scholarly journals Single-cell transcriptomics reveal cell type-specific molecular changes and altered intercellular communications in chronic obstructive pulmonary disease

2021 ◽  
Author(s):  
Qiqing Huang ◽  
Jingshen Wang ◽  
Shaoran Shen ◽  
Yuanyuan Wang ◽  
Yan Chen ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Single Cell ◽  
Pulmonary Disease ◽  
Alveolar Epithelium ◽  
Cell Types ◽  
Chronic Obstructive ◽  
Cell Type ◽  
Obstructive Pulmonary Disease ◽  
Cell Type Specific ◽  
Intercellular Communications

AbstractChronic obstructive pulmonary disease (COPD) is a common and heterogeneous respiratory disease, the molecular complexity of which remains poorly understood, as well as the mechanisms by which aging and smoking facilitate COPD development. Here, using single-cell RNA sequencing of more than 65,000 cells from COPD and age-stratified control lung tissues of donors with different smoking histories, we identified monocytes, club cells, and macrophages as the most disease-, aging-, and smoking-relevant cell types, respectively. Notably, we found these highly cell-type specific changes under different conditions converged on cellular dysfunction of the alveolar epithelium. Deeper investigations revealed that the alveolar epithelium damage could be attributed to the abnormally activated monocytes in COPD lungs, which could be amplified via exhaustion of club cell stemness as ages. Moreover, the enhanced intercellular communications in COPD lungs as well as the pro-inflammatory interaction between macrophages and endothelial cells indued by smoking could facilitate signaling between monocyte and the alveolar epithelium. Our findings complement the existing model of COPD pathogenesis by emphasizing the contributions of the previously less appreciated cell types, highlighting their candidacy as potential therapeutic targets for COPD.

scholarly journals Roles of Mesenchymal Cells in the Lung: From Lung Development to Chronic Obstructive Pulmonary Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3467
Author(s):  
Amel Nasri ◽  
Florent Foisset ◽  
Engi Ahmed ◽  
Zakaria Lahmar ◽  
Isabelle Vachier ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Lung Development ◽  
Lung Diseases ◽  
Mesenchymal Cells ◽  
Chronic Obstructive ◽  
Multilineage Differentiation ◽  
Cell Type ◽  
Obstructive Pulmonary Disease ◽  
Lung Regeneration

Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications. They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling after injury. However, much less is known about their function in lung disease. In this review, we discuss the origins of mesenchymal cells during lung development, their crosstalk with the epithelium, and their role in lung diseases, particularly in chronic obstructive pulmonary disease.

scholarly journals Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

2019 ◽  
Vol 51 (3) ◽  
pp. 494-505 ◽  
Author(s):  
Phuwanat Sakornsakolpat ◽  
◽  
Dmitry Prokopenko ◽  
Maxime Lamontagne ◽  
Nicola F. Reeve ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Chronic Obstructive ◽  
Cell Type ◽  
Obstructive Pulmonary Disease ◽  
Genetic Landscape

scholarly journals Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations

2018 ◽  
Author(s):  
Phuwanat Sakornsakolpat ◽  
Dmitry Prokopenko ◽  
Maxime Lamontagne ◽  
Nicola F. Reeve ◽  
Anna L. Guyatt ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Lung Function ◽  
Pulmonary Disease ◽  
Genetic Risk ◽  
Chronic Obstructive ◽  
Alveolar Type ◽  
Imaging Features ◽  
Cell Type ◽  
Obstructive Pulmonary Disease ◽  
A Genome

SummaryChronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. To broaden COPD genetic risk loci discovery and identify cell type and phenotype associations we performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P value < 5×10−8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and alveolar type II cells. We found 9 shared genomic regions between COPD and asthma and 5 between COPD and pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

scholarly journals Muscarinic Receptors and Their Antagonists in COPD: Anti-Inflammatory and Antiremodeling Effects

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
George Karakiulakis ◽  
Michael Roth
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Extracellular Matrix ◽  
Pulmonary Disease ◽  
Muscarinic Receptors ◽  
Cell Types ◽  
Matrix Metalloproteases ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Obstructive Pulmonary Disease ◽  
Anti Inflammatory

