Explicating miRNA-mediated regulation of inflammatory pathways in COPD, MS, and lung cancer using explainable artificial intelligence: insights from peripheral blood profiles.

A new cytokine target for chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous, progressive inflammatory airway disease associated with a significant impact on patients' lives, including morbidity and mortality, and significant healthcare costs. Current pharmacologic strategies, including first- and second-line therapies such as long-acting β2-agonists, long-acting muscarinic antagonists, inhaled corticosteroids, phosphodiesterase-4 inhibitors, and macrolides, provide relief to patients with COPD. However, many patients remain symptomatic, with persistent symptoms and/or acute exacerbations and progressive lung function loss. Although neutrophilic inflammation is the most common type of inflammation in COPD, 20-40% of patients with COPD exhibit type 2 inflammation, with roles for CD4+ (cluster of differentiation 4) T-helper cell type 1 cells, type 2 innate lymphoid cells, eosinophils, and alternatively activated macrophages. On the basis of the current limitations of available therapies, a significant unmet need exists in COPD management, including the need for targeted therapies to address the underlying pathophysiology leading to disease progression, such as type 2 inflammation, as well as biomarkers to help select the patients who would most benefit from the new therapies. Significant progress is being made, with evolving understanding of the pathobiology of COPD leading to novel therapeutic targets including epithelial alarmins. In this review, we describe the current therapeutic landscape in COPD, discuss unmet treatment needs, review the current knowledge of type 2 inflammation and epithelial alarmins in COPD, explore potential biomarkers of type 2 inflammation in COPD, and finally provide a rationale for incorporating therapies targeting type 2 inflammation and epithelial alarmins in COPD. Video Abstract available online at www.atsjournals.org.

Antibiotics for treatment and prevention of exacerbations of chronic obstructive pulmonary disease

Current concepts on the role of inflammation in COPD and lung cancer.

Two symposia occurred during the European Respiratory Society (ERS) Congress 2024, highlighting the heterogeneity in chronic inflammatory pathways that underlie chronic obstructive pulmonary disease (COPD) pathophysiology. In 'A Breath of Fresh Air: A Greater Understanding of COPD With Type 2 Inflammation', Henrik Watz (Chair), German Center for Lung Research, Grosshansdorf, Germany, provided an overview of both the pathophysiology and the burden of disease of COPD. He discussed how exacerbations, which may be increased in those with evidence of Type 2 inflammation, contribute to the cycle of worsening COPD. Mona Bafadhel, King’s College London, UK, provided an examination of the mechanisms and biomarkers of Type 2 inflammation in COPD. Finally, Alberto Papi, University of Ferrara, Italy, summarised the latest research on biological treatments targeting Type 2 inflammation in COPD. The second symposium, 'Targeting interleukin-33 (IL-33) in COPD: Exploring New Frontiers for COPD Management', discussed inflammation in COPD, focusing on the central role of IL-33 as a mediator for both Type 2 and Type 1/Type 3 inflammation. Klaus Rabe (Chair), LungenClinic, Grosshansdorf, Germany, reviewed the structure and function of IL-33 and its initial processes that lead to downstream immune responses. Stephanie Christenson, University of California, San Francisco, USA, explored how genetic and environmental factors contribute to IL-33 activity in COPD pathology. Next, Paola Rogliani, University of Rome ‘Tor Vergata’, Italy, presented an examination of IL-33 inflammatory processes and evidence from COPD animal models illustrating the role of IL-33 in airway inflammation and lung function decline. Klaus Rabe concluded with an examination of IL-33 as a target for new COPD treatment approaches.

The holistic perspective of chronic obstructive pulmonary disease: doubt some more

Reducing inflammation in COPD: the evidence builds

The relationship between systemic inflammation and comorbidities in patients with chronic obstructive pulmonary disease (COPD) is unclear. This article discusses (1) the prevalence and clinical impact of comorbidities in COPD; (2) the current knowledge on definition, prevalence, consequences, and treatment of systemic inflammation in COPD; and (3) the relationship of systemic inflammation and lung cancer in COPD.

