Idiopathic Subglottic Stenosis and the Epithelial Interface of Host and Environment
- PMID: 39902917
- PMCID: PMC12266974
- DOI: 10.1097/XCS.0000000000001340
Idiopathic Subglottic Stenosis and the Epithelial Interface of Host and Environment
Abstract
Background: Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult White women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Disease rarity and wide geographic patient distribution have previously limited substantive mechanistic investigation into iSGS pathogenesis.
Study design: Harnessing pathogenic mucosa from an international iSGS patient cohort and single-cell RNA sequencing, we provide an unbiased characterization of the cell subsets present in the proximal airway scar and detail their molecular phenotypes.
Results: Airway epithelium in patients with iSGS is depleted of basal progenitor cells and the residual epithelial cells acquire a mesenchymal phenotype. Observed displacement of bacteria beneath the lamina propria provides functional support for the molecular evidence of epithelial dysfunction. Matched superficial and deep tissue microbiomes support displacement of the native microbiome into the lamina propria of patients iSGS rather than disrupted bacterial community structure. However, animal models confirm that bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity. Human samples from iSGS airway scar demonstrate adaptive immune activation in response to the proximal airway microbiome of both matched patients with iSGS and healthy controls. Clinical outcome data from patients with iSGS suggests that surgical extirpation of airway scar and reconstitution with unaffected tracheal mucosa halts the progressive fibrosis.
Conclusions: Our novel data support an iSGS disease model in which epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. Overall, these results refine our understanding of iSGS and implicate shared pathogenic mechanisms with distal airway fibrotic diseases.
Copyright © 2025 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.
Update of
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Idiopathic subglottic stenosis arises at the epithelial interface of host and pathogen.Res Sq [Preprint]. 2023 May 19:rs.3.rs-2945067. doi: 10.21203/rs.3.rs-2945067/v1. Res Sq. 2023. Update in: J Am Coll Surg. 2025 Aug 1;241(2):180-192. doi: 10.1097/XCS.0000000000001340. PMID: 37292825 Free PMC article. Updated. Preprint.
References
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- Maldonado F, Loiselle A, Depew ZS, et al. Idiopathic subglottic stenosis: an evolving therapeutic algorithm. Laryngoscope. 2014;124(2):498–503. - PubMed
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- Gnagi SH, Howard BE, Anderson C, Lott DG. Idiopathic Subglottic and Tracheal Stenosis: A Survey of the Patient Experience. Ann Otol Rhinol Laryngol. 2015;124(9):734–9. - PubMed
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