• Alexander Gelbard, Meghan H Shilts, Austin Hoke, Britton Strickland, Kevin Motz, Hsiu-Wen Tsai, Helen Boone, Wonder P Drake, Celestine Wanjalla, SmithPaula MarincolaPMDepartment of Surgery, Vanderbilt University Medical Center, Nashville, TN., Hunter Brown, Jason Powell, Marisol Ramirez-Solano, James B Atkinson, John Simpson, Seesandra V Rajagopala, Simon Mallal, Quanhu Sheng, Alexander T Hillel, and Suman R Das.
• Department of Otolaryngology-Head & Neck Surgery, Vanderbilt University Medical Center, Nashville, TN.
• J. Am. Coll. Surg. 2025 Feb 4.

BackgroundIdiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult Caucasian women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Disease rarity and wide geographic patient distribution has previously limited substantive mechanistic investigation into iSGS pathogenesis.Study DesignHarnessing 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.ResultsAirway epithelium in iSGS patients 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 iSGS patients rather than disrupted bacterial community structure. However, animal models confirm 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 iSGS patients and healthy controls. Clinical outcome data from iSGS patients suggests surgical extirpation of airway scar and reconstitution with unaffected tracheal mucosa halts the progressive fibrosis.ConclusionOur novel data support an iSGS disease model where 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.

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