HEALTH CARE RESOURCE UTILIZATION IN THE YEAR PRIOR TO DEATH AMONG PATIENTS WITH LUNG CANCER AND COPD IN SASKATCHEWAN

BackgroundIncreased airway resistance and hyperinflation in chronic obstructive pulmonary disease (COPD) are associated with increased mechanical stress that modulate many essential pathophysiological functions including airway remodeling and inflammation. Our present study aimed to investigate the role of transient receptor potential canonical 1 (TRPC1), a mechanosensitive cation channel in airway remodeling and inflammation in COPD and the effect of glucocorticoid on this process.MethodsIn patients, we investigated the effect of pathological high mechanical stress on the expression of airway remodeling-related cytokines transforming growth factor β1 (TGF-β1), matrix metalloproteinase-9 (MMP9) and the count of inflammatory cells in endotracheal aspirates (ETAs) by means of different levels of peak inspiratory pressure (PIP) under mechanical ventilation, and analyzed their correlation with TRPC1. Based on whether patients regularly used inhaled corticosteroid (ICS), COPD patients were further divided into ICS group (n = 12) and non-ICS group (n=15). The ICS effect on the expression of TRPC1 was detected by Western blot. In vitro, we imitated the mechanical stress using cyclic stretch and examined the levels of TGF-β1 and MMP-9. The role of TRPC1 was further explored by siRNA transfection and dexamethasone administration.ResultsOur results revealed that the TRPC1 level and the inflammatory cells counts were significantly higher in COPD group. After mechanical ventilation, the expression of TGF-β1 and MMP-9 in all COPD subgroups was significantly increased, while in the control group, only high PIP subgroup increased. Meanwhile, TRPC1 expression was positively correlated with the counts of inflammatory cells and the levels of TGF-β1 and MMP-9. In vitro, mechanical stretch significantly increased TGF-β1 and MMP-9 levels and such increase was greatly attenuated by TRPC1 siRNA transfection and dexamethasone administration.ConclusionOur results suggest that the increased TRPC1 may play a role in the airway inflammation and airway remodeling in COPD under high airway pressure. Glucocorticoid could in some degree alleviate airway remodeling via inhibition of TRPC1.

Chronic obstructive pulmonary disease (COPD) and lung cancer are leading causes of morbidity and mortality worldwide. At least 85 to 90% of all COPD and human lung cancers are related to cigarette smoke (CS), but genetic susceptibility and environmental factors also contribute to the pathogenesis. Chronic airway inflammation has been indicated as a major risk factor in COPD and has been suggested to be associated with an increased risk of human cancer, including lung cancer. Therefore, we hypothesize that COPD and lung cancer may share chronic inflammation as one of the common pathogenic mechanisms. We developed two animal exposure paradigms to elucidate roles of chronic inflammation in COPD and lung cancer. In the COPD study, mice were separated into four treatment groups: filtered-air control, lipopolysaccharides (LPS), CS, and LPS1CS. For the lung cancer study, mice were assigned into four different treatment groups: saline control, LPS, NNK (a major cigarette smoke carcinogen), and LPS1NNK. Mice were killed after 4 to 6 months of treatment and lung tissues were collected to assess alveolar space enlargement, lung tumors, and the inflammatory response. The LPS group showed increased inflammation but no alveolar space enlargement or tumor formation. LPS1CS displayed enhanced alveolar space enlargement when compared with CS alone, but neither group developed lung tumor. On the lung cancer study, we observed a more than sixfold increase in tumor numbers in the LPS1NNK group compared with the NNK alone group, but no alveolar space enlargement was observed. There were significant increases of inflammatory cells, particularly macrophages, in all treatment groups except NNK and controls. The increased alveolar macrophage population displayed an alternatively activated M2 phenotype in both COPD and lung cancer models. Our results suggest that chronic inflammation enhances emphysemalike alveolar space enlargement and also synergistically promotes cigarette smoke carcinogen–induced lung tumorigenesis.

