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Indomethacin Treatment Post-irradiation Improves Mouse Parotid Salivary Gland Function via Modulation of Prostaglandin E(2) Signaling

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 qua...

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Autores principales: Gilman, Kristy E., Camden, Jean M., Woods, Lucas T., Weisman, Gary A., Limesand, Kirsten H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351468/
https://www.ncbi.nlm.nih.gov/pubmed/34381764
http://dx.doi.org/10.3389/fbioe.2021.697671
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author Gilman, Kristy E.
Camden, Jean M.
Woods, Lucas T.
Weisman, Gary A.
Limesand, Kirsten H.
author_facet Gilman, Kristy E.
Camden, Jean M.
Woods, Lucas T.
Weisman, Gary A.
Limesand, Kirsten H.
author_sort Gilman, Kristy E.
collection PubMed
description 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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2) signaling in irradiated salivary glands is unclear and understanding the mechanism of PGE(2) 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 PGE(2) production via inhibition of cyclooxygenase-1 (COX-1), improves salivary gland function compared to irradiated vehicle-treated mice. To define the signaling pathway whereby PGE(2) induces salivary gland dysfunction, primary parotid gland cells treated with PGE(2) 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 PGE(2) 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 PGE(2) 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.
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spelling pubmed-83514682021-08-10 Indomethacin Treatment Post-irradiation Improves Mouse Parotid Salivary Gland Function via Modulation of Prostaglandin E(2) Signaling Gilman, Kristy E. Camden, Jean M. Woods, Lucas T. Weisman, Gary A. Limesand, Kirsten H. Front Bioeng Biotechnol Bioengineering and Biotechnology 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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2) signaling in irradiated salivary glands is unclear and understanding the mechanism of PGE(2) 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 PGE(2) production via inhibition of cyclooxygenase-1 (COX-1), improves salivary gland function compared to irradiated vehicle-treated mice. To define the signaling pathway whereby PGE(2) induces salivary gland dysfunction, primary parotid gland cells treated with PGE(2) 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 PGE(2) 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 PGE(2) 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. Frontiers Media S.A. 2021-07-21 /pmc/articles/PMC8351468/ /pubmed/34381764 http://dx.doi.org/10.3389/fbioe.2021.697671 Text en Copyright © 2021 Gilman, Camden, Woods, Weisman and Limesand. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Bioengineering and Biotechnology
Gilman, Kristy E.
Camden, Jean M.
Woods, Lucas T.
Weisman, Gary A.
Limesand, Kirsten H.
Indomethacin Treatment Post-irradiation Improves Mouse Parotid Salivary Gland Function via Modulation of Prostaglandin E(2) Signaling
title Indomethacin Treatment Post-irradiation Improves Mouse Parotid Salivary Gland Function via Modulation of Prostaglandin E(2) Signaling
title_full Indomethacin Treatment Post-irradiation Improves Mouse Parotid Salivary Gland Function via Modulation of Prostaglandin E(2) Signaling
title_fullStr Indomethacin Treatment Post-irradiation Improves Mouse Parotid Salivary Gland Function via Modulation of Prostaglandin E(2) Signaling
title_full_unstemmed Indomethacin Treatment Post-irradiation Improves Mouse Parotid Salivary Gland Function via Modulation of Prostaglandin E(2) Signaling
title_short Indomethacin Treatment Post-irradiation Improves Mouse Parotid Salivary Gland Function via Modulation of Prostaglandin E(2) Signaling
title_sort indomethacin treatment post-irradiation improves mouse parotid salivary gland function via modulation of prostaglandin e(2) signaling
topic Bioengineering and Biotechnology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351468/
https://www.ncbi.nlm.nih.gov/pubmed/34381764
http://dx.doi.org/10.3389/fbioe.2021.697671
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