Idiopathic subglottic stenosis is associated with activation of the inflammatory IL‐17A/IL‐23 axis

Abstract

Rationale Idiopathic subglottic stenosis (iSGS) is a rare and devastating extrathoracic obstruction involving the lower laryngeal and upper tracheal airway. It arises without known antecedent injury or associated disease process. Persistent mucosal inflammation and a localized fibrotic response are hallmarks of the disease. Despite the initial clinical description of iSGS more than 40 year ago, there have been no substantive investigations into the pathogenesis of this enigmatic and progressive airway obstruction. Objectives In these studies, we present the initial characterization of the molecular pathogenesis underlying the fibrosing phenotype of iSGS. Methods Utilizing 20 human iSGS and healthy control specimens we applied histologic, immunohistochemical, molecular and immunologic techniques. Main Results We demonstrate significant activation of the canonical IL-23/IL-17A pathway in the tracheal mucosa of iSGS patients, as well as identify γδ T cells as the primary cellular source of IL-17A. Conclusions Our results suggest that aberrant mucosal immune activation is a component in of the pathogenesis of iSGS. Most critically, our work offers new targets for future therapeutic intervention. Level of Evidence NA

T‐Helper 2 Lymphocyte Immunophenotype Is Associated With Iatrogenic Laryngotracheal Stenosis

“…Through a combination of gene and protein analysis of human and mouse specimens, the proinflammatory cytokine IL‐4 was consistently expressed at higher levels than normal controls, supporting a T H 2 immunophenotype in iLTS. These findings presented here expand on recent publications investigating immune cell presence in murine and human ILTS . Although Ghosh et al implicated lymphocytes in murine laryngotracheal stenosis, the data presented here more specifically nominate CD4 + T‐lymphocytes as the critical adaptive immune cells associated with fibrosis.…”

Quantification of Inflammatory Markers in Laryngotracheal Stenosis

“…In iSGS the IL-23/IL-17A signaling axis has been demonstrated to be upregulated compared to iLTS and suggests that there are differences in the pathogenesis of this disease as it relates to the immune response. 16 The differences in INF-Υ expression between the two subgroups of LTS in this study further supports that different underlying immunological mechanisms in iSGS and iLTS exist. In the current study, when samples were stratified into idiopathic and iatrogenic subgroups gene expression of INF-Υ was significantly elevated in the iSGS group.…”

Targeting metabolic abnormalities to reverse fibrosis in iatrogenic laryngotracheal stenosis

“…The most predominant etiology of LTS is iatrogenic (iLTS), in which intubation injury to the epithelium promotes prolonged subepithelial inflammation and subsequently fibroblast proliferation and collagen deposition . This dysregulated wound‐healing response is driven by complex signaling between epithelial cells, immune mediators, and fibroblasts, which stimulates deposition of excessive collagen, leading to airway narrowing . Mild airway restriction secondary to this narrowing impacts quality of life, and in severe cases requires surgical intervention to relieve the resultant dyspnea.…”