Chronic obstructive pulmonary disease (COPD) is a major global health problem. It results from chronic inflammation and causes irreversible airway damage. Levels of different serum cytokines could be surrogate biomarkers for inflammation and lung function in COPD. We aimed to determine the serum levels of different biomarkers in COPD patients, the association between cytokine levels and various prognostic parameters, and the key pathways/networks involved in stable COPD. In this study, serum levels of 48 cytokines were examined by multiplex assays in 30 subjects (control, n=9; COPD, n=21). Relationships between serum biomarkers and forced expiratory volume in 1 second, peak oxygen uptake, body mass index, dyspnea score, and smoking were assessed. Enrichment pathways and network analyses were implemented, using a list of cytokines showing differential expression between healthy controls and patients with COPD by Cytoscape and GeneGo Metacore™ software (Thomson-Reuters Corporation, New York, NY, USA). Concentrations of cutaneous T-cell attracting chemokine, eotaxin, hepatocyte growth factor, interleukin 6 (IL-6), IL-16, and stem cell factor are significantly higher in COPD patients compared with in control patients. Notably, this study identifies stem cell factor as a biomarker for COPD. Multiple regression analysis predicts that cutaneous T-cell-attracting chemokine, eotaxin, IL-6, and stem cell factor are inversely associated with forced expiratory volume in 1 second and peak oxygen uptake change, whereas smoking is related to eotaxin and hepatocyte growth factor changes. Enrichment pathways and network analyses reveal the potential involvement of specific inflammatory and immune process pathways in COPD. Identified network interaction and regulation of different cytokines would pave the way for deeper insight into mechanisms of the disease process.

Patients with multiple sclerosis (MS) face a heightened risk of developing chronic obstructive pulmonary disease (COPD). Despite this widely reported association, the pathogenic contributors and processes that may favor the development of COPD in MS patients have yet to be identified. Recent studies have suggested peripheral blood leukocytes as a potential link between COPD and autoimmune disorders. Therefore, this study aimed to unveil shared molecular signatures between MS and COPD using blood transcriptomes. To this end, gene expression datasets obtained from MS and COPD blood specimens were retrieved from the Gene Expression Omnibus (GEO) database. By integrating datasets belonging to each disorder, differentially expressed genes (DEGs) were determined for each disease. Then, the protein-protein interaction (PPI) network was constructed for shared DEGs between MS and COPD. Subsequently, the network was analyzed to identify hub genes and key regulatory miRNAs. The integrated data for MS encompassed 51 samples (28 from MS patients and 23 from controls), and the integrated data for COPD included 450 samples (275 from COPD patients and 175 from controls). A total of 246 genes were found to exhibit identical directions of expression in both MS and COPD. By applying a high confidence threshold (0.7), a PPI network with 74 nodes was constructed. TP53, H4C6, SNRPE, and RPS11 were identified as hub genes according to the degree measure. In addition, 8 miRNAs were identified as key regulators, each interacting with 6 mRNAs. Among these miRNAs, miR-218-5p and miR-142-5p have been previously reported to contribute to the pathogenesis of these diseases, and here they were identified as key regulators of the shared PPI network, suggesting a potential epigenetic link between MS and COPD. In conclusion, the results highlighted the potential role of peripheral blood leucocytes as a bridge between MS and COPD. These findings broaden our understanding of pathogenic contributors linking MS and COPD. While this transcriptomics study identified multiple key players, such as TP53, miR-218-5p, and miR-142-5p, the assessment of their therapeutic efficacy demands further experimental studies.

Highly elevated C-reactive protein levels in obese patients with COPD: A fat chance?

Understanding the chronic inflammatory process that affects the airways of patients with chronic obstructive pulmonary disease (COPD) is an important clue in the search for new therapeutic options. The main inflammatory cells and mediators involved in COPD pathogenesis have been identified, but there is still little knowledge about their mutual interactions that result in the final outcome, that is, structural airway changes and progressive airflow limitation. Recent studies created novel theories on the inflammatory pathway in COPD and focused not only on the influence of cigarette smoke but also on other factors initiating airway inflammation. There is evidence that apart from neutrophils and macrophages, eosinophils may play an important role in the pathogenesis of COPD and patients with eosinophilic inflammation may present a distinct phenotype. This may have therapeutic implications. New cytokines (e.g. interleukin 32) involved in COPD pathogenesis have been identified. The increased number of inflammatory cell subpopulations need not necessarily be associated with their increased activity, suggesting their complex role in inducing/sustaining airway inflammation in COPD. The presence of inflammation in the upper airways in the course of COPD has also been found. There are many questions concerning the pathogenesis of COPD yet to be answered. Results of recently published studies show a new approach to airway inflammation in COPD and indicate new interesting directions in COPD research.