Muscarinic receptors are expressed by most cell types and mediate cellular signaling of their natural ligand acetylcholine. Thereby, they control numerous central and peripheral physiological organ responses to neuronal activity. In the human lung, muscarinic receptors are predominantly expressed by smooth muscle cells, epithelial cells, and fibroblasts. Antimuscarinic agents are used for the treatment of chronic obstructive pulmonary disease and to a lesser extent for asthma. They are primarily used as bronchodilators, but it is now accepted that they are also associated with anti-inflammatory, antiproliferative, and antiremodeling effects. Remodeling of the small airways is a major pathology in COPD and impairs lung function through changes of the extracellular matrix. Glycosaminoglycans, particularly hyaluronic acid, and matrix metalloproteases are among extracellular matrix molecules that have been associated with tissue inflammation and remodeling in lung diseases, including chronic obstructive pulmonary disease and asthma. Since muscarinic receptors have been shown to influence the homeostasis of glycosaminoglycans and matrix metalloproteases, these molecules may be proved valuable endpoint targets in clinical studies for the pharmacological exploitation of the anti-inflammatory and antiremodeling effects of muscarinic inhibitors in the treatment of chronic obstructive pulmonary disease and asthma.

scholarly journals Single-cell RNA sequencing identifies aberrant transcriptional profiles of cellular populations and altered alveolar niche signalling networks in Chronic Obstructive Pulmonary Disease (COPD)

2020 ◽  
Author(s):  
Maor Sauler ◽  
John E McDonough ◽  
Taylor S Adams ◽  
Neeha Kothapalli ◽  
Jonas S Schupp ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Single Cell ◽  
Pulmonary Disease ◽  
Rna Sequencing ◽  
Cell Communication ◽  
Chronic Obstructive ◽  
Alveolar Type ◽  
Obstructive Pulmonary Disease ◽  
Transcriptional Profiles ◽  
Single Cell Rna Sequencing

ABSTRACT Chronic Obstructive Pulmonary Disease (COPD) pathogenesis involves a failure to maintain alveolar homeostasis due to repetitive injury and inflammation. In order to improve our understanding of cell-specific mechanisms contributing to COPD pathogenesis, we analysed single-cell RNA sequencing (scRNAseq) profiles of explanted parenchymal lung tissue from 17 subjects with advanced COPD requiring transplant and 15 control donor lungs. We identified a subpopulation of alveolar type II epithelial cells that uniquely express HHIP and have aberrant stress tolerance profiles in COPD. Amongst endothelial cells, we identified overlapping and unique shifts in transcriptional profiles of endothelial subtypes that may contribute to vascular inflammation and susceptibility to injury. We also identified population composition changes amongst alveolar macrophages. Finally, application of integrative analyses to our scRNAseq data identified cell-specific contributions to COPD heritability and dysfunctional cell-cell communication pathways that occur within the COPD alveolar niche. These findings provide cell type-specific resolution of transcriptional changes associated with advanced COPD that may underlie disease pathogenesis.

scholarly journals Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

2020 ◽  
Author(s):  
Kevin Baßler ◽  
Wataru Fujii ◽  
Theodore S. Kapellos ◽  
Arik Horne ◽  
Benedikt Reiz ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Single Cell ◽  
Pulmonary Disease ◽  
Molecular Mechanisms ◽  
Chronic Obstructive ◽  
Alveolar Space ◽  
Proliferating Cells ◽  
Tissue Samples ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

AbstractDespite the epidemics of chronic obstructive pulmonary disease (COPD), the cellular and molecular mechanisms of this disease are far from being understood. Here, we characterize and classify the cellular composition within the alveolar space and peripheral blood of COPD patients and control donors using a clinically applicable single-cell RNA-seq technology corroborated by advanced computational approaches for: machine learning-based cell-type classification, identification of differentially expressed genes, prediction of metabolic changes, and modeling of cellular trajectories within a patient cohort. These high-resolution approaches revealed: massive transcriptional plasticity of macrophages in the alveolar space with increased levels of invading and proliferating cells, loss of MHC expression, reduced cellular motility, altered lipid metabolism, and a metabolic shift reminiscent of mitochondrial dysfunction in COPD patients. Collectively, single-cell omics of multi-tissue samples was used to build the first cellular and molecular framework for COPD pathophysiology as a prerequisite to develop molecular biomarkers and causal therapies against this deadly disease.

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