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Войти в исследования Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · 2025
Localized Knockout of E-Cadherin in Subglottic Mucosa Increases Fibrosis.
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So Raymond J, Collins Samuel L, Chan-Li Yee, Lina Ioan, Gelbard Alexander, Motz Kevin M, Hillel Alexander T
Аннотация
OBJECTIVE: To assess the effects of localized subglottic knockout of E-cadherin (CDH1-/-) on survival, tracheal luminal thickness, and fibrotic gene expression in a mouse model of subglottic stenosis.
STUDY DESIGN: Case-control in vivo mouse study.
SETTING: Tertiary care academic hospital.
METHODS: Mice with loxP sites flanking E-cadherin underwent extratracheal placement of a fibrin-plasmin gel embedded with either CRE-expressing or control adenovirus. Mice then underwent chemomechanical injury to induce laryngotracheal stenosis, with harvest of subglottis/tracheas 21 days later. Immunofluorescence and Western blotting were used to confirm E-cadherin knockout. Outcomes of interest included Kaplan-Meier survival curves (n = 40), lamina propria thickness on hematoxylin-eosin (H&E) histology (n = 8), and fibrotic gene expression (n = 3).
RESULTS: Immunofluorescence and Western blotting confirmed decreased E-cadherin expression in CDH1-/-. On H&E, lamina propria thickness was greater in CDH1-/- mice (mean difference [95% CI] in μm, 107.2 [74.8-139.7], P < .001). Survival was significantly shorter for knockout mice relative to control (median survival in days, 5.0 vs 8.5; P = .007). Further, fibrotic gene expression of COL1 (mean difference [95% CI] in log-fold change, 11.5 [1.9-21.0]; P = .03), COL3 (31.0 [11.5-50.5]; P = .01), COL5 (6.8 [3.1-10.4]; P = .007), and FN1 (6.9 [1.3-12.6]; P = .03) was significantly greater relative to control.
CONCLUSION: CDH1-/- results in greater fibrosis and increased mortality, further supporting the role of epithelial barrier dysfunction in the pathogenesis of subglottic stenosis. Therapies that restore epithelial integrity may therefore represent a rational pharmacologic target.
STUDY DESIGN: Case-control in vivo mouse study.
SETTING: Tertiary care academic hospital.
METHODS: Mice with loxP sites flanking E-cadherin underwent extratracheal placement of a fibrin-plasmin gel embedded with either CRE-expressing or control adenovirus. Mice then underwent chemomechanical injury to induce laryngotracheal stenosis, with harvest of subglottis/tracheas 21 days later. Immunofluorescence and Western blotting were used to confirm E-cadherin knockout. Outcomes of interest included Kaplan-Meier survival curves (n = 40), lamina propria thickness on hematoxylin-eosin (H&E) histology (n = 8), and fibrotic gene expression (n = 3).
RESULTS: Immunofluorescence and Western blotting confirmed decreased E-cadherin expression in CDH1-/-. On H&E, lamina propria thickness was greater in CDH1-/- mice (mean difference [95% CI] in μm, 107.2 [74.8-139.7], P < .001). Survival was significantly shorter for knockout mice relative to control (median survival in days, 5.0 vs 8.5; P = .007). Further, fibrotic gene expression of COL1 (mean difference [95% CI] in log-fold change, 11.5 [1.9-21.0]; P = .03), COL3 (31.0 [11.5-50.5]; P = .01), COL5 (6.8 [3.1-10.4]; P = .007), and FN1 (6.9 [1.3-12.6]; P = .03) was significantly greater relative to control.
CONCLUSION: CDH1-/- results in greater fibrosis and increased mortality, further supporting the role of epithelial barrier dysfunction in the pathogenesis of subglottic stenosis. Therapies that restore epithelial integrity may therefore represent a rational pharmacologic target.