Restoration of radiation therapy-induced salivary gland dysfunction in mice by post therapy IGF-1 administration

Abstract

BackgroundRadiotherapy for head and neck cancer results in severe and chronic salivary gland dysfunction in most individuals. This results in significant side effects including xerostomia, dysphagia, and malnutrition which are linked to significant reductions in patients' quality of life. Currently there are few xerostomia treatment approaches that provide long-term results without significant side effects. To address this problem we investigated the potential for post-therapeutic IGF-1 to reverse radiation-induced salivary gland dysfunction.MethodsFVB mice were treated with targeted head and neck radiation and significant reductions in salivary function were confirmed 3 days after treatment. On days 4-8 after radiation, one group of mice was injected intravenously with IGF-1 while a second group served as a vehicle control. Stimulated salivary flow rates were evaluated on days 30, 60, and 90 and histological analysis was performed on days 9, 30, 60, and 90.ResultsIrradiated animals receiving vehicle injections have 40-50% reductions in stimulated salivary flow rates throughout the entire time course. Mice receiving injections of IGF-1 have improved stimulated salivary flow rates 30 days after treatment. By days 60-90, IGF-1 injected mice have restored salivary flow rates to unirradiated control mice levels. Parotid tissue sections were stained for amylase as an indicator of functioning acinar cells and significant reductions in total amylase area are detected in irradiated animals compared to unirradiated groups on all days. Post-therapeutic injections of IGF-1 results in increased amylase-positive acinar cell area and improved amylase secretion. Irradiated mice receiving IGF-1 show similar proliferation indices as untreated mice suggesting a return to tissue homeostasis.ConclusionsPost-therapeutic IGF-1 treatment restores salivary gland function potentially through normalization of cell proliferation and improved expression of amylase. These findings could aid in the rational design of therapy protocols or drugs for the treatment of radiation-induced salivary gland dysfunction in patients who have completed their anti-cancer therapies.

Growth Factors Polymerized Within Fibrin Hydrogel Promote Amylase Production in Parotid Cells

“…However, results of a subsequent study involving mice undergoing radiation treatment (which typically results in salivary gland dysfunction) indicate IGF-1 restores cell proliferation and amylase secretion. 41 Furthermore, both growth factors synergistically suppress apoptosis in salivary acinar cells. 37 Given these studies and because of the presence of EGF and IGF-1 in GFR-MG, we decided to test whether these growth factors polymerized within FH were able to show similar effects as those observed in Par-C10 and PGs when grown on the combined matrix (i.e., FH + GFR-MG).…”

P2X7 receptor activation induces inflammatory responses in salivary gland epithelium

“…P2X7R activation by BzATP perfusion induces apoptosis in wild-type SMG. Numerous studies (5,33,34,44,45) have indicated that apoptosis of salivary gland epithelial cells contributes to salivary gland dysfunction. The presence of apoptotic salivary gland epithelial cells in minor salivary gland biopsies has been reported in a number of patients with SS (40,82,87).…”

Botulinum Toxin Confers Radioprotection in Murine Salivary Glands

“…Loss of acinar cells through apoptosis occurs during the acute phase. This process is p53 dependent and can be reversed by immunoglobulin F-1, CDK inhibition, or Wnt/β-catenin activation (6)(7)(8)(9)(10)(11). Alternatively, membrane lipid peroxidation is thought to induce damage to the secretory granules and acinar cellular lysis (12,13).…”