Journal article
Modulated Fibrosis and Mechanosensing of Fibroblasts by SB525334 in Pediatric Subglottic Stenosis
LARYNGOSCOPE, v 134(1)
Jan 2024
PMID: 37458368
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Objective: Subglottic 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-beta 1 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-beta and Hippo, impact scarring and assess the impact of inhibiting these pathways with potential therapeutic small molecules SB525334 and DRD1 agonist dihydrexidine hydrochloride (DHX). Methods: Laryngeal fibroblasts isolated from subglottic as well as distal control biopsies of patients with evolving and maturing subglottic stenosis were assessed by alpha-smooth muscle actin immunostaining and gene expression for alpha-SMA, FN, HGF, and CTGF markers. TGF-beta and Hippo signaling pathways were modulated during TGF-beta 1-induced fibrosis using the inhibitor SB525334 or DHX and analyzed by RT-qPCR for differential gene expression and atomic force microscopy for ECM stiffness. Results: SGS fibroblasts exhibited higher alpha-SMA staining and greater inflammatory cytokine and fibrotic marker expression upon TGF-beta 1 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). Conclusion: We demonstrate that distinct fibroblast phenotypes from diseased and healthy regions of pediatric SGS patients respond differently to TGF-beta 1 stimulation, and SB525334 has the superior potential for subglottic stenosis treatment by simultaneously modulating TGF-beta and Hippo signaling pathways.
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Details
- Title
- Modulated Fibrosis and Mechanosensing of Fibroblasts by SB525334 in Pediatric Subglottic Stenosis
- Publication Details
- LARYNGOSCOPE, v 134(1)
- Publisher
- WILEY; HOBOKEN
- Grant note
- This work was supported in part by the Children's Hospital of Philadelphia Research Institute (RG), the Frontier Program in Airway Disorders of the Children's Hospital of Philadelphia (INJ, RG), Foerderer Grant (RG), National Science Foundation (NSF) CMMI-1751898 (LH), the NSF Graduate Research Fellowship No. DGE 1845298 (MRA, RF), and Drexel University's Research and Engineering for Pediatrics by Interdisciplinary Collaboration Leveraging Education and Partnerships for Pediatric Healthcare (R-EPIC LEAP for Pediatric Healthcare) from the U. S. Department of Education's Graduate Assistance in Areas of National Need (GAANN) Program Fellowship (NP).
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:001031093900001
- Scopus ID
- 2-s2.0-85165000520
- Other Identifier
- 991021861175504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Medicine, Research & Experimental
- Otorhinolaryngology