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Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction

Alcohol use disorders (AUD) cause alveolar macrophage (AM) immune dysfunction and increase risk of lung infections. Excessive alcohol use causes AM oxidative stress, which impairs AM phagocytosis and pathogen clearance from the alveolar space. Alcohol induces expression of NADPH oxidases (Noxes), pr...

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Autores principales: Yeligar, Samantha M., Harris, Frank L., Brown, Lou Ann S., Hart, C. Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080543/
https://www.ncbi.nlm.nih.gov/pubmed/36328183
http://dx.doi.org/10.1016/j.alcohol.2022.10.003
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author Yeligar, Samantha M.
Harris, Frank L.
Brown, Lou Ann S.
Hart, C. Michael
author_facet Yeligar, Samantha M.
Harris, Frank L.
Brown, Lou Ann S.
Hart, C. Michael
author_sort Yeligar, Samantha M.
collection PubMed
description Alcohol use disorders (AUD) cause alveolar macrophage (AM) immune dysfunction and increase risk of lung infections. Excessive alcohol use causes AM oxidative stress, which impairs AM phagocytosis and pathogen clearance from the alveolar space. Alcohol induces expression of NADPH oxidases (Noxes), primary sources of oxidative stress in AM. In contrast, alcohol decreases AM peroxisome proliferator-activated receptor gamma (PPARγ), a critical regulator of AM immune function. To explore the underlying molecular mechanisms for these effects of alcohol, we hypothesized that ethanol promotes CCAAT/enhancer-binding protein beta (C/EBPβ)-mediated suppression of Nox-related microRNAs (miRs), in turn enhancing AM Nox expression, oxidative stress, and phagocytic dysfunction. We also hypothesized that PPARγ activation with pioglitazone (PIO) would reverse alcohol-induced C/EBPβ expression and attenuate AM oxidative stress and phagocytic dysfunction. Cells from the mouse AM cell line (MH-S) were exposed to ethanol in vitro or primary AM were isolated from mice fed ethanol in vivo. Ethanol enhanced C/EBPβ expression, decreased Nox 1-related miR-1264 and Nox 2-related miR-107 levels, and increased Nox1, Nox2, and Nox 4 expression in MH-S cells in vitro and mouse AM in vivo. These alcohol-induced AM derangements were abrogated by loss of C/EBPβ, overexpression of miRs-1264 or −107, or PIO treatment. These findings identify C/EBPβ and Nox-related miRs as novel therapeutic targets for PPARγ ligands, which could provide a translatable strategy to mitigate susceptibility to lung infections in people with a history of AUD. These studies further clarify the molecular underpinnings for a previous clinical trial using short-term PIO treatment to improve AM immunity in AUD individuals.
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spelling pubmed-100805432023-04-07 Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction Yeligar, Samantha M. Harris, Frank L. Brown, Lou Ann S. Hart, C. Michael Alcohol Article Alcohol use disorders (AUD) cause alveolar macrophage (AM) immune dysfunction and increase risk of lung infections. Excessive alcohol use causes AM oxidative stress, which impairs AM phagocytosis and pathogen clearance from the alveