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Original Investigation
November 2017

Interferon-γ Treatment of Human Laryngotracheal Stenosis–Derived Fibroblasts

Author Affiliations
  • 1Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
JAMA Otolaryngol Head Neck Surg. 2017;143(11):1134-1140. doi:10.1001/jamaoto.2017.0977
Key Points

Question  Can the helper T cell 1 cytokine interferon-γ inhibit laryngotracheal stenosis–derived fibroblasts in vitro?

Findings  Interferon-γ reduced proliferation and collagen expression and production in laryngotracheal stenosis–derived fibroblasts while also reducing the expression of the profibrotic cytokine transforming growth factor β.

Meaning  Immunomodulatory strategies that focus on increasing interferon-γ may be able to attenuate the progression of laryngotracheal stenosis.

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.

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