Hsiu-Wen Tsai1, Ioan Lina1, Kevin M Motz1, Liam Chung2,3, Dacheng Ding1, Michael K Murphy4, Michael Feeley5, Jennifer H Elisseeff2,3, Alexander T Hillel1. 1. Department of Otolaryngology Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A. 2. Bloomberg Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. 3. Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, U.S.A. 4. Department of Otolaryngology and Communication, State University of New York Upstate Medical University, Syracuse, New York, U.S.A. 5. Department of Biomedical Engineering, Widener University, Chester, Pennsylvania, U.S.A.
Abstract
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.
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.
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