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Pharmacological activation of the EDA/EDAR signaling pathway restores salivary gland function following radiation-induced damage.

Hill G, Headon D, Harris ZI, Huttner K, Limesand KH - PLoS ONE (2014)

Bottom Line: Radiotherapy of head and neck cancers often results in collateral damage to adjacent salivary glands associated with clinically significant hyposalivation and xerostomia.In addition, salivary gland structure and homeostasis is restored to pre-irradiation levels.These results suggest that transient activation of pathways involved in salivary gland development could facilitate regeneration and restoration of function following damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutritional Sciences, University of Arizona, Tucson, Arizona, United States of America.

ABSTRACT
Radiotherapy of head and neck cancers often results in collateral damage to adjacent salivary glands associated with clinically significant hyposalivation and xerostomia. Due to the reduced capacity of salivary glands to regenerate, hyposalivation is treated by substitution with artificial saliva, rather than through functional restoration of the glands. During embryogenesis, the ectodysplasin/ectodysplasin receptor (EDA/EDAR) signaling pathway is a critical element in the development and growth of salivary glands. We have assessed the effects of pharmacological activation of this pathway in a mouse model of radiation-induced salivary gland dysfunction. We report that post-irradiation administration of an EDAR-agonist monoclonal antibody (mAbEDAR1) normalizes function of radiation damaged adult salivary glands as determined by stimulated salivary flow rates. In addition, salivary gland structure and homeostasis is restored to pre-irradiation levels. These results suggest that transient activation of pathways involved in salivary gland development could facilitate regeneration and restoration of function following damage.

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Analysis of Edar expression following radiation and experimental design of study.(A) On day 0 the head and neck region of mice was exposed to a single dose of 5 Gy radiation. Edar expression (mRNA) in parotid salivary glands was determined on days 4–10 post-radiation as described in the materials and methods and graphed as fold over unirradiated (UT). Significant differences (p<0.05) were determined using an ANOVA followed by a Bonferroni post-hoc test. Treatment groups with the same lower case letters are not significantly different from each other. N = 4 mice per group. (B) Experimental design timeline. (C) Three days post-radiation stimulated salivary flow rates were determined as described in the materials and methods. Irradiated flow rates were normalized to corresponding unirradiated (UT) controls. There were 60 animals in the control (UT) and 62 animals in the irradiated group (5Gy). Significant difference (p<0.05) was determined by t-test and designated by an asterisk (*). All error bars represent standard error of the mean (SEM).
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pone-0112840-g001: Analysis of Edar expression following radiation and experimental design of study.(A) On day 0 the head and neck region of mice was exposed to a single dose of 5 Gy radiation. Edar expression (mRNA) in parotid salivary glands was determined on days 4–10 post-radiation as described in the materials and methods and graphed as fold over unirradiated (UT). Significant differences (p<0.05) were determined using an ANOVA followed by a Bonferroni post-hoc test. Treatment groups with the same lower case letters are not significantly different from each other. N = 4 mice per group. (B) Experimental design timeline. (C) Three days post-radiation stimulated salivary flow rates were determined as described in the materials and methods. Irradiated flow rates were normalized to corresponding unirradiated (UT) controls. There were 60 animals in the control (UT) and 62 animals in the irradiated group (5Gy). Significant difference (p<0.05) was determined by t-test and designated by an asterisk (*). All error bars represent standard error of the mean (SEM).

Mentions: Salivary flow rates were normalized by collection day to corresponding untreated group for each time point and analyzed by ANOVA with a Student-Newman-Keuls post-hoc test. For Figure 1C only, salivary flow rate comparison between unirradiated (UT) and irradiated (5Gy) was determined by t-test using Microsoft Excel. Real-time RT/PCR, vacuole area, amylase area and PCNA indices were analyzed by ANOVA with a Bonferroni post-hoc test. Statistical analysis of data and graph generation was completed using Graph-Pad software. All error bars represent standard error of the mean (SEM). Multiple comparison statistical differences are represented by lower case letters within individual graphs. Treatment groups with the same letters are not significantly different from each other. Therefore if a group is designated as “a” then it is statistically different from a group designated as “b” or “c”. If a group is designated as “ab” then it is not statistically different from a group designated as “a” or “b”.


