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

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%,  = .017). Elastin was preserved postinjury by halofuginone treatment in contrast with all steroid treated animals where significant loss of elastin was noted ( <.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 ( <.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.