Interferon-γ treatment of human laryngotracheal stenosis–derived fibroblasts

Kevin Motz, Idris Samad, Linda X. Yin, Michael K. Murphy, Madhavi Duvvuri, Dacheng Ding, Alexander Tell Hillel

Research output: Contribution to journalArticle

Abstract

IMPORTANCE: Laryngotracheal stenosis (LTS) is a fibroproliferative disorder of the glottis, subglottis, and trachea. In models of fibrosis from other organ systems, the CD4+ T-cell response has been shown to regulate extracellular matrix deposition. Specifically, helper T cell 2 (TH2) promotes fibrosis, whereas TH1 and associated cytokines have been shown to be antifibrotic. However, this antifibrotic effect of the TH1 response has not been demonstrated in LTS. OBJECTIVE: To determine whether the TH1 cytokine interferon-γ inhibits the function of LTS-derived fibroblasts in vitro. DESIGN, SETTING, AND PARTICIPANTS: This in vitro controlled study included 6 patients with iatrogenic LTS undergoing routine surgical subglottic and tracheal dilation at a single institution. Fibroblasts were isolated from biopsy specimens of laryngotracheal scar and normal-appearing trachea. The presence of fibroblasts was confirmed by an immunohistochemical analysis. Laryngotracheal stenosis–derived fibroblasts were treated with interferon-γ and compared with untreated controls (2 sets of untreated, LTS-derived fibroblasts [media did not contain interferon-γ]) and normal airway fibroblasts (fibroblasts isolated from normal trachea). Data were collected from August 2015 through June 2016. INTERVENTIONS: Treatment with interferon-γ, 10 ng/mL. MAIN OUTCOMES AND MEASURES: Cellular proliferation, fibrosis gene expression (using quantitative reverse transcription polymerase chain reaction analysis), soluble collagen, and cellular histologic features were assessed. RESULTS: Among the 6 patients (6 women; mean [SD] age, 38.3 [17.2] years), LTS-derived fibroblast proliferation was reduced in patients who received interferon-γ treatment compared with untreated controls on days 3 (mean difference, −6515 cells; 95% CI, −10 630 to −2600 cells) to 6 (mean difference, −47 521 cells; 95% CI, −81 285 to −13 757 cells). Interferon-γ treatment reduced collagen types I and III gene expression by 86% and 68%, respectively, and resulted in lower total collagen production (10.94 vs 14.89 μg/mL). In addition, interferon-γ treatment resulted in a 32% reduction in expression of transforming growth factor β in LTS-derived fibroblasts. CONCLUSIONS AND RELEVANCE: Interferon-γ reduced proliferation, soluble collagen production, and collagen expression in LTS-derived fibroblasts while also reducing the expression of the profibrotic cytokine transforming growth factor β. These findings suggest that therapeutics aimed at increasing interferon-γ and the TH1 response could attenuate LTS.

Original languageEnglish (US)
Pages (from-to)1134-1140
Number of pages7
JournalJAMA Otolaryngology - Head and Neck Surgery
Volume143
Issue number11
DOIs
Publication statusPublished - Nov 1 2017

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ASJC Scopus subject areas

  • Surgery
  • Otorhinolaryngology

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