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

ABSTRACT: Annually, >600,000 new cases of head and neck cancer (HNC) are diagnosed worldwide with primary treatment being surgery and radiotherapy. During ionizing radiation (IR) treatment of HNC, healthy salivary glands are collaterally damaged, leading to loss of function that severely diminishes the quality of life for patients due to increased health complications, including oral infections and sores, cavities, and malnutrition, among others. Therapies for salivary hypofunction are ineffective and largely palliative, indicating a need for further research to uncover effective approaches to prevent or restore loss of salivary gland function following radiotherapy. Previous work in our lab implicated prostaglandin E₂ (PGE₂) as an inflammatory mediator whose release from radiation-exposed cells promotes salivary gland damage and loss of function. Deletion of the P2X7 purinergic receptor for extracellular ATP reduces PGE₂ secretion in irradiated primary parotid gland cells, and salivary gland function is enhanced in irradiated P2X7R^-/- mice compared to wild-type mice. However, the role of PGE₂ signaling in irradiated salivary glands is unclear and understanding the mechanism of PGE₂ action is a goal of this study. Results show that treatment of irradiated mice with the non-steroidal anti-inflammatory drug (NSAID) indomethacin, which reduces PGE₂ production via inhibition of cyclooxygenase-1 (COX-1), improves salivary gland function compared to irradiated vehicle-treated mice. To define the signaling pathway whereby PGE₂ induces salivary gland dysfunction, primary parotid gland cells treated with PGE₂ have increased c-Jun N-terminal Kinase (JNK) activation and cell proliferation and reduced amylase levels and store-operated calcium entry (SOCE). The in vivo effects of blocking PGE₂ production were also examined and irradiated mice receiving indomethacin injections have reduced JNK activity at 8 days post-irradiation and reduced proliferation and increased amylase levels at day 30, as compared to irradiated mice without indomethacin. Combined, these data suggest a mechanism whereby irradiation-induced PGE₂ signaling to JNK blocks critical steps in saliva secretion manifested by a decrease in the quality (diminished amylase) and quantity (loss of calcium channel activity) of saliva, that can be restored with indomethacin. These findings encourage further attempts evaluating indomethacin as a viable therapeutic option to prevent damage to salivary glands caused by irradiation of HNC in humans.

SUBMITTER: Gilman KE

PROVIDER: S-EPMC8351468 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Radiotherapy of head and neck cancer is accompanied by unavoidable co-irradiation of the salivary gland, often resulting in hyposalivation and reduced quality of life. Irradiated salivary gland tissue is characterized by the presence of cellular senescence, fibrosis, and a chronic inflammatory state changing the cellular microenvironment. These microenvironmental changes may be unfavorable for the regenerative potential of tissue stem cells inhibiting regenerative medicine options. Therefore, we investigated microenvironmental changes of the irradiated murine salivary gland and their effect on the potency of salivary gland stem/progenitor cells (SGSCs). After 15 Gy local irradiation of murine salivary glands, alongside an in time advancing decline in function, the submandibular gland (SMG) showed extensive fibrosis, p21-expressing senescent cells, and immune cell infiltration, all indicative of microenvironmental changes. Additionally, irradiated SMG contained a lower number of CD24++/CD29++ and CD24++/CD29+ stem/progenitor cell enrichment marker-expressing cells 30 days post-irradiation which coincides with a reduction in salisphere formation potential over time. However, after subsequent passaging of organoids derived from glands obtained 14 days after irradiation, and to a lesser extent at 30 days post-irradiation, the ability to form secondary organoids recovered to control levels. In contrast, cells obtained from glands at 90, 180, and 360 days post-irradiation irreversibly lost their ability to form organoids, indicating a time-dependent loss of regenerative potential. Transcriptomic analysis showed overexpression of Bmp4 in day 90 organoids derived from irradiated glands compared to the ones from day 14. Inhibition of Bmp4 using Noggin reversed this adverse response suggesting an important role in modulating SGSC function. Thus, early after irradiation, the regenerative potential of surviving SGSCs is preserved and comparable to that of unirradiated cells. At later time points after irradiation, SGSCs lose their regenerative potential suggesting that the prolonged exposure to a deleterious microenvironment leads to an irreversible decline in stemness. Modulation of Bmp4 signaling pathway might improve the regenerative potential of surviving SGSCs and enhance the efficiency of stem cell therapy in restoring the functionality of irradiated salivary glands.

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

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

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