title: Radiation fibrosis of the vocal fold: from man to mouse.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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)-β increased in the lamina propria.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department Otolaryngology-Head and Neck Surgery, NYU Voice Center, New York University, New York, New York, USA. michael.johns2@emory.edu
authors.forename: Michael M
authors.initials: MM
authors.lastname: Johns
authors.forename: Vasantha
authors.initials: V
authors.lastname: Kolachala
authors.forename: Eric
authors.initials: E
authors.lastname: Berg
authors.forename: Susan
authors.initials: S
authors.lastname: Muller
authors.forename: Frances X
authors.initials: FX
authors.lastname: Creighton
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Branski
mesh_terms: D000818:Animals; D017209:Apoptosis; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression / Q000528:radiation effects*; D006258:Head and Neck Neoplasms / Q000532:radiotherapy; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D012313:RNA / Q000235:genetics; D011832:Radiation Injuries / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D011878:Radiotherapy / Q000009:adverse effects*; D060888:Real-Time Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014827:Vocal Cords / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*
chemical_list: D005353:Fibronectins; D016212:Transforming Growth Factor beta; D012313:RNA; D003094:Collagen