Murine Model of Airway Fibrosis has Anatomic, Physiologic, and Molecular Congruency to Human iSGS.

Abstract

OBJECTIVE: To narrow knowledge gaps in the pathophysiology of idiopathic subglottic stenosis (iSGS) through comparison of a murine subglottic stenosis model with iSGS. STUDY DESIGN: In vivo animal study. SETTING: Academic institution. METHODS: Murine samples/measurements were obtained from mice that underwent chemomechanical injury with a wire brush and bleomycin. Human samples/measurements were obtained from iSGS patients. Anatomic, physiologic, and epithelial molecular data were collected using histology, human peak expiratory flow (PEF) and murine airway conductance, gene expression analysis with quantitative polymerase chain reaction, and protein analysis with quantitative immunohistochemistry. RESULTS: Anatomic patterns of scars at the subglottis and proximal trachea seen in the murine model are similar to iSGS patients. Subglottic stenosis (SGS) mice had a decrease (P&#x2009;=&#x2009;.0194) in airway conductance compared to healthy controls, similar to a decrease (P&#x2009;=&#x2009;.0001) in predilation PEF versus postdilation in iSGS patients. There was decreased epithelial gene expression of E-cadherin (ECAD) (P&#x2009;<&#x2009;0.01), occludin (OCLN) (P&#x2009;<&#x2009;.01), and cytokeratin-5 (CK5) (P&#x2009;<&#x2009;.05) and protein expression of ECAD&#xa0;(H/M: P&#x2009;<&#x2009;.001), OCLN (H: P&#x2009;<&#x2009;0.05, M: P&#x2009;<&#x2009;.001), and CK5 (H: P&#x2009;<&#x2009;.001, M: P&#x2009;<&#x2009;.01) in murine SGS and iSGS versus controls. CONCLUSION: The murine SGS model shows anatomic, physiologic, and molecular congruency with human iSGS, making it a reasonable model to investigate iSGS. The molecular similarities in epithelial barrier dysfunction suggest it may best be suited to explore epithelial mechanisms of iSGS and therapies directed at epithelial reconstitution. This model provides a foundation to collect data that will improve understanding of iSGS, and, ultimately, translate into more accurate animal models for future use.