P2X7 receptor deletion suppresses γ-radiation-induced hyposalivation

Kristy E. Gilman, Jean M. Camden, Rob R. Klein, Qionghui Zhang, Gary A. Weisman, Kirsten Limesand

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Head and neck cancer treatments typically involve a combination of surgery and radiotherapy, often leading to collateral damage to nearby tissues causing unwanted side effects. Radiation damage to salivary glands frequently leads to irreversible dysfunction by poorly understood mechanisms. The P2X7 receptor (P2X7R) is a ligand-gated ion channel activated by extracellular ATP released from damaged cells as "danger signals." P2X7R activation initiates apoptosis and is involved in numerous inflammatory disorders. In this study, we utilized P2X7R knockout (P2X7R-/-) mice to determine the role of the receptor in radiation-induced salivary gland damage. Results indicate a dose-dependent increase in γ-radiation-induced ATP release from primary parotid gland cells of wild-type but not P2X7R-/- mice. Despite these differences, apoptosis levels are similar in parotid glands of wild-type and P2X7R-/- mice 24-72 h after radiation. However, γ-radiation caused elevated prostaglandin E2 (PGE2) release from primary parotid cells of wild-type but not P2X7R-/- mice. To attempt to uncover the mechanism underlying differential PGE2 release, we evaluated the expression and activities of cyclooxygenase and PGE synthase isoforms. There were no consistent trends in these mediators following radiation that could explain the reduction in PGE2 release in P2X7R-/- mice. Irradiated P2X7R-/- mice have stimulated salivary flow rates similar to unirradiated controls, whereas irradiated wild-type mice have significantly decreased salivary flow rates compared with unirradiated controls. Notably, treatment with the P2X7R antagonist A438079 preserves stimulated salivary flow rates in wild-type mice following γ-radiation. These data suggest that P2X7R antagonism is a promising approach for preventing γ-radiation-induced hyposalivation.

Original languageEnglish (US)
Pages (from-to)R687-R696
JournalAmerican journal of physiology. Regulatory, integrative and comparative physiology
Volume316
Issue number5
DOIs
StatePublished - May 1 2019

Keywords

  • cell biology
  • P2X7 receptor
  • P2X7R
  • radiation
  • salivary glands
  • xerostomia

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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