Reversal of Vocal Fold Mucosal Fibrosis Using siRNA against the Collagen-Specific Chaperone Serpinh1

Abstract

Vocal fold (VF) mucosal fibrosis results in substantial voice impairment and is recalcitrant to current treatments. To reverse this chronic disorder, anti-fibrotic therapies should target the molecular pathology of aberrant collagen accumulation in the extracellular matrix. We investigated the therapeutic potential of siRNA against Serpinh1 , a collagen-specific chaperone that enables cotranslational folding and assembly of procollagens in the endoplasmic reticulum. We implemented a previously validated siRNA construct, conducted transfection experiments using in vitro and in vivo rat models, and measured knockdown efficiency, dose responses, delivery strategies, and therapeutic outcomes. Liposome-mediated delivery of Serpinh1 -siRNA downregulated collagen production in naive and scar VF fibroblasts as well as naive VF mucosa; moreover, sustained Serpinh1 knockdown in fibrotic VF mucosa reversed scar-associated collagen accumulation within 4 weeks. Analysis of therapeutic effects at the transcriptome level showed evidence of cell cycle upregulation, catabolism, matrix disassembly, and morphogenesis. These findings indicate that Serpinh1 -siRNA holds potential as a molecular therapy for chronic VF mucosal fibrosis.

In vitro mechanical vibration down-regulates pro-inflammatory and pro-fibrotic signaling in human vocal fold fibroblasts

“…The gene expression level of ACTA2 , the gene encoding for α-SMA, also decreased, but without reaching statistical significance. It is known that VFF transformation into myofibroblasts during inflammation is accompanied by an increase in α-SMA, a well-established myofibroblast marker [ 29 , 69 , 70 ]. Myofibroblasts appear to be responsible for wound contraction as well as increased collagen deposition and could lead to a deterioration of VF oscillation [ 70 ].…”

The Role of Cytokines in Modulating Vocal Fold Fibrosis: A Contemporary Review

“…Therefore, to successfully treat VF scarring, the normal structure of the ECM and the pliability of the SLP need to be restored. 8,9 In the last 10 years, several cytokines have been thoroughly investigated. Among these cytokines, the available evidence regarding prostaglandin E2 10 (PGE2), granulocyte-macrophage colony-stimulating factor 11 (GM-CSF), interleukin-10 12 (IL-10), transforming growth factor-β3 13 (TGF-β3), basic fibroblast growth factor (bFGF), 14 and hepatocyte growth factor (HGF) 15 suggests that cytokine treatment improves subjective parameters, histological examination results, and cell fibrosis-related behavior and shows potential for restoring VF scars.…”

Phlorotannins ameliorate extracellular matrix production in human vocal fold fibroblasts and prevent vocal fold fibrosis via aerosol inhalation in a laser‐induced fibrosis model

“…for patients due to changes in biomechanical properties caused by excessive accumulation of the ECM (Hiwatashi et al, 2017;Kishimoto et al, 2019). Therapeutic approaches to VF fibrosis include scar excision, biomaterial injection or implantation, and localized steroid injection.…”

“…For example, VF fibrosis can arise due to various forms of trauma (e.g., irradiation, intubation, and surgery), inflammatory responses (e.g., laryngitis and dust), and iatrogenic causes (Hiwatashi, Bing, Kraja, & Branski, 2017; Kumai, 2019). VF fibrosis can also lead to intractable dysphonia, including substantial communication difficulties, insufficient glottal closure, and a reduction in the quality of life for patients due to changes in biomechanical properties caused by excessive accumulation of the ECM (Hiwatashi et al, 2017; Kishimoto et al, 2019). Therapeutic approaches to VF fibrosis include scar excision, biomaterial injection or implantation, and localized steroid injection.…”

“…Therapeutic approaches to VF fibrosis include scar excision, biomaterial injection or implantation, and localized steroid injection. However, most of these treatments produce inconsistent and unsatisfactory results (Kishimoto et al, 2019; Zhang et al, 2018). Therefore, there is a crucial need to develop a more consistent and effective strategy for VF fibrosis that has minimal side effects.…”