosis comorbidity of asthma (10.1% vs 5.6%), depression (5.0% vs 2.8%), type II diabetes (5.6% vs 3.8%), osteoporosis (1.3% vs 0.7%), fractures (7.5% vs 5.7%), cardiovascular disease (30.2% vs 21.6%), rheumatoid arthritis (1.5% vs 0.9%), and lung cancer (0.4% vs 0.1%) was observed in COPD patients compared with reference patients. Two years post-diagnosis, the comorbidity rate increased for both the COPD and the reference patients, but the proportion of COPD patients with each comorbidity was considerably higher than for the reference patients. Costs of treating COPD comorbidities were higher than COPD-related costs at all time points (e.g. €8,295 vs €620 for non-COPD vs COPD-related hospital nights, respectively, in 2013). Conclusion: Comorbidities are more prevalent in COPD than non-COPD patients and are the major contributor to healthcare costs.

Rationale: Chronic obstructive pulmonary disease (COPD) is a lung disorder associated with aberrant immune and structural responses of the airways to inhaled toxics. While accumulation of B cells and formation of lymphoid follicles (LF) have been described in COPD airways, the functional status of lung B cells remains poorly known. Objectives: The aim of this study was to further characterize LF observed in COPD airways, in terms of IgA expression. Methods: The presence of LF and CD20 and CD21 expression were determined within the lung from COPD patients (n=21) versus controls (n=18), while intra-follicular IgA expression was assessed by immunohistochemistry (quantified by TissueIA software, Leica microsystems). Results: A significant increase was observed both in the percentage of B cells among total cells as well as the number of peri-bronchial and parenchymal LF in lung tissue of severe COPD patients as compared to controls (respectively p=0.02 and p=0.03). While these LF were clearly observed in COPD, 47 % of these were displaying evidence of CD21+ follicular DCs. In another hand, IgA+ B-cell numbers were up-regulated in LF from severe COPD patients compared with controls, particularly in distal airways (p=0.02). Conclusions: This study shows that IgA production occurs within LF from severe COPD, presumably representing an end-stage feature of exacerbated mucosal immune responses against cigarette smoke and/or chronic infection. In addition, these LF are observed in the absence of CD21+ follicular DCs.

Lentiviral-mediated integration of a CFTR transgene cassette into airway basal cells is a strategy being considered for cystic fibrosis (CF) cell-based therapies. However, CFTR expression is highly regulated in differentiated airway cell types and a subset of intermediate basal cells destined to differentiate. Since basal stem cells typically do not express CFTR, suppressing the CFTR expression from the lentiviral vector in airway basal cells may be beneficial for maintaining their proliferative capacity and multipotency. We identified miR-106b as highly expressed in proliferating airway basal cells and extinguished in differentiated columnar cells. Herein, we developed lentiviral vectors with the miR-106b-target sequence (miRT) to both study miR-106b regulation during basal cell differentiation and detarget CFTR expression in basal cells. Given that miR-106b is expressed in the 293T cells used for viral production, obstacles of viral genome integrity and titers were overcome by creating a 293T-B2 cell line that inducibly expresses the RNAi suppressor B2 protein from flock house virus. While miR-106b vectors effectively detargeted reporter gene expression in proliferating basal cells and following differentiation in the air–liquid interface and organoid cultures, the CFTR-miRT vector produced significantly less CFTR-mediated current than the non-miR-targeted CFTR vector following transduction and differentiation of CF basal cells. These findings suggest that miR-106b is expressed in certain airway cell types that contribute to the majority of CFTR anion transport in airway epithelium.

Background: Cysteine-rich 61 (CYR61) and inflammation was upregulated in the lungs of patients with chronic obstructive pulmonary disease (COPD). However, the association between CYR61 and inflammation was unclear in COPD patients. This study aimed to analyze the association of serum CYR61 with pulmonary inflammation and lung function indexes in COPD patients. Methods: One hundred and fifty COPD patients and 150 control subjects were enrolled. Serum and pulmonary CYR61 was detected. Lung function indexes were evaluated in COPD patients. Results: Serum CYR61 level was elevated and pulmonary CYR61 expression was upregulated in COPD patients. An increased CYR61 was associated with decreased pulmonary function indexes in COPD patients. Further analyses showed that nuclear factor-kappa B (NF-κB) p65-positive nuclei was elevated in the lungs of COPD patients with high level of CYR61. Accordingly, serum monocyte chemotactic protein (MCP)-1 and tumor necrosis factor α (TNF-α), two downstream inflammatory cytokines of NF-κB pathway, were increased in parallel with CYR61, among which serum MCP-1 and TNF-α were the highest in COPD patients with high level of CYR61. Moreover, a positive correlation, determined by multivariate regression that excluded the influence of age, gender and smoking, was observed between serum CYR61 and inflammatory cytokines in COPD patients. Conclusion: These results provide evidence that an increased CYR61 is associated with pulmonary inflammation and COPD progression. Inflammatory cytokines may be the mediators between CYR61 elevation and COPD progression.

