*3.4. Generation of Inflammatory Responses*

Inflammatory responses may also contribute to IR-induced salivary gland dysfunction. Extracellular ATP (eATP), a damage-associated molecular pattern (DAMP) that commonly activates neighboring cells due to ATP release from adjacent damaged cells, is released from primary parotid gland cells immediately following 2–10 Gy IR exposure [48]. Additionally, levels of the inflammation-associated lipid, prostaglandin E2 (PGE2), are increased in parotid acinar cell culture supernatant 24–72 h following 5 Gy IR, with reduced levels of eATP and PGE2 release shown in mice deficient in the ATP-activated, P2X7 purinergic receptor (P2X7R), which correlates with improved saliva flow by days 3–30 post-IR [48]. Surprisingly, these pathways do not impact cell death induction in parotid glands post-IR [48], but may play a role in the inflammatory response to IR-induced salivary gland damage. It also has been observed that mRNA levels of the inflammatory cytokine interleukin (IL)-6 in irradiated salivary glands increased at 3 h post-13 Gy IR exposure and were reduced by 6 h post-IR, but increased again by day 14 post-IR. Interestingly, this increase correlated with elevated serum IL-6 levels at 6–12 h post-IR and again by day 14 [67]. IL-6 is a pro-inflammatory cytokine with diverse functions. However, the exact role that IL-6 plays in salivary glands post-IR has not been well defined. These data suggest that IR-induced damage to salivary glands leads to diverse inflammatory responses that should be further investigated.
