Response of an ovine laryngeal injury model to a novel fibrosis inhibitor

Allen, Jacqueline

doi:10.1111/ans.13852

Cited by 3 publications

(5 citation statements)

References 31 publications

(94 reference statements)

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Section: Discussionsupporting

confidence: 85%

“…Changes in the VF secondary to injury were confirmed including reduction of epithelial thickness, reduction in collagen density at 1 month and loss of elastin (matching previously published data in this model). 25 Both halofuginone and dexamethasone moderated collagen loss but halofuginone treatment was also protective against elastin depletion. In addition, Smad3 binding in both halofuginone and dexamethasone‐treated sheep was significantly less prominent than in triamcinolone‐treated sheep suggesting modulation of the Smad3 fibrotic pathway.…”

Section: Discussionmentioning

confidence: 95%

“…(*Only two control sheep were added to this study as the Animal Ethics Committee recommended reducing animal numbers and evaluating data from a prior study including seven control sheep with the same right VF injury. 25 )…”

Section: Methodsmentioning

confidence: 99%

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Effects of corticosteroids vs halofuginone on vocal fold wound healing in an ovine model

Allen

2021

Laryngoscope Investig Oto

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Objectives To evaluate antifibrotic effects of corticosteroids and halofuginone, a small molecule inhibitor of Smad3, in an ovine model of vocal fold (VF) injury. Methods Thirty sheep, using a paired study design, underwent controlled right VF injury by biopsy and then were treated with either no treatment, oral dexamethasone, intralesional triamcinolone, or oral halofuginone. Larynges were evaluated for histological evidence of fibrosis, immunohistochemical presence of Smad3, and vibratory parameters. Outcomes were compared across treatment groups. Results Following injury, VF collagen density decreased in both halofuginone‐treated and dexamethasone‐treated sheep but not in triamcinolone treated sheep. A significant difference was noted between halofuginone and triamcinolone treated sheep (27.8% vs 37%, P = .017). Elastin was preserved postinjury by halofuginone treatment in contrast with all steroid treated animals where significant loss of elastin was noted (P <.05). Smad3 staining was up‐regulated at all injury sites compared to normal left VFs however halofuginone and dexamethasone treatment reduced Smad3 activity significantly whereas triamcinolone treatment did not (P <.05). Ex‐vivo stroboscopic evaluation demonstrated mucosal wave in all excised larynges with a normalized glottal gap less than 3, suggesting adequate glottal closure. Conclusions VF injury in an ovine model results in a wound response able to be modified by Smad3 inhibitor, halofuginone, with benefit to vibratory function. Halofuginone treated sheep demonstrated reduced collagenization of lamina propria with greater elastin density after injury, than sheep treated with either steroid medication. These data support this pathway as a suitable target for manipulation to prevent or reverse fibrosis in the glottis and restore voice quality. Level of Evidence: NA.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 95%

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Effects of corticosteroids vs halofuginone on vocal fold wound healing in an ovine model

Allen

2021

Laryngoscope Investig Oto

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“…Ertugrul et al 16 administered halofuginone topically for 5 minutes in a rat model of subglottic trauma and reported a preventive effect of halofuginone on fibrosis and stenosis. In another study, Allen 26 administered halofuginone orally for 10 weeks and observed a trend toward a decrease in the collagen density after injury in an ovine laryngeal injury model. Halofuginone can be administered orally, intravenously, intraperitoneally, and topically.…”

Section: Discussionmentioning

confidence: 97%

The Effects of Halofuginone on Wound Healing in the Rat Nasal Mucosa

Ceylan

Uysal

Sökücü

et al. 2019

Am J Rhinol�Allergy

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Background Halofuginone is an alkaloid febrifugine analogue and bioactive molecule that was isolated incidentally from the Dichroa febrifuga plant. The therapeutic efficacy of halofuginone in parasitic infections, scleroderma, inflammation, and fibrosis-related diseases, as well as in some types of cancer, has been previously reported. The effects of halofuginone on nasal mucosal damage are not yet known. Objective The aim of this study was to investigate the potential effect of topically applied halofuginone on wound healing in the mechanically injured nasal mucosa of rats. Methods A unilateral mucosal wound was created in the nasal cavity of 32 rats (aged 4 weeks) using the brushing technique. These rats were randomly divided into 4 groups. Although the control group did not receive an intervention, a dry pad, a saline-impregnated pad, or a pad impregnated with halofuginone were placed in the rats of the other 3 groups and left for 5 minutes. Rats were sacrificed on the 14th day, and a histological examination was performed. The nasal mucosa was assessed via hematoxylin-eosin and Masson’s trichrome staining. Results There were no statistically significant differences in epithelial thickness, inflammation, goblet cell formation, and epithelial disarray values between the halofuginone group and the control group ( P > .05). The subepithelial thickness was significantly decreased in the saline-treated group and the halofuginone-treated group ( P < .05), but a significantly lower level of subepithelial fibrosis was only observed in the halofuginone group compared to the other groups ( P < .05). Conclusions Topical halofuginone administration reduces the development of fibrosis and subepithelial edema after experimentally induced nasal mucosal injury, but it does not exert therapeutic or preventive effects on epithelial damage, inflammation, and goblet cell hyperplasia.

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“…This process suppressed type 1A collagen production with minimal effect on other normal collagen subtypes. Allen et al demonstrated that administration of halofuginone resulted in decreased elastin and collagen deposition in acute VF injury using ovine in vivo model [112].…”

Section: New Strategies For Vf Scar Including Regenerative Medicinmentioning

confidence: 99%

Pathophysiology of Fibrosis in the Vocal Fold: Current Research, Future Treatment Strategies, and Obstacles to Restoring Vocal Fold Pliability

Kumai

2019

IJMS

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Communication by voice depends on symmetrical vibrations within the vocal folds (VFs) and is indispensable for various occupations. VF scarring is one of the main reasons for permanent dysphonia and results from injury to the unique layered structure of the VFs. The increased collagen and decreased hyaluronic acid within VF scars lead to a loss of pliability of the VFs and significantly decreases their capacity to vibrate. As there is currently no definitive treatment for VF scarring, regenerative medicine and tissue engineering have become increasingly important research areas within otolaryngology. Several recent reviews have described the problem of VF scarring and various possible solutions, including tissue engineered cells and tissues, biomaterial implants, stem cells, growth factors, anti-inflammatory cytokines antifibrotic agents. Despite considerable research progress, these technical advances have not been established as routine clinical procedures. This review focuses on emerging techniques for restoring VF pliability using various approaches. We discuss our studies on interactions among adipose-derived stem/stromal cells, antifibrotic agents, and VF fibroblasts using an in vitro model. We also identify some obstacles to advances in research.

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Response of an ovine laryngeal injury model to a novel fibrosis inhibitor

Abstract: In an ovine laryngeal injury model, administration of a fibrosis inhibitor resulted in altered elastin and collagen deposition after injury in the glottis. Further investigation is warranted to examine whether these tissue changes affect vocal fold dynamics.

Cited by 3 publications

References 31 publications

Effects of corticosteroids vs halofuginone on vocal fold wound healing in an ovine model

Effects of corticosteroids vs halofuginone on vocal fold wound healing in an ovine model

The Effects of Halofuginone on Wound Healing in the Rat Nasal Mucosa

Pathophysiology of Fibrosis in the Vocal Fold: Current Research, Future Treatment Strategies, and Obstacles to Restoring Vocal Fold Pliability

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