Response of an ovine laryngeal injury model to a novel fibrosis inhibitor
Vocal fold scar has been studied in animals and humans. A predictable sequence of events and gene expression has been documented. These changes can be linked to morphological changes in glottic tissue. Critical signalling molecules flow through the transforming growth factor‐beta (TGF‐β) cascade with hyaluronic acid synthase (HAS), procollagen‐1 and ‐3 and matrix metalloproteinases (MMPs) all up‐regulated within 72 h.2 The consistency of the results, even in different species, suggests a relatively conserved vocal fold response. These cytokines influence the fibrous proteins of the vocal fold (collagen and elastin), with changes in both well documented following acute injury.3 In addition, the cytokine milieu regulates extracellular matrix (ECM) turnover which may be the ultimate determinant of vocal fold function.7
In order to investigate these processes further and develop novel targets and therapies, reliable, controlled experimental conditions are required – something difficult to achieve in human subjects. Animal models have been employed by many investigators in place of direct human trials.2 We have developed an ovine laryngeal injury model (Allen J, pers. comm., 2014) which demonstrated consistent histological changes following injury to the true vocal fold. We then sought to test a novel anti‐fibrotic agent, halofuginone, in this ovine model.
Halofuginone (Collgard Phamaceuticals, Tel Aviv, Israel), an inhibitor of the TGF‐β fibrotic cascade, has been developed and is in phase II human trials in the treatment of muscular dystrophy (Pines M, pers. comm., 2014). Halofuginone selectively inhibits smad‐3 activation of pro‐collagen mRNA transcription, limiting type 1A collagen production (scar collagen) with minimal effect on other collagen subtypes that are required for normal basement membrane recycling.2
This study examined halofuginone effects in wounded ovine larynges by histological evaluation.