2 Citations (Scopus)

Abstract

Alcohol use disorder (AUD) is a strong risk factor for development and mortality of pneumonia. Mucociliary clearance, a key innate defense against pneumonia, is perturbed by alcohol use. Specifically, ciliated airway cells lose the ability to increase ciliary beat frequency (CBF) to β-agonist stimulation after prolonged alcohol exposure. We previously found that alcohol activates protein phosphatase 1 (PP1) through a redox mechanism to cause ciliary dysfunction. Therefore, we hypothesized that PP1 activity is enhanced by alcohol exposure through an S-nitrosothiol-dependent mechanism resulting in desensitization of CBF stimulation. Bronchoalveolar S-nitrosothiol (SNO) content and tracheal PP1 activity was increased in wild-type (WT) mice drinking alcohol for 6-weeks compared to control mice. In contrast, alcohol drinking did not increase SNO content or PP1 activity in nitric oxide synthase 3-deficient mice. S-nitrosoglutathione induced PP1-dependent CBF desensitization in mouse tracheal rings, cultured cells and isolated cilia. In vitro expression of mutant PP1 (cysteine 155 to alanine) in primary human airway epithelial cells prevented CBF desensitization after prolonged alcohol exposure compared to cells expressing WT PP1. Thus, redox modulation in the airways by alcohol is an important ciliary regulatory mechanism. Pharmacologic strategies to reduce S-nitrosation may enhance mucociliary clearance and reduce pneumonia prevalence, mortality and morbidity with AUD.

Original languageEnglish (US)
Article number9701
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Nitrosation
Protein Phosphatase 1
Alcohols
S-Nitrosothiols
Mucociliary Clearance
Pneumonia
Alcohol Drinking
Oxidation-Reduction
S-Nitrosoglutathione
Aptitude
Mortality
Cilia
Mutant Proteins
Nitric Oxide Synthase
Alanine
Cysteine
Cultured Cells
Epithelial Cells
Morbidity

ASJC Scopus subject areas

  • General

Cite this

S-nitrosation of protein phosphatase 1 mediates alcohol-induced ciliary dysfunction. / Price, Michael E.; Case, Adam; Pavlik, Jacqueline A.; Devasure, Jane M.; Wyatt, Todd A; Zimmerman, Matthew C; Sisson, Joseph Harold.

In: Scientific reports, Vol. 8, No. 1, 9701, 01.12.2018.

Research output: Contribution to journalArticle

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abstract = "Alcohol use disorder (AUD) is a strong risk factor for development and mortality of pneumonia. Mucociliary clearance, a key innate defense against pneumonia, is perturbed by alcohol use. Specifically, ciliated airway cells lose the ability to increase ciliary beat frequency (CBF) to β-agonist stimulation after prolonged alcohol exposure. We previously found that alcohol activates protein phosphatase 1 (PP1) through a redox mechanism to cause ciliary dysfunction. Therefore, we hypothesized that PP1 activity is enhanced by alcohol exposure through an S-nitrosothiol-dependent mechanism resulting in desensitization of CBF stimulation. Bronchoalveolar S-nitrosothiol (SNO) content and tracheal PP1 activity was increased in wild-type (WT) mice drinking alcohol for 6-weeks compared to control mice. In contrast, alcohol drinking did not increase SNO content or PP1 activity in nitric oxide synthase 3-deficient mice. S-nitrosoglutathione induced PP1-dependent CBF desensitization in mouse tracheal rings, cultured cells and isolated cilia. In vitro expression of mutant PP1 (cysteine 155 to alanine) in primary human airway epithelial cells prevented CBF desensitization after prolonged alcohol exposure compared to cells expressing WT PP1. Thus, redox modulation in the airways by alcohol is an important ciliary regulatory mechanism. Pharmacologic strategies to reduce S-nitrosation may enhance mucociliary clearance and reduce pneumonia prevalence, mortality and morbidity with AUD.",
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AU - Price, Michael E.

AU - Case, Adam

AU - Pavlik, Jacqueline A.

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AU - Wyatt, Todd A

AU - Zimmerman, Matthew C

AU - Sisson, Joseph Harold

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