Restoring the Secretory Function of Irradiation-Damaged Salivary Gland by Administrating Deferoxamine in Mice

Abstract

ObjectivesOne of the major side effects of radiotherapy for treatments of the head and neck cancer is the radiation-induced dysfunction of salivary glands. The aim of the present study is to investigate the efficacy of deferoxamine (DFO) to restore the secretory function of radiation-damaged salivary glands in mice.MethodsDFO (50 mg/kg/d) was administered intraperitoneally in C57BL/6 mice for 3 days before and/or after point-fixed irradiation (18 Gy) of submandibular glands. The total 55 mice were randomly divided into: (1) Normal group: mice received no treatment (n = 5); (2) Irradiation group (IR): mice only received irradiation (n = 5); (3) Pre-DFO group (D+IR) (n = 10); (4) Pre+Post DFO group (D+IR+D) (n = 10); (5) Post-DFO group (IR+D) (n = 10); (6) For each DFO-treated group, the mice were intraperitoneally injected with 0.1 ml sterilized water alone (by which DFO was dissolved) for 3 days before and/or after irradiation, and served as control. Sham1: Pre-sterilized water group (n = 5); sham2: Pre+Post sterilized water group (n = 5); sham3: Post-sterilized water group (n = 5). The salivary flow rate (SFR) was assessed at 30th, 60th and 90th day after irradiation, respectively. After 90 days, all mice were sacrificed and their submandibular glands were removed for further examinations.ResultsThe salivary glands showed remarkable dysfunction and tissue damage after irradiation. DFO restored SFR in the irradiated glands to a level comparable to that in normal glands and angiogenesis in damaged tissue was greatly increased. DFO also increased the expression levels of HIF-1α and VEGF while reduced apoptotic cells. Furthermore, Sca-1+cells were preserved in the salivary glands treated with DFO before IR.ConclusionsOur results indicate DFO could prevent the radiation-induced dysfunction of salivary glands in mice. The mechanism of this protective effect may involve increased angiogenesis, reduced apoptosis of acinar cells and more preserved stem cells.

Endothelial cell regulation of salivary gland epithelial patterning

“…In fact, similar pathologies are associated with diseases that result in xerostomia, such as Sjögren's syndrome and irradiation damage as a result of treatment of head and neck cancers, suggesting that a continued interaction of the vasculature and the epithelium may be a component of homeostasis or a response to injury in adult glands. Consistent with our findings in development, several studies have suggested that the vasculature is damaged in salivary gland pathologies and that gland regeneration is enhanced by restoration of the vasculature (Cotrim et al, 2007;Zhang et al, 2014;An et al, 2015).…”

VEGF released by deferoxamine preconditioned mesenchymal stem cells seeded on collagen-GAG substrates enhances neovascularization

“…Furthermore, Zhang et al . found that irradiated mice treated with DFO showed increased healing and function of salivary glands22. Elevated HIF-1α levels lead to an upregulation of VEGF, as well as several other genes, such as erythropoietin, increased cell survival, and glycolysis2324, which would in turn lead to improved healing.…”

Resident CD34-positive cells contribute to peri-endothelial cells and vascular morphogenesis in salivary gland after irradiation

“…According to several previous studies it leads to side effects such as apoptosis of acinar cells and their loss that in turn results in reduction of saliva production and thus xerostomia. However, the detailed mechanisms of radiation-induced xerostomia remain unclear (Lim et al 2013 ; Zhang et al 2014 ). Since CD44 has been shown to be expressed in acinar epithelial cells of SG, we performed immunostaining for CD44 to assess severity of acinar cell damage as an indicative parameter for SG hypofunction after IR.…”