Dataset Information

Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium.

ABSTRACT:

Rationale

Small airways are the primary site of pathologic changes in chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder.

Objectives

On the basis of the concept of proximal-distal patterning that determines regional specialization of the airway epithelium during lung development, we hypothesized that a similar program operates in the adult human lung being altered by smoking, leading to decreased regional identity of the small airway epithelium (SAE).

Methods

The proximal and distal airway signatures were identified by comparing the transcriptomes of large and small airway epithelium samples obtained by bronchoscopy from healthy nonsmokers. The expression of these signatures was evaluated in the SAE of healthy smokers and smokers with COPD compared with that of healthy nonsmokers. The capacity of airway basal stem cells (BCs) to maintain region-associated phenotypes was evaluated using the air-liquid interface model.

Measurements and main results

The distal and proximal airway signatures, containing 134 and 233 genes, respectively, were identified. These signatures included known developmental regulators of airway patterning, as well as novel regulators such as epidermal growth factor receptor, which was associated with the proximal airway phenotype. In the SAE of smokers with COPD, there was a dramatic smoking-dependent loss of the regional transcriptome identity with concomitant proximalization. This repatterning phenotype was reproduced by stimulating SAE BCs with epidermal growth factor, which was up-regulated in the SAE of smokers, during differentiation of SAE BCs in vitro.

Conclusions

Smoking-induced global distal-to-proximal reprogramming of the SAE represents a novel pathologic feature of COPD and is mediated by exaggerated epidermal growth factor/epidermal growth factor receptor signaling in SAE BCs.

SUBMITTER: Yang J

PROVIDER: S-EPMC5549864 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium.

Yang Jing J Zuo Wu-Lin WL Fukui Tomoya T Chao IonWa I Gomi Kazunori K Lee Busub B Staudt Michelle R MR Kaner Robert J RJ Strulovici-Barel Yael Y Salit Jacqueline J Crystal Ronald G RG Shaykhiev Renat R

American journal of respiratory and critical care medicine 20170801 3

<h4>Rationale</h4>Small airways are the primary site of pathologic changes in chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder.<h4>Objectives</h4>On the basis of the concept of proximal-distal patterning that determines regional specialization of the airway epithelium during lung development, we hypothesized that a similar program operates in the adult human lung being altered by smoking, leading to decreased regional identity of the small airway epithelium ( ...[more]

PMID: 28345955

Similar Datasets

Project description:Background & aimsSingle-cell transcriptomics offer unprecedented resolution of tissue function at the cellular level, yet studies analyzing healthy adult human small intestine and colon are sparse. Here, we present single-cell transcriptomics covering the duodenum, jejunum, ileum, and ascending, transverse, and descending colon from 3 human beings.MethodsA total of 12,590 single epithelial cells from 3 independently processed organ donors were evaluated for organ-specific lineage biomarkers, differentially regulated genes, receptors, and drug targets. Analyses focused on intrinsic cell properties and their capacity for response to extrinsic signals along the gut axis across different human beings.ResultsCells were assigned to 25 epithelial lineage clusters. Multiple accepted intestinal stem cell markers do not specifically mark all human intestinal stem cells. Lysozyme expression is not unique to human Paneth cells, and Paneth cells lack expression of expected niche factors. Bestrophin 4 (BEST4)+ cells express Neuropeptide Y (NPY) and show maturational differences between the small intestine and colon. Tuft cells possess a broad ability to interact with the innate and adaptive immune systems through previously unreported receptors. Some classes of mucins, hormones, cell junctions, and nutrient absorption genes show unappreciated regional expression differences across lineages. The differential expression of receptors and drug targets across lineages show biological variation and the potential for variegated responses.ConclusionsOur study identifies novel lineage marker genes, covers regional differences, shows important differences between mouse and human gut epithelium, and reveals insight into how the epithelium responds to the environment and drugs. This comprehensive cell atlas of the healthy adult human intestinal epithelium resolves likely functional differences across anatomic regions along the gastrointestinal tract and advances our understanding of human intestinal physiology.

Project description:Waterpipe (also called hookah, shisha, or narghile) smoking is a common form of tobacco use in the Middle East. Its use is becoming more prevalent in Western societies, especially among young adults as an alternative form of tobacco use to traditional cigarettes. While the risk to cigarette smoking is well documented, the risk to waterpipe smoking is not well defined with limited information on its health impact at the epidemiologic, clinical and biologic levels with respect to lung disease. Based on the knowledge that airway epithelial cell DNA methylation is modified in response to cigarette smoke and in cigarette smoking-related lung diseases, we assessed the impact of light-use waterpipe smoking on DNA methylation of the small airway epithelium (SAE) and whether changes in methylation were linked to the transcriptional output of the cells. Small airway epithelium was obtained from 7 nonsmokers and 7 light-use (2.6 ± 1.7 sessions/wk) waterpipe-only smokers. Genome-wide comparison of SAE DNA methylation of waterpipe smokers to nonsmokers identified 727 probesets differentially methylated (fold-change >1.5, p<0.05) representing 673 unique genes. Dominant pathways associated with these epigenetic changes include those linked to G-protein coupled receptor signaling, aryl hydrocarbon receptor signaling and xenobiotic metabolism signaling, all of which have been associated with cigarette smoking and lung disease. Of the genes differentially methylated, 11.3% exhibited a corresponding significant (p<0.05) change in gene expression with enrichment in pathways related to regulation of mRNA translation and protein synthesis (eIF2 signaling and regulation of eIF4 and p70S6K signaling). Overall, these data demonstrate that light-use waterpipe smoking is associated with epigenetic changes and related transcriptional modifications in the SAE, the cell population demonstrating the earliest pathologic abnormalities associated with chronic cigarette smoking.

Dataset Information

Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets