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Objective To elucidate the role of hypoxia and inflammatory pathways in the pathogenesis of iatrogenic laryngotracheal stenosis (iLTS). Study Design (1) Examination of mucosal surface gene expression in human iLTS. (2) In vitro comparison of normal and scar laryngotracheal fibroblasts under normoxic and hypoxic conditions. Setting Tertiary care hospital in a research university (2012-2016). Subjects and Methods Brush biopsies were obtained from normal laryngotracheal tissue and scar in iLTS patients; gene expression was compared. Fibroblasts were isolated from normal and scarred trachea and grown in vitro in either a 1% O 2 or normoxic environment. Cell growth and gene and protein expression were compared. Statistical analysis utilized a multilevel mixed effects model. Results Expression of IL-6 (fold change = 2.8, P < .01), myofibroblast marker αSMA (fold change = 3.0, P = .01), and MMP13 (fold change = 5.4, P = .02) was significantly increased in scar biopsy samples as compared to normal. Under hypoxic conditions in vitro, normal laryngotracheal fibroblasts proliferated significantly faster (n = 8, P < .01 each day). Expression of IL-6 (n = 8, fold change = 2.6, P < .01) increased significantly after 12 hours under hypoxia. Expression of αSMA (n = 8, fold change= 2.0, P = .03), COL1 (n = 8, fold change = 1.1, P = .03), and MMP13 (n = 8, fold change = 1.6, P = .01) increased significantly after 48 hours under hypoxia. Scar fibroblasts also proliferated significantly faster under hypoxic conditions but did not display the same expression profile. Conclusion Human iLTS scar has a myofibroblast phenotype. Under hypoxic conditions in vitro, normal laryngotracheal fibroblasts can transdifferentiate into a similar phenotype. These changes may be mediated by IL-6, a fibrosis-related cytokine.

Objective Laryngotracheal stenosis (LTS) is a fibrotic process that narrows the upper airway and has a significant impact on breathing and phonation. Iatrogenic injury from endotracheal and/or tracheostomy tubes is the most common etiology. This study investigates differences in LTS etiologies as they relate to tracheostomy dependence and dilation interval. Study Design Case series with chart review. Setting Single-center tertiary care facility. Subjects and Methods Review of adult patients with LTS was performed between 2004 and 2015. The association of patient demographics, comorbidities, disease etiology, and treatment modalities with patient outcomes was assessed. Multiple logistic regression analysis and Kaplan-Meier analysis were performed to determine factors associated with tracheostomy dependence and time to second procedure, respectively. Results A total of 262 patients met inclusion criteria. Iatrogenic patients presented with greater stenosis ( P = .023), greater length of stenosis ( P = .004), and stenosis farther from the vocal folds ( P < .001) as compared with other etiologies. Iatrogenic patients were more likely to be African American, use tobacco, and have obstructive sleep apnea, type II diabetes, hypertension, chronic obstructive pulmonary disease, or a history of stroke. Iatrogenic LTS (odds ratio [OR] = 3.1, 95% confidence interval [95% CI] = 1.2-8.2), Cotton-Myer grade 3-4 (OR = 2.6, 95% CI = 1.1-6.4), and lack of intraoperative steroids (OR = 2.9, 95% CI = 1.2-6.9) were associated with tracheostomy dependence. Nonsmokers, patients without tracheostomy, and idiopathic LTS patients had a significantly longer time to second dilation procedure. Conclusion Iatrogenic LTS presents with a greater disease burden and higher risk of tracheostomy dependence when compared with other etiologies of LTS. Comorbid conditions promoting microvascular injury-including smoking, COPD, and diabetes-were prevalent in the iatrogenic cohort. Changes in hospital practice patterns to promote earlier tracheostomy in high-risk patients could reduce the incidence of LTS.