Alcohol Decreases RhoA Activity Through a Nitric Oxide (NO)/Cyclic GMP(cGMP)/Protein Kinase G (PKG)-Dependent Pathway in the Airway Epithelium

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Abstract

Background: Alcohol has been shown to have a number of harmful effects on the lung, including increasing the risk of pneumonia and bronchitis. How alcohol increases the risk of these diseases is poorly defined. RhoA is a small guanosine triphosphate (GTP)ase that plays an integral role in many basic functions of airway epithelial cells. It is not known how alcohol affects RhoA activity in the airway epithelium. We hypothesized that brief alcohol exposure modulates RhoA activity in the airway epithelium through a nitric oxide (NO)/cyclic GMP (cGMP)/protein kinase G (PKG)-dependent pathway. Methods: Primary airway epithelial cells were cultured and exposed to ethanol at various concentrations and times. The cell layers were harvested and RhoA activity was measured. Results: Alcohol induced a time- and concentration-dependent decrease in RhoA activity in airway epithelial cells. We were able to block this decrease in activity using Nω-nitro-l-arginine methyl ester (L-NAME) hydrochloride, a nitric oxide synthase (NOS) inhibitor. Likewise, we were able to demonstrate the same decrease in RhoA activation using 0.1μM sodium nitroprusside, an NO donor. To determine the role of cGMP/PKG, we pretreated the cells with a cGMP antagonist analog, Rp-8Br-cGMPS. This blocked the decrease in RhoA activity caused by alcohol, suggesting that alcohol exerts its effect on RhoA activity through cGMP/PKG. Conclusions: Alcohol decreases airway epithelial RhoA activity through an NO/cGMP/PKG-dependent pathway. RhoA activity controls many aspects of basic cellular function, including cell morphology, tight junction formation, and cell cycle progression and gene regulation. Dysregulation of RhoA activity can potentially have several consequences, including dysregulation of inflammation. This may partially explain how alcohol increases the risk of pneumonia and bronchitis.

Original languageEnglish (US)
Pages (from-to)1277-1281
Number of pages5
JournalAlcoholism: Clinical and Experimental Research
Volume35
Issue number7
DOIs
StatePublished - Jul 1 2011

Fingerprint

Guanylate Kinases
Cyclic GMP-Dependent Protein Kinases
Cyclic GMP
Nitric Oxide
Epithelium
Alcohols
Bronchitis
Epithelial Cells
Pneumonia
Cells
cdc Genes
Gastrin-Secreting Cells
Arginine
Nitric Oxide Donors
Tight Junctions
NG-Nitroarginine Methyl Ester
Nitroprusside
Guanosine Triphosphate
Gene expression
Nitric Oxide Synthase

Keywords

  • Airway Epithelium
  • Cyclic GMP
  • Ethanol
  • Nitric Oxide
  • Protein Kinase G

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

@article{e750da7e3f824310a3cfd4dcba2347e6,
title = "Alcohol Decreases RhoA Activity Through a Nitric Oxide (NO)/Cyclic GMP(cGMP)/Protein Kinase G (PKG)-Dependent Pathway in the Airway Epithelium",
abstract = "Background: Alcohol has been shown to have a number of harmful effects on the lung, including increasing the risk of pneumonia and bronchitis. How alcohol increases the risk of these diseases is poorly defined. RhoA is a small guanosine triphosphate (GTP)ase that plays an integral role in many basic functions of airway epithelial cells. It is not known how alcohol affects RhoA activity in the airway epithelium. We hypothesized that brief alcohol exposure modulates RhoA activity in the airway epithelium through a nitric oxide (NO)/cyclic GMP (cGMP)/protein kinase G (PKG)-dependent pathway. Methods: Primary airway epithelial cells were cultured and exposed to ethanol at various concentrations and times. The cell layers were harvested and RhoA activity was measured. Results: Alcohol induced a time- and concentration-dependent decrease in RhoA activity in airway epithelial cells. We were able to block this decrease in activity using Nω-nitro-l-arginine methyl ester (L-NAME) hydrochloride, a nitric oxide synthase (NOS) inhibitor. Likewise, we were able to demonstrate the same decrease in RhoA activation using 0.1μM sodium nitroprusside, an NO donor. To determine the role of cGMP/PKG, we pretreated the cells with a cGMP antagonist analog, Rp-8Br-cGMPS. This blocked the decrease in RhoA activity caused by alcohol, suggesting that alcohol exerts its effect on RhoA activity through cGMP/PKG. Conclusions: Alcohol decreases airway epithelial RhoA activity through an NO/cGMP/PKG-dependent pathway. RhoA activity controls many aspects of basic cellular function, including cell morphology, tight junction formation, and cell cycle progression and gene regulation. Dysregulation of RhoA activity can potentially have several consequences, including dysregulation of inflammation. This may partially explain how alcohol increases the risk of pneumonia and bronchitis.",
keywords = "Airway Epithelium, Cyclic GMP, Ethanol, Nitric Oxide, Protein Kinase G",
author = "Bailey, {Kristina L} and Robinson, {James E.} and Sisson, {Joseph Harold} and Wyatt, {Todd A}",
year = "2011",
month = "7",
day = "1",
doi = "10.1111/j.1530-0277.2011.01463.x",
language = "English (US)",
volume = "35",
pages = "1277--1281",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell",
number = "7",

