Radiation fibrosis of the vocal fold: From man to mouse

Objectives/Hypothesis: To characterize fundamental late tissue effects in the human vocal fold following radiation therapy. To develop a murine model of radiation fibrosis in order to ultimately develop both treatment and prevention paradigms. Design: Translational study using archived human and fresh murine irradiated vocal fold tissue. Methods: 1) Irradiated vocal fold tissue from patients undergoing laryngectomy for loss of function from radiation fibrosis was identified from pathology archives. Histomorphometry, immunohistochemistry, and whole-genome microarray, as well as real-time transcriptional analyses, were performed. 2) Focused radiation to the head and neck was delivered to mice in a survival fashion. One month following radiation, vocal fold tissue was analyzed with histomorphometry, immunohistochemistry, and real-time PCR transcriptional analysis for selected markers of fibrosis. Results: Human irradiated vocal folds demonstrated increased collagen transcription, with increased deposition and disorganization of collagen in both the thyroarytenoid muscle and the superficial lamina propria. Fibronectin were increased in the superficial lamina propria. Laminin decreased in the thyroarytenoid muscle. Whole genome microarray analysis demonstrated increased transcription of markers for fibrosis, oxidative stress, inflammation, glycosaminoglycan production, and apoptosis. Irradiated murine vocal folds demonstrated increases in collagen and fibronectin transcription and deposition in the lamina propria. Transforming growth factor (TGF)-beta increased in the lamina propria. Conclusion: Human irradiated vocal folds demonstrate molecular changes leading to fibrosis that underlie loss of vocal fold pliability occurring in patients following laryngeal irradiation. The irradiated murine tissue demonstrates similar findings, and this mouse model may have utility in creating prevention and treatment strategies for vocal fold radiation fibrosis.