Evidence map›Paper›PMID 41559520›Full record

ArticleRespirology (Carlton, Vic.)2026

Epigenetic Dysregulation of the NKX2-1/SPDEF Axis Drives Persistent Goblet Cell Differentiation and Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease.

Ayaka Shiota, Keiko Kan-O, Yumiko Ishii, Tomoaki Koga, Takeshi Sawada, Kei-Ichiro Yasunaga, Shingo Usuki, Tatsuya Katsuno, Shigesato Inoue, Tomohiro Ogawa and 8 more

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In one paragraph

Article in Respirology (Carlton, Vic.), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Ayaka ShiotaDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Keiko Kan-ODepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.ORCID https://orcid.org/0000-0002-7736-588X
Yumiko IshiiDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Tomoaki KogaDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Takeshi SawadaDivision of Histology and Neuroanatomy, Department of Anatomy and Physiology, Faculty of Medicine, Saga University, Saga, Japan.
Kei-Ichiro YasunagaLiaison Laboratory Research Promotion Center, IMEG, Kumamoto University, Kumamoto, Japan.
Shingo UsukiLiaison Laboratory Research Promotion Center, IMEG, Kumamoto University, Kumamoto, Japan.
Tatsuya KatsunoCenter for Anatomical Studies, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Shigesato InoueDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Tomohiro OgawaDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Akihiro JoDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Satoru FukuyamaDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Mitsuyoshi NakaoDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Hiroaki OgataDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Mizuho A KidoDivision of Histology and Neuroanatomy, Department of Anatomy and Physiology, Faculty of Medicine, Saga University, Saga, Japan.
Sachiko TsukitaAdvanced Comprehensive Research Organization, Teikyo University, Tokyo, Japan.
Koichiro MatsumotoDepartment of Medicine, Division of Oral and Medical Management, Fukuoka Dental College, Fukuoka, Japan.
Isamu OkamotoDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.ORCID https://orcid.org/0000-0002-7587-6096

Funding

Coalition of Universities for Research Excellence Program (CURE) JPMXP1323015486JSPS KAKENHI JP24K11316NEXT Promotion of Development of a Joint Usage/Research System ProjectProgram of the Joint Usage/Research Center for Developmental MedicineResearch Program for Inter-University Research Network for High Depth Omics, IMEG, Kumamoto University
6 · The paper itself

Abstract

BACKGROUND AND

objectiveDespite improved respiratory symptoms after smoking cessation, patients with chronic obstructive pulmonary disease (COPD) remain susceptible to exacerbations and persistent airway inflammation, wherein the underlying mechanisms for sustained inflammation remain unclear. To address this knowledge gap, we investigated the persistence of airway epithelial barrier dysfunction in ex-smokers with COPD and examined the relationship between goblet cell hyperplasia and barrier dysfunction.

methodsWe analysed differentiated primary bronchial epithelial cells from never smokers with normal lung function, ex-smokers (> 10-year cessation), and current smokers with COPD using RNA sequencing, ATAC sequencing, and single-cell analyses to examine barrier function and cell differentiation.

resultsGenes associated with ciliary formation and motility were progressively downregulated from never smokers to ex-smokers to current smokers with COPD. The expression of junction-associated molecules was decreased in both ex-smokers and current smokers, showing a significant inverse correlation with the proportion of MUC5AC-positive cells. Single-cell analyses revealed distinct alterations in cell differentiation trajectories, particularly persistent goblet cell hyperplasia associated with increased expression of the transcription factor SPDEF, linked to epigenetic changes in the NKX2-1 gene regulatory regions.

conclusionEpigenetic mechanisms maintain persistent alterations in airway epithelial differentiation after smoking cessation, leading to mucus-producing cell hyperplasia through dysregulation of the NKX2-1/SPDEF axis. This hyperplasia correlates with reduced junction-associated molecule expression and subsequent barrier dysfunction. Therapeutic strategies targeting epithelial barrier restoration and/or normalisation of epigenetic dysregulation may benefit patients with COPD, even after smoking cessation.

Indexed as

Epigenesis, GeneticGoblet CellsProto-Oncogene Proteins c-etsPulmonary Disease, Chronic ObstructiveThyroid Nuclear Factor 1AgedCell DifferentiationEpithelial CellsFemaleHumansHyperplasiaMaleMiddle AgedRespiratory MucosaSmokingSmoking CessationNKX2-1 protein, humanProto-Oncogene Proteins c-etsSPDEF protein, humanThyroid Nuclear Factor 1airway epithelial barrier functionchronic obstructive pulmonary diseaseepigeneticsgoblet cellssingle‐cell analysis

Identifiers

PMID41559520
PMCPMC13125390

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.