Loss of cAMP-dependent stimulation of isolated cilia motility by alcohol exposure is oxidant-dependent

Michael E. Price, Carresse L. Gerald, Jacqueline A. Pavlik, Sarah L. Schlichte, Matthew C. Zimmerman, Jane M. DeVasure, Todd A. Wyatt, Joseph H. Sisson

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Alcohol exposure is associated with decreased mucociliary clearance, a key innate defense essential to lung immunity. Previously, we identified that prolonged alcohol exposure results in dysfunction of airway cilia that persists at the organelle level. This dysfunction is characterized by a loss of 3′,5′-cyclic adenosine monophosphate (cAMP)-mediated cilia stimulation. However, whether or not ciliary dysfunction develops intrinsically at the organelle level has not been explored. We hypothesized that prolonged alcohol exposure directly to isolated demembranated cilia (axonemes) causes ciliary dysfunction. To test this hypothesis, we exposed isolated axonemes to alcohol (100 mM) for 1–24 h and assessed ciliary beat frequency (CBF) in response to cAMP at 1, 3, 4, 6, and 24 h post-exposure. We found that after 1 h of alcohol exposure, cilia axonemes do not increase CBF in response to cAMP. Importantly, by 6 h after the initial exposure to alcohol, cAMP-mediated CBF was restored to control levels. Additionally, we found that thioredoxin reverses ciliary dysfunction in axonemes exposed to alcohol. Finally, we identified, using a combination of a xanthine oxidase oxidant-generating system, direct application of hydrogen peroxide, and electron paramagnetic resonance, that hydrogen peroxide versus superoxide, is likely the key oxidant species driving alcohol-induced ciliary dysfunction in isolated axonemes. These data highlight the role of alcohol to stimulate local production of oxidants in the axoneme to cause ciliary dysfunction. Additionally, these data specifically add hydrogen peroxide as a potential therapeutic target in the treatment or prevention of alcohol-associated ciliary dysfunction and subsequent pneumonia.

Original languageEnglish (US)
Pages (from-to)91-98
Number of pages8
JournalAlcohol
Volume80
DOIs
StatePublished - Nov 2019

Keywords

  • alcohol
  • axoneme
  • cilia
  • hydrogen peroxide
  • redox

ASJC Scopus subject areas

  • Health(social science)
  • Biochemistry
  • Toxicology
  • Neurology
  • Behavioral Neuroscience

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