The Laryngoscope · 2025
S100A8/A9 Promotes Fibrosis in Iatrogenic Laryngotracheal Stenosis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Mafla Laura M, Abd-Elazem Ibrahim, So Raymond J, Collins Samuel L, Chan-Li Yee, Hillel Alexander T, Motz Kevin M
Аннотация
OBJECTIVE: Iatrogenic Laryngotracheal Stenosis (iLTS) is a pathologic narrowing of the laryngotracheal airway secondary to intubation injury. Inflammation plays a critical role in iLTS pathogenesis. However, the local immune mediators promoting inflammation and subsequent fibrosis remain poorly understood. Transcriptomic analysis of iLTS specimens using single-cell RNA sequencing has revealed increased expression of the damage-associated molecular pattern (DAMP), S100A8/A9. The goal of this study is to define the role of S100A8/A9 in iLTS pathogenesis in vivo.
METHODS: S100A8/A9 expression was assessed using single-cell RNA sequencing and immunofluorescence in human iLTS and unaffected tracheal controls. To assess the fibrogenicity of S100A8/A9, iLTS-induced mice were treated with recombinant S100A8/A9 (0.1 mg/kg) or a vehicle control. Fibrosis was assessed by measurement of tracheal lamina propria (LP) thickness and fibrosis-related gene expression.
RESULTS: Immunofluorescence of human iLTS specimens demonstrated increased expression of S100A8/A9 in the LP compared to controls. In iLTS-induced mice, S100A8/A9 treatment resulted in greater LP thickness compared to control-treated mice (117.7 ± 23.72 vs. 67.7 ± 33.11 μM, p = 0.03). Gene expression analysis demonstrated a 4.42 ± 0.73 fold increase in Col1a1 expression in S100A8/A9-treated iLTS mice (p = 0.01). S100A8/A9's downstream regulatory protein MYD88 is increased in human iLTS and in iLTS mice treated with S100A8/A9.
CONCLUSION: S100A8/A9 is abundant in human iLTS and promotes fibrosis in a murine model. Targeting S100A8/A9 and its downstream signaling protein MYD88 may be an effective treatment strategy to attenuate iLTS. Investigation into therapies that target S100A8/A9 signaling is warranted.
LEVEL OF EVIDENCE: NA.
METHODS: S100A8/A9 expression was assessed using single-cell RNA sequencing and immunofluorescence in human iLTS and unaffected tracheal controls. To assess the fibrogenicity of S100A8/A9, iLTS-induced mice were treated with recombinant S100A8/A9 (0.1 mg/kg) or a vehicle control. Fibrosis was assessed by measurement of tracheal lamina propria (LP) thickness and fibrosis-related gene expression.
RESULTS: Immunofluorescence of human iLTS specimens demonstrated increased expression of S100A8/A9 in the LP compared to controls. In iLTS-induced mice, S100A8/A9 treatment resulted in greater LP thickness compared to control-treated mice (117.7 ± 23.72 vs. 67.7 ± 33.11 μM, p = 0.03). Gene expression analysis demonstrated a 4.42 ± 0.73 fold increase in Col1a1 expression in S100A8/A9-treated iLTS mice (p = 0.01). S100A8/A9's downstream regulatory protein MYD88 is increased in human iLTS and in iLTS mice treated with S100A8/A9.
CONCLUSION: S100A8/A9 is abundant in human iLTS and promotes fibrosis in a murine model. Targeting S100A8/A9 and its downstream signaling protein MYD88 may be an effective treatment strategy to attenuate iLTS. Investigation into therapies that target S100A8/A9 signaling is warranted.
LEVEL OF EVIDENCE: NA.