Does Chronic Obstructive Pulmonary Disease Originate from Different Cell Types?

Abstract

The onset of chronic obstructive pulmonary disease (COPD) is heterogeneous, and current approaches to define distinct disease phenotypes are lacking. In addition to clinical methodologies, subtyping COPD has also been challenged by the reliance on human lung samples from late-stage diseases. Different COPD phenotypes may be initiated from the susceptibility of different cell types to cigarette smoke, environmental pollution, and infections at early stages that ultimately converge at later stages in airway remodeling and destruction of the alveoli when the disease is diagnosed. This perspective provides discussion points on how studies to date define different cell types of the lung that can initiate COPD pathogenesis, focusing on the susceptibility of macrophages, T and B cells, mast cells, dendritic cells, endothelial cells, and airway epithelial cells. Additional cell types, including fibroblasts, smooth muscle cells, neuronal cells, and other rare cell types not covered here, may also play a role in orchestrating COPD. Here, we discuss current knowledge gaps, such as which cell types drive distinct disease phenotypes and/or stages of the disease and which cells are primarily affected by the genetic variants identified by whole genome-wide association studies. Applying new technologies that interrogate the functional role of a specific cell type or a combination of cell types as well as single-cell transcriptomics and proteomic approaches are creating new opportunities to understand and clarify the pathophysiology and thereby the clinical heterogeneity of COPD.

Keywords: gene-and-environment interaction; lineage tracing; lung cell types; single nucleotide polymorphisms; single-cell transcriptomics.

Figure 1.

Effects of SNPs in different cell types to cause subtypes of and advanced chronic obstructive pulmonary disease (COPD). The genetic susceptibility factors as SNPs can enhance the response to environmental stressors to provide chronic changes in specific cell types, including autophagy, senescence, cell death, mucociliary dysfunction, and autoimmunity; AT2, mucous, and macrophages are denoted as examples. A single SNP or multiple SNPs can affect one or multiple cell types, and each can amplify the response to pollutants and the resulting cellular interactions in the lung. New approaches to analyze genomics, chromatin profiling, transcriptomics, proteomics, and protein interactions at the single-cell level can help identify which cell types are affected by the SNPs and elucidate how these modifications lead to chronic inflammation, airway remodeling, and emphysema. These cell type–specific changes cause different COPD subtypes, characterized primarily by emphysema, airway-predominant, or combined emphysema and airway diseases. Other cell types, such as eosinophils, may cause an eosinophilic COPD subtype. In later stages, when advanced disease sets in, other cell types and other organs are affected to create a complex and severe disease phenotype. AEC = alveolar epithelial cell; AF1 = type 1 alveolar fibroblast; AF2 = type 1 alveolar fibroblast; Alv. T II = alveolar type II cell; AM = airway macrophage; ASMC = airway smooth muscle cell; AT1 = alveolar type I cell; AT2 = alveolar type II cell; CAP1 = type 1 capillary cell; CAP2 = type 2 capillary cell; cDC1 = type 1 conventional dendritic cell; cDC2 = type 2 conventional dendritic cell; ILC = innate lymphoid cell; IM = interstitial macrophage; iMON = inflammatory monocyte; LEC = lymphatic endothelial cell; maDC = mature dendritic cell; MEC = microvessel endothelial cell; NK = natural killer cell; pDC = plasmacytoid dendritic cell; pMON = patrolling monocyte; PNEC = pulmonary neuroendocrine cell; RAS = respiratory airway secretory cell; SCMF = secondary crest myofibroblast; SMG = submucosal gland; SVEC = splenic vascular endothelial cell; Treg = regulatory T cell; VEC = vascular endothelial cell; VSMC = vascular smooth muscle cell.