Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene–environment interactions across the lifespan

Agustí, Àlvar; Melén, Erik; DeMeo, Dawn L.; Breyer‐Kohansal, Robab; Faner, Rosa

doi:10.1016/s2213-2600(21)00555-5

Cited by 136 publications

(136 citation statements)

References 131 publications

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“…In this context, the use of polygenic risk scores offers an attractive analytical approach, as exemplified in recent COPD studies [71]. 8) The integration of metabolomics with other types of omics data, such as epigenetics and transcriptomics [72], will improve the interrogation and understanding of pathophysiological pathways mediating air pollution effects on lung function across the life-course [9]. In addition to the above shortcomings, the challenges of the life-course perspective in exposome research for respiratory health need to be acknowledged, discussed and considered to optimise the use of the metabolome as a mediator.…”

Section: Conclusion and Recommendations For Future Researchmentioning

confidence: 99%

Air pollution, metabolites and respiratory health across the life-course

Gruzieva

Jeong

et al. 2022

Eur Respir Rev

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Previous studies have explored the relationships of air pollution and metabolic profiles with lung function. However, the metabolites linking air pollution and lung function and the associated mechanisms have not been reviewed from a life-course perspective. Here, we provide a narrative review summarising recent evidence on the associations of metabolic profiles with air pollution exposure and lung function in children and adults. Twenty-six studies identified through a systematic PubMed search were included with 10 studies analysing air pollution-related metabolic profiles and 16 studies analysing lung function-related metabolic profiles. A wide range of metabolites were associated with short- and long-term exposure, partly overlapping with those linked to lung function in the general population and with respiratory diseases such as asthma and COPD. The existing studies show that metabolomics offers the potential to identify biomarkers linked to both environmental exposures and respiratory outcomes, but many studies suffer from small sample sizes, cross-sectional designs, a preponderance on adult lung function, heterogeneity in exposure assessment, lack of confounding control and omics integration. The ongoing EXposome Powered tools for healthy living in urbAN Settings (EXPANSE) project aims to address some of these shortcomings by combining biospecimens from large European cohorts and harmonised air pollution exposure and exposome data.

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Section: Conclusion and Recommendations For Future Researchmentioning

confidence: 99%

Air pollution, metabolites and respiratory health across the life-course

Gruzieva

Jeong

et al. 2022

Eur Respir Rev

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“…COPD is the third leading cause of death worldwide, and affects approximately 300 million people in the world [ 1 ]. Although cigarette smoking has been considered the most frequent cause of COPD, about half of cases are linked to non-tobacco-related risk factors, such as outdoor air pollution, biomass smoke, and occupational exposure to fumes and dust [ 2 ]. In COPD, the small conducting airways (<2 mm in diameter) are the major site of airflow obstruction, inflammation, and destruction [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Differentiation of Human Induced Pluripotent Stem Cells from Patients with Severe COPD into Functional Airway Epithelium

Ahmed

Fieldès

Bourguignon

et al. 2022

Cells

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Background: Chronic Obstructive Pulmonary Disease (COPD), a major cause of mortality and disability, is a complex disease with heterogeneous and ill-understood biological mechanisms. Human induced pluripotent stem cells (hiPSCs) are a promising tool to model human disease, including the impact of genetic susceptibility. Methods: We developed a simple and reliable method for reprogramming peripheral blood mononuclear cells into hiPSCs and to differentiate them into air–liquid interface bronchial epithelium within 45 days. Importantly, this method does not involve any cell sorting step. We reprogrammed blood cells from one healthy control and three patients with very severe COPD. Results: The mean cell purity at the definitive endoderm and ventral anterior foregut endoderm (vAFE) stages was >80%, assessed by quantifying C-X-C Motif Chemokine Receptor 4/SRY-Box Transcription Factor 17 (CXCR4/SOX17) and NK2 Homeobox 1 (NKX2.1) expression, respectively. vAFE cells from all four hiPSC lines differentiated into bronchial epithelium in air–liquid interface conditions, with large zones covered by beating ciliated, basal, goblets, club cells and neuroendocrine cells, as found in vivo. The hiPSC-derived airway epithelium (iALI) from patients with very severe COPD and from the healthy control were undistinguishable. Conclusions: iALI bronchial epithelium is ready for better understanding lung disease pathogenesis and accelerating drug discovery.

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“…COPD itself is a highly heterogeneous disease of complex and diverse origins. Instead of tobacco-stimulated chronic inflammation in genetically susceptible individuals, COPD has recently been recognised as an accumulation of gene-exposure interactions accompanied by aging [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Combining single-cell RNA sequencing of peripheral blood mononuclear cells and exosomal transcriptome to reveal the cellular and genetic profiles in COPD

et al. 2022

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Background It has been a long-held consensus that immune reactions primarily mediate the pathology of chronic obstructive pulmonary disease (COPD), and that exosomes may participate in immune regulation in COPD. However, the relationship between exosomes and peripheral immune status in patients with COPD remains unclear. Methods In this study, we sequenced plasma exosomes and performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) from patients with COPD and healthy controls. Finally, we constructed competing endogenous RNA (ceRNA) and protein–protein interaction (PPI) networks to delineate the interactions between PBMCs and exosomes within COPD. Results We identified 135 mRNAs, 132 lncRNAs, and 359 circRNAs from exosomes that were differentially expressed in six patients with COPD compared with four healthy controls. Functional enrichment analyses revealed that many of these differentially expressed RNAs were involved in immune responses including defending viral infection and cytokine–cytokine receptor interaction. We also identified 18 distinct cell clusters of PBMCs in one patient and one control by using an unsupervised cluster analysis called uniform manifold approximation and projection (UMAP). According to resultant cell identification, it was likely that the proportions of monocytes, dendritic cells, and natural killer cells increased in the COPD patient we tested, meanwhile the proportions of B cells, CD4 + T cells, and naïve CD8 + T cells declined. Notably, CD8 + T effector memory CD45RA + (Temra) cell and CD8 + effector memory T (Tem) cell levels were elevated in patient with COPD, which were marked by their lower capacity to differentiate due to their terminal differentiation state and lower reactive capacity to viral pathogens. Conclusions We generated exosomal RNA profiling and single-cell transcriptomic profiling of PBMCs in COPD, described possible connection between impaired immune function and COPD development, and finally determined the possible role of exosomes in mediating local and systemic immune reactions.

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Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene–environment interactions across the lifespan

Cited by 136 publications

References 131 publications

Air pollution, metabolites and respiratory health across the life-course

Air pollution, metabolites and respiratory health across the life-course

Differentiation of Human Induced Pluripotent Stem Cells from Patients with Severe COPD into Functional Airway Epithelium

Combining single-cell RNA sequencing of peripheral blood mononuclear cells and exosomal transcriptome to reveal the cellular and genetic profiles in COPD

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