Glutamine Inhibition Reduces Iatrogenic Laryngotracheal Stenosis

Laryngoscope. 2021 Jul;131(7):E2125-E2130. doi: 10.1002/lary.29385. Epub 2021 Jan 12.


Objective/hypothesis: Glutamine inhibition has been demonstrated an antifibrotic effect in iatrogenic laryngotracheal stenosis (iLTS) scar fibroblasts in vitro. We hypothesize that broadly active glutamine antagonist, DON will reduce collagen formation and fibrosis-associated gene expression in iLTS mice.

Study design: Prospective controlled animal study.

Methods: iLTS in mice were induced by chemomechanical injury of the trachea using a bleomycin-coated wire brush. PBS or DON (1.3 mg/kg) were administered by intraperitoneal injection (i.p.) every other day. Laryngotracheal complexes were harvested at days 7 and 14 after the initiation of DON treatment for the measurement of lamina propria thickness, trichrome stain, immunofluorescence staining of collagen 1, and fibrosis-associated gene expression.

Results: The study demonstrated that DON treatment reduced lamina propria thickness (P = .025) and collagen formation in trichrome stain and immunofluorescence staining of collagen 1. In addition, DON decreased fibrosis-associated gene expression in iLTS mice. At day 7, DON inhibited Col1a1 (P < .0001), Col3a1 (P = .0046), Col5a1 (P < .0001), and Tgfβ (P = .023) expression. At day 14, DON reduced Co1a1 (P = .0076) and Tgfβ (P = .023) expression.

Conclusions: Broadly active glutamine antagonist, DON, significantly reduces fibrosis in iLTS mice. These results suggest that the concept of glutamine inhibition may be a therapeutic option to reduce fibrosis in the laryngotracheal stenosis.

Level of evidence: N/A Laryngoscope, 131:E2125-E2130, 2021.

Keywords: DON; Laryngotracheal stenosis; fibrosis; glutaminase; glutamine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin
  • Collagen / biosynthesis
  • Diazooxonorleucine / pharmacology*
  • Disease Models, Animal
  • Fibroblasts / drug effects
  • Fibrosis / chemically induced
  • Fibrosis / drug therapy
  • Gene Expression / drug effects
  • Glutamine / antagonists & inhibitors*
  • Iatrogenic Disease
  • Injections, Intraperitoneal
  • Laryngostenosis / chemically induced
  • Laryngostenosis / drug therapy*
  • Mice
  • Mucous Membrane / drug effects
  • Prospective Studies
  • Trachea / injuries*
  • Tracheal Stenosis / chemically induced
  • Tracheal Stenosis / drug therapy*


  • Diazooxonorleucine
  • Glutamine
  • Bleomycin
  • Collagen