Pharmacological activation of the EDA/EDAR signaling pathway restores salivary gland function following radiation-induced damage.

Hill G, Headon D, Harris ZI, Huttner K, Limesand KH - PLoS ONE (2014)

Analysis of Edar expression following radiation and experimental design of study.(A) On day 0 the head and neck region of mice was exposed to a single dose of 5 Gy radiation. Edar expression (mRNA) in parotid salivary glands was determined on days 4–10 post-radiation as described in the materials and methods and graphed as fold over unirradiated (UT). Significant differences (p<0.05) were determined using an ANOVA followed by a Bonferroni post-hoc test. Treatment groups with the same lower case letters are not significantly different from each other. N = 4 mice per group. (B) Experimental design timeline. (C) Three days post-radiation stimulated salivary flow rates were determined as described in the materials and methods. Irradiated flow rates were normalized to corresponding unirradiated (UT) controls. There were 60 animals in the control (UT) and 62 animals in the irradiated group (5Gy). Significant difference (p<0.05) was determined by t-test and designated by an asterisk (*). All error bars represent standard error of the mean (SEM).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4237357&req=5

pone-0112840-g001: Analysis of Edar expression following radiation and experimental design of study.(A) On day 0 the head and neck region of mice was exposed to a single dose of 5 Gy radiation. Edar expression (mRNA) in parotid salivary glands was determined on days 4–10 post-radiation as described in the materials and methods and graphed as fold over unirradiated (UT). Significant differences (p<0.05) were determined using an ANOVA followed by a Bonferroni post-hoc test. Treatment groups with the same lower case letters are not significantly different from each other. N = 4 mice per group. (B) Experimental design timeline. (C) Three days post-radiation stimulated salivary flow rates were determined as described in the materials and methods. Irradiated flow rates were normalized to corresponding unirradiated (UT) controls. There were 60 animals in the control (UT) and 62 animals in the irradiated group (5Gy). Significant difference (p<0.05) was determined by t-test and designated by an asterisk (*). All error bars represent standard error of the mean (SEM).
Mentions: Salivary flow rates were normalized by collection day to corresponding untreated group for each time point and analyzed by ANOVA with a Student-Newman-Keuls post-hoc test. For Figure 1C only, salivary flow rate comparison between unirradiated (UT) and irradiated (5Gy) was determined by t-test using Microsoft Excel. Real-time RT/PCR, vacuole area, amylase area and PCNA indices were analyzed by ANOVA with a Bonferroni post-hoc test. Statistical analysis of data and graph generation was completed using Graph-Pad software. All error bars represent standard error of the mean (SEM). Multiple comparison statistical differences are represented by lower case letters within individual graphs. Treatment groups with the same letters are not significantly different from each other. Therefore if a group is designated as “a” then it is statistically different from a group designated as “b” or “c”. If a group is designated as “ab” then it is not statistically different from a group designated as “a” or “b”.

Bottom Line: Radiotherapy of head and neck cancers often results in collateral damage to adjacent salivary glands associated with clinically significant hyposalivation and xerostomia.In addition, salivary gland structure and homeostasis is restored to pre-irradiation levels.These results suggest that transient activation of pathways involved in salivary gland development could facilitate regeneration and restoration of function following damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutritional Sciences, University of Arizona, Tucson, Arizona, United States of America.

ABSTRACT
Radiotherapy of head and neck cancers often results in collateral damage to adjacent salivary glands associated with clinically significant hyposalivation and xerostomia. Due to the reduced capacity of salivary glands to regenerate, hyposalivation is treated by substitution with artificial saliva, rather than through functional restoration of the glands. During embryogenesis, the ectodysplasin/ectodysplasin receptor (EDA/EDAR) signaling pathway is a critical element in the development and growth of salivary glands. We have assessed the effects of pharmacological activation of this pathway in a mouse model of radiation-induced salivary gland dysfunction. We report that post-irradiation administration of an EDAR-agonist monoclonal antibody (mAbEDAR1) normalizes function of radiation damaged adult salivary glands as determined by stimulated salivary flow rates. In addition, salivary gland structure and homeostasis is restored to pre-irradiation levels. These results suggest that transient activation of pathways involved in salivary gland development could facilitate regeneration and restoration of function following damage.

Show MeSH
Related in: MedlinePlus