Glutamine Inhibition Reduces Iatrogenic Laryngotracheal Stenosis.
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.
['Tsai|Hsiu-Wen|HW|0000-0002-2837-6769', 'Lina|Ioan|I|0000-0002-8619-7312', 'Motz|Kevin M|KM|', 'Chung|Liam|L|', 'Ding|Dacheng|D|', 'Murphy|Michael K|MK|', 'Feeley|Michael|M|', 'Elisseeff|Jennifer H|JH|', 'Hillel|Alexander T|AT|0000-0001-8471-5449']
D000818:Animals D001761:Bleomycin D003094:Collagen D003980:Diazooxonorleucine D004195:Disease Models, Animal D005347:Fibroblasts D005355:Fibrosis D015870:Gene Expression D005973:Glutamine D007049:Iatrogenic Disease D007274:Injections, Intraperitoneal D007829:Laryngostenosis D051379:Mice D009092:Mucous Membrane D011446:Prospective Studies D014132:Trachea D014135:Tracheal Stenosis
glutamine Laryngotracheal stenosis DON fibrosis glutaminase