Radiation fibrosis of the vocal fold: From man to mouse

Abstract

Objectives To characterize fundamental late tissue effects in the human vocal fold following radiation therapy. To develop a murine model of radiation fibrosis 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 were identified from pathology archives. Histomorphometry, immunohistochemistry, and whole-genome microarray as well as real-time transcriptional analyses was 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. Conclusion Human irradiated vocal folds demonstrate molecular changes leading to fibrosis that underlie loss of vocal fold pliability that occurs in patients following laryngeal irradiation. Irradiated murine tissue demonstrates similar findings, and this mouse model may have utility in creating prevention and treatment strategies for vocal fold radiation fibrosis.

RETRACTED: Laryngeal Function After Radiation Therapy

“…A fibroblastic response related to acute oxidative injury with resulting cell damage, ischemia, and inflammatory response has been hypothesized. 23 Despite these changes in some patients, the loss of vocal fold pliability chronically related to radiation fibrosis is thought to lead to hoarseness, inability to be heard over noise, and vocal strain with communication. The morbidity from radiation to the vocal folds for glottic larynx tumors has been described extensively and more recent data have also confirmed some decreased laryngeal function following radiation for nonglottic head and neck tumors.…”

Management of Dysphonia After Radiation Therapy

“…23,24 However, laryngeal salivary tissue is damaged by radiation and can result in laryngeal desiccation that can affect vocal performance. 11,25 There are no published data regarding whether this is an early-or latephase response to radiation, but our clinical experience indicates that desiccation can occur in either timeframe. Patients should maintain adequate systemic hydration to maximize vocal function during and after radiation treatment.…”

“…As the acute phase subsides, a fibroblastic response develops, resulting in long-term deposition of collagen and fibrosis. 11 Fibrosis leads to reduced tissue viscosity, which dampens the normal vibratory patterns that are required for normal voice. 12 These tissue changes make rehabilitation difficult because there is currently no therapy that can improve the vibratory capacity of the vocal folds.…”

Polarization response of second-harmonic images for different collagen spatial distributions

“…[6][7][8] Although it is well known that polarization modulates the spatial distribution of the SHG signal from collagen fibers, this has only been analyzed in detail for regular patterns [9][10][11] (i.e., when the fibers are aligned along a preferential direction and the SHG signal is coherently produced). 12 However, the spatial distribution is not always uniform 13,14 and can be modified with aging, 3,15,16 mechanical damage, 17 and pathological processes [18][19][20] among others. In those cases, the response of the tissue to incident polarization might be noticeably different.…”