Introduction: Little is known about protease, anti-protease markers in chronic obstructive pulmonary disease (COPD) patients. Objectives: The objective of present study was to identify and try to correlate serum markers of protease and anti-protease with pulmonary functions in different stages of patients with COPD and to determine the ratio of neutrophil elastase/alpha-1-antitrypsin in different stages of COPD patients. Methods: This prospective observational study was carried out in patients with stable COPD. Activities of serum alpha-1-antitrypsin and neutrophil elastase were measured in 220 stable COPD patients and in 60 healthy controls by ELISA method. 220 COPD patients were divided into 4 stages according to severity: stage I, II, III and IV. Results: An increase in serum neutrophil elastase and neutrophil elastase/alpha-1-antitrypsin ratio was observed in COPD patients with the advancement of the stage. In contrast to that, decreased activity of alpha-1-antitrypsin in serum was observed in different stages of COPD and is correlated positively with lung function parameters. Conclusion: From these findings we conclude that as the severity increases there is decrease in alpha-1-antitrypsin resulting in concomitant increase in neutrophil elastase activity causing imbalance between protease-antiprotease in COPD patients and this imbalance is associated with impairment of lung function. The neutrophil elastase/ α-1-antitrypsin ratio can tell us the severity of the chronic obstructive pulmonary disease it may be in terms of increased fibrosis of the lung. Though the magnitude of neutrophil elatase/alpha-1-antitrypsin ratio is minute, still it can be a good marker of pulmonary function in term of severity of the COPD.

The mechanism responsible for the reversibility of airflow limitation in stable chronic obstructive pulmonary disease (COPD) patients is unknown. The aim of this study is to assess the relationship between the reversibility of airflow limitation, the redox balance and the inflammatory cells in the sputum of patients with stable COPD. For this purpose we examined 15 normal healthy control subjects and 20 nonatopic COPD patients. The COPD patients were divided into two groups: reversible COPD (increase in FEV1> 200 ml and/or > or =12> or = after 200 microg of inhaled salbutamol) or non-reversible COPD. GSH, GSSG were measured in induced sputum and blood. Protein carbonyls were evaluated by WB in sputum and IL-4 and IL-6 and TNF-alpha in plasma and sputum. GSH oxidation and protein oxidation were lower in reversible COPD patients than in those with no reversibility. The sputum eosinophil count was significantly higher in the reversible group than in the non-reversible group, and IL-4 concentration was higher in the same patients both in sputum and in plasma. In contrast, IL-6 and TNF-alpha were increased in non-reversible COPD patients in both biological samples. We conclude that airflow reversibility in COPD patients is associated with airway oxidative stress and activation of eosinophil inflammatory pattern in sputum and blood, suggesting that these patients could respond to specific pharmacological treatment.

BackgroundAirway basal cells (BC) from patients with chronic obstructive pulmonary disease (COPD) regenerate abnormal airway epithelium and this was associated with reduced expression of several genes involved in epithelial repair. Quercetin reduces airway epithelial remodeling and inflammation in COPD models, therefore we examined whether quercetin promotes normal epithelial regeneration from COPD BC by altering gene expression.MethodsCOPD BC treated with DMSO or 1 µM quercetin for three days were cultured at air/liquid interface (ALI) for up to 4 weeks. BC from healthy donors cultured at ALI were used as controls. Polarization of cells was determined at 8 days of ALI. The cell types and IL-8 expression in differentiated cell cultures were quantified by flow cytometry and ELISA respectively. Microarray analysis was conducted on DMSO or 1 µM quercetin-treated COPD BC for 3 days to identify differentially regulated genes (DEG). Bronchial brushings obtained from COPD patients with similar age and disease status treated with either placebo (4 subjects) or 2000 mg/day quercetin (7 subjects) for 6 months were used to confirm the effects of quercetin on gene expression.ResultsCompared to placebo-, quercetin-treated COPD BC showed significantly increased transepithelial resistance, more ciliated cells, fewer goblet cells, and lower IL-8. Quercetin upregulated genes associated with tissue and epithelial development and differentiation in COPD BC. COPD patients treated with quercetin, but not placebo showed increased expression of two developmental genes HOXB2 and ELF3, which were also increased in quercetin-treated COPD BC with FDR < 0.001. Active smokers showed increased mRNA expression of TGF-β (0.067) and IL-8 (22.0), which was reduced by 3.6 and 4.14 fold respectively after quercetin treatment.ConclusionsThese results indicate that quercetin may improve airway epithelial regeneration by increasing the expression of genes involved in epithelial development/differentiation in COPD.Trial registrationThis study was registered at ClinicalTrials.gov on 6-18-2019. The study number is NCT03989271.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12931-024-02742-0.