**6. Summary**

Whether as a result of direct radiation exposure or due to bystander effects, radiotherapy of the head and neck region results in damage to salivary glands that often leads to permanent dysfunction and associated complications, such as increased oral infections, functional impairments in speaking, swallowing, and eating and diminished quality of life. The mechanisms of acute and chronic dysfunction have been investigated using multiple animal models. In the present review, we discussed the available data describing the mechanisms of acute and chronic IR-induced salivary gland dysfunction. In animal models of RT, acute salivary gland dysfunction involves DNA damage and insufficient repair, aberrant calcium signaling, acinar cell apoptosis and ROS production. While these mechanisms contribute to long-term loss of function, sustained salivary dysfunction is further influenced by inflammatory responses, neuronal and vascular changes, loss of epithelial polarity, compensatory proliferation, impaired stem or progenitor cell populations, cytoskeletal rearrangements and fibrosis. One area that deserves further investigation is the contribution of immune cells to IR-induced salivary gland dysfunction. IR-induced immunomodulation is a well-appreciated driver of damage in other models of IR, both with regard to direct IR exposure as well as influencing bystander effects. Further, our overall understanding of bystander effects in the salivary glands following irradiation is inadequate. Building on research performed in other IR-induced damage models, we propose that purinergic signaling through P2 receptors in the salivary gland may be a critical mediator of bystander effects in IR-induced salivary gland dysfunction. At present, artificial saliva and sialagogues provide inadequate and temporary symptom relief in RT. The therapeutic benefit of amifostine, the only FDA-approved radioprotective treatment, is questionable due to toxicity concerns. The need for additional preventative and regenerative approaches is essential. Here, we discussed current and future therapeutic approaches for the treatment or prevention of RT-induced salivary gland damage, including a number of promising radioprotective and regenerative therapies being investigated in preclinical animal models and clinical trials. Radioprotective approaches currently being investigated target many of the signaling pathways discussed in this review, while regenerative approaches include gene therapy, pharmacological interventions and stem cell transplantation.

**Author Contributions:** K.J.J., K.E.G. and K.M.F. reviewed available literature and wrote the manuscript. G.A.W. and K.H.L. critically revised the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by National Institute of Dental and Craniofacial Research grants R01DE007389 (G.A.W.), R01DE023534 (K.H.L.), R01DE029166 (K.H.L.), F31DE028737 (K.E.G.) and R01DE023342 (G.A.W. and K.H.L.) and a Sjögrens Syndrome Foundation grant (K.J.J.). K.M.F. is supported by a University of Missouri Life Sciences Fellowship and a fellowship from the Wayne L. Ryan Foundation.

**Conflicts of Interest:** The authors declare no conflict of interest.
