In vivo and in vitro models of ionizing radiation to the vocal folds

Saltman, Benjamin; Kraus, Dennis H.; Szeto, Hazel; Parashar, Bhupesh; Ghossein, Ronald; Felsen, Diane; Branski, Ryan C.

doi:10.1002/hed.21212

Cited by 12 publications

(23 citation statements)

References 17 publications

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“…Increased expression of MMP-1 and TGF-β has been seen previously following single doses of radiation in immortalized human VFF. 7 However, these increases were observed with higher doses of radiation (5-20 Gy) than that used in the current study as well as only 1 hour following treatment. Furthermore, within 2 hours, a fractionated radiation scheme with dosing similar to that used here induces alterations in the expression of a variety of genes-related ECM remodeling in subcutaneous fibroblasts.…”

Section: Discussioncontrasting

confidence: 57%

“…A similar experimental design has been utilized previously to investigate the effect of radiation on VFF gene expression. 7 Growth arresting cells in serum-free media also reduces the influence of cell cycle parameters and serum on changes in gene expression and viability that could potentially influence experimental results. 12 In addition, in vivo most healthy fibroblasts exist in a relatively quiescent state, G0 and G1 state.…”

Section: Methodsmentioning

confidence: 99%

“…1,6 Similar findings have been observed in vocal folds from mice and rats examined 4 to 12 weeks following completion of radiation treatment. 6,7 …”

Section: Introductionmentioning

confidence: 99%

“…To date, only one investigation has reported on how radiation affects VFF. 7 More work is desperately needed in this area to elucidate how VFF may contribute to early and late vocal fold tissue changes associated with radiation therapy.…”

Section: Introductionmentioning

confidence: 99%

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Early Cellular Response to Radiation in Human Vocal Fold Fibroblasts

Erickson‐DiRenzo

Enos

Thibeault

2015

Ann Otol Rhinol Laryngol

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Objectives Radiation therapy is a common treatment strategy for laryngeal carcinoma. However, radiation is not without adverse side effects, especially toward healthy vocal fold tissue, which can lead to long-term impairments in vocal function. The objective of this preliminary study was to investigate early responses of healthy human vocal fold fibroblasts (VFF) to radiation. Methods VFF were exposed to a single or fractionated dose radiation scheme. Nonradiated VFF served as controls. Morphology of radiated and control VFF was subjectively examined. Quantitative polymerase chain reaction was used to evaluate the effect of radiation on extracellular matrix and inflammatory-related genes. VFF viability was investigated using a LIVE/DEAD and clonogenic assay. Results Single or fractioned dose radiated VFF were morphologically indistinguishable from control VFF. No significant differences in gene expression were observed following either radiation scheme and as compared to controls. Clonogenic assay revealed reduced VFF viability following the fractionated but not single dose scheme. No changes in viability were detected using the LIVE/DEAD assay. Conclusions We present one of the first investigations to evaluate early responses of healthy VFF to radiation. Findings will contribute to a growing body of literature seeking to elucidate the biological mechanisms underlying voice changes following radiation therapy for laryngeal carcinoma.

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Section: Discussioncontrasting

confidence: 57%

Section: Methodsmentioning

confidence: 99%

“…1,6 Similar findings have been observed in vocal folds from mice and rats examined 4 to 12 weeks following completion of radiation treatment. 6,7 …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Early Cellular Response to Radiation in Human Vocal Fold Fibroblasts

Erickson‐DiRenzo

Enos

Thibeault

2015

Ann Otol Rhinol Laryngol

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“…Once suitable specimens were identified and collected, control samples were also collected from three adult human male autopsy specimens with no history of intubation, laryngeal carcinoma, or radiation treatment. The specific markers of vocal fold fibrosis were chosen based on previously observed changes in animal vocal fold models, as well as in radiation‐induced pulmonary and renal fibrosis 6, 8–11…”

Section: Methodsmentioning

confidence: 99%

Radiation fibrosis of the vocal fold: From man to mouse

et al. 2012

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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.

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