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TY - JOUR

T1 - Alcohol Decreases RhoA Activity Through a Nitric Oxide (NO)/Cyclic GMP(cGMP)/Protein Kinase G (PKG)-Dependent Pathway in the Airway Epithelium

AU - Bailey, Kristina L

AU - Robinson, James E.

AU - Sisson, Joseph Harold

AU - Wyatt, Todd A

PY - 2011/7/1

Y1 - 2011/7/1

N2 - Background: Alcohol has been shown to have a number of harmful effects on the lung, including increasing the risk of pneumonia and bronchitis. How alcohol increases the risk of these diseases is poorly defined. RhoA is a small guanosine triphosphate (GTP)ase that plays an integral role in many basic functions of airway epithelial cells. It is not known how alcohol affects RhoA activity in the airway epithelium. We hypothesized that brief alcohol exposure modulates RhoA activity in the airway epithelium through a nitric oxide (NO)/cyclic GMP (cGMP)/protein kinase G (PKG)-dependent pathway. Methods: Primary airway epithelial cells were cultured and exposed to ethanol at various concentrations and times. The cell layers were harvested and RhoA activity was measured. Results: Alcohol induced a time- and concentration-dependent decrease in RhoA activity in airway epithelial cells. We were able to block this decrease in activity using Nω-nitro-l-arginine methyl ester (L-NAME) hydrochloride, a nitric oxide synthase (NOS) inhibitor. Likewise, we were able to demonstrate the same decrease in RhoA activation using 0.1μM sodium nitroprusside, an NO donor. To determine the role of cGMP/PKG, we pretreated the cells with a cGMP antagonist analog, Rp-8Br-cGMPS. This blocked the decrease in RhoA activity caused by alcohol, suggesting that alcohol exerts its effect on RhoA activity through cGMP/PKG. Conclusions: Alcohol decreases airway epithelial RhoA activity through an NO/cGMP/PKG-dependent pathway. RhoA activity controls many aspects of basic cellular function, including cell morphology, tight junction formation, and cell cycle progression and gene regulation. Dysregulation of RhoA activity can potentially have several consequences, including dysregulation of inflammation. This may partially explain how alcohol increases the risk of pneumonia and bronchitis.

AB - Background: Alcohol has been shown to have a number of harmful effects on the lung, including increasing the risk of pneumonia and bronchitis. How alcohol increases the risk of these diseases is poorly defined. RhoA is a small guanosine triphosphate (GTP)ase that plays an integral role in many basic functions of airway epithelial cells. It is not known how alcohol affects RhoA activity in the airway epithelium. We hypothesized that brief alcohol exposure modulates RhoA activity in the airway epithelium through a nitric oxide (NO)/cyclic GMP (cGMP)/protein kinase G (PKG)-dependent pathway. Methods: Primary airway epithelial cells were cultured and exposed to ethanol at various concentrations and times. The cell layers were harvested and RhoA activity was measured. Results: Alcohol induced a time- and concentration-dependent decrease in RhoA activity in airway epithelial cells. We were able to block this decrease in activity using Nω-nitro-l-arginine methyl ester (L-NAME) hydrochloride, a nitric oxide synthase (NOS) inhibitor. Likewise, we were able to demonstrate the same decrease in RhoA activation using 0.1μM sodium nitroprusside, an NO donor. To determine the role of cGMP/PKG, we pretreated the cells with a cGMP antagonist analog, Rp-8Br-cGMPS. This blocked the decrease in RhoA activity caused by alcohol, suggesting that alcohol exerts its effect on RhoA activity through cGMP/PKG. Conclusions: Alcohol decreases airway epithelial RhoA activity through an NO/cGMP/PKG-dependent pathway. RhoA activity controls many aspects of basic cellular function, including cell morphology, tight junction formation, and cell cycle progression and gene regulation. Dysregulation of RhoA activity can potentially have several consequences, including dysregulation of inflammation. This may partially explain how alcohol increases the risk of pneumonia and bronchitis.

KW - Airway Epithelium

KW - Cyclic GMP

KW - Ethanol

KW - Nitric Oxide

KW - Protein Kinase G

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DO - 10.1111/j.1530-0277.2011.01463.x

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JO - Alcoholism: Clinical and Experimental Research

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