Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

Abstract

Salivary glands sustain collateral damage following radiotherapy (RT) to treat cancers of the head and neck, leading to complications, including mucositis, xerostomia and hyposalivation. Despite salivary gland-sparing techniques and modified dosing strategies, long-term hypofunction remains a significant problem. Current therapeutic interventions provide temporary symptom relief, but do not address irreversible glandular damage. In this review, we summarize the current understanding of mechanisms involved in RT-induced hyposalivation and provide a framework for future mechanistic studies. One glaring gap in published studies investigating RT-induced mechanisms of salivary gland dysfunction concerns the effect of irradiation on adjacent non-irradiated tissue via paracrine, autocrine and direct cell–cell interactions, coined the bystander effect in other models of RT-induced damage. We hypothesize that purinergic receptor signaling involving P2 nucleotide receptors may play a key role in mediating the bystander effect. We also discuss promising new therapeutic approaches to prevent salivary gland damage due to RT.

Laminin-1 Peptides Conjugated to Fibrin Hydrogels Promote Salivary Gland Regeneration in Irradiated Mouse Submandibular Glands

“…Salivary gland tissue damage is a late degenerative response observed after radiation therapy (Wu and Leung, 2019;Jasmer et al, 2020). To confirm L 1p -FH regenerative effects in a more clinically relevant animal model, a widely accepted head and neck irradiated mouse model was used for this study (Deasy et al, 2010;Varghese et al, 2018).…”

“…According to the American Cancer Society, each year more than 80,000 people develop head and neck cancer in the United States (Siegel et al, 2021). A first-line treatment for head and neck cancer is radiation therapy (Sroussi et al, 2017), but ionizing radiation typically leads to chronic oral complications such as xerostomia (i.e., hyposalivation) (Chambers et al, 2004;Grundmann et al, 2010;Jensen et al, 2010;Pinna et al, 2015;Sroussi et al, 2017;Jensen et al, 2019;Haderlein et al, 2020;Jasmer et al, 2020). This condition contributes to oral microbial infections and impairs activities of daily life such as speaking, chewing, and swallowing (Lovelace et al, 2014;Brook, 2021).…”

Indomethacin Treatment Post-irradiation Improves Mouse Parotid Salivary Gland Function via Modulation of Prostaglandin E2 Signaling

“…Hemostasis/inflammatory responses begin immediately following a wounding event and typically last for about 3 days ( Reinke and Sorg, 2012 ). Radiation-induced inflammatory responses have been studied in salivary glands but present conflicting results ( Jasmer et al, 2020 ). Research suggests that interleukin (IL)-6 mediates induction of cellular senescence in irradiated (13 Gy) submandibular glands (SMGs), with elevated levels seen at 3 h and 14 days post-IR.…”

Epigallocatechin-3-Gallate Protects Pro-Acinar Epithelia Against Salivary Gland Radiation Injury

“…The advancement of linear accelerator (LINAC) technologies together with intensity-modulated radiation therapy (IMRT) techniques have enhanced the precision and efficiency of fractionated RT for HNC [ 2 , 3 , 4 ]. Emerging research efforts have also been undertaken to understand these RT technologies’ ability to spare the function of neighboring healthy tissues or organs like the salivary glands (SG) [ 5 , 6 , 7 , 8 ].…”