Drug delivery to the pediatric upper airway

Ghavimi, Soheila Ali Akbari; Gehret, Paul M.; Aronson, Matthew R.; Schipani, Rossana; Smith, Kyra W.Y.; Borek, Ryan C.; Germiller, John A.; Jacobs, Ian N.; Zur, Karen B.; Gottardi, Riccardo

doi:10.1016/j.addr.2021.04.004

Cited by 4 publications

(2 citation statements)

References 213 publications

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“…Following local injury, fibroblasts differentiate into myofibroblasts increasing size, stiffness, and contractility in the region. Fibrotic airway diseases, namely, subglottic stenosis (SGS), often occur following trauma to the airway during intubation, and that scar tissue build‐up progressively occludes the airway manifesting as phonation and breathing morbidities 7 . Furthermore, the persistence of the myofibroblast phenotype is characterized by increased alpha‐smooth muscle actin within fibroblasts; increased ECM deposition, assembly, and cross‐linking; and increased contractility all of which lead to scar tissue that progressively occludes the airway.…”

Section: Introductionmentioning

confidence: 99%

“…Fibrotic airway diseases, namely, subglottic stenosis (SGS), often occur following trauma to the airway during intubation, and that scar tissue build-up progressively occludes the airway manifesting as phonation and breathing morbidities. 7 Furthermore, the persistence of the myofibroblast phenotype is characterized by increased alpha-smooth muscle actin within fibroblasts; increased ECM deposition, assembly, and cross-linking; and increased contractility all of which lead to scar tissue that progressively occludes the airway. Understanding the fundamental mechanisms of native and myofibrotic fibroblast phenotypes, as well as how they respond to stimuli, is a prerequisite to fully comprehending scarring of the upper airway leading to the development of innovative therapeutic solutions.…”

Section: Introductionmentioning

confidence: 99%

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Modulated Fibrosis and Mechanosensing of Fibroblasts by SB525334 in Pediatric Subglottic Stenosis

et al. 2023

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ObjectiveSubglottic stenosis (SGS) may result from prolonged intubation where fibrotic scar tissue narrows the airway. The scar forms by differentiated myofibroblasts secreting excessive extracellular matrix (ECM). TGF‐β1 is widely accepted as a regulator of fibrosis; however, it is unclear how biomechanical pathways co‐regulate fibrosis. Therefore, we phenotyped fibroblasts from pediatric patients with SGS to explore how key signaling pathways, TGF‐β and Hippo, impact scarring and assess the impact of inhibiting these pathways with potential therapeutic small molecules SB525334 and DRD1 agonist dihydrexidine hydrochloride (DHX).MethodsLaryngeal fibroblasts isolated from subglottic as well as distal control biopsies of patients with evolving and maturing subglottic stenosis were assessed by α‐smooth muscle actin immunostaining and gene expression for α‐SMA, FN, HGF, and CTGF markers. TGF‐β and Hippo signaling pathways were modulated during TGF‐β1‐induced fibrosis using the inhibitor SB525334 or DHX and analyzed by RT‐qPCR for differential gene expression and atomic force microscopy for ECM stiffness.ResultsSGS fibroblasts exhibited higher α‐SMA staining and greater inflammatory cytokine and fibrotic marker expression upon TGF‐β1 stimulation (p < 0.05). SB525334 restored levels to baseline by reducing SMAD2/3 nuclear translocation (p < 0.0001) and pro‐fibrotic gene expression (p < 0.05). ECM stiffness of stenotic fibroblasts was greater than healthy fibroblasts and was restored to baseline by Hippo pathway modulation using SB525334 and DHX (p < 0.01).ConclusionWe demonstrate that distinct fibroblast phenotypes from diseased and healthy regions of pediatric SGS patients respond differently to TGF‐β1 stimulation, and SB525334 has the superior potential for subglottic stenosis treatment by simultaneously modulating TGF‐β and Hippo signaling pathways.Level of EvidenceN/A Laryngoscope, 2023

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modulated Fibrosis and Mechanosensing of Fibroblasts by SB525334 in Pediatric Subglottic Stenosis

et al. 2023

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Azithromycin Prevents Subglottic Stenosis in Mice

Ghaderi,

Aronson,

Mehta

et al. 2024

The Laryngoscope

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ObjectivePediatric subglottic stenosis (SGS) is characterized by subglottic narrowing which occurs when pathological fibroblasts deposit extracellular matrix that reduces airway patency. Recent clinical observations have suggested that azithromycin may have favorable impacts on SGS reduction while treating airway infections; furthermore, our recent work in mice demonstrated that the airway microbiome influences SGS. In this work, we characterize the protective effect of azithromycin as an immunomodulatory and antibacterial therapeutic against subglottic stenosis.MethodsImmunomodulatory and antifibrotic effects of azithromycin were assessed on TGF‐β1‐stimulated airway fibroblasts at 10 μg/mL for 5 days. Changes in gene expression were quantified by RT‐qPCR and myofibroblast differentiation by α‐SMA immunostaining. Murine airways were pretreated (2‐weeks) with intranasal azithromycin before SGS injury by a twisted wire brush. Disease severity and immune response were characterized by histology and immunostaining for immune cells.ResultsIn vitro, azithromycin treatment of TGF‐β1‐stimulated fibroblasts exhibited strong reductions in extracellular matrix (COL1A1, LOX) and myofibroblast‐related gene expression (ACTA2). Notably, there was a significant reduction in pro‐fibrotic expression, which was observed with 10 μg/mL azithromycin. Immunostaining of fibroblasts for α‐SMA revealed strong reductions in the number of positive‐staining cells and the intensity of each positive cell. In vivo, azithromycin exhibited a significant decrease in lamina propria thickness indicative of reduced stenosis with associated changes in T‐cell infiltration.ConclusionsOverall, we show azithromycin prevents pro‐fibrotic gene expression and myofibroblast differentiation and can help protect mice from developing SGS. This introduces azithromycin as a potential treatment for SGS.Level of EvidenceNA Laryngoscope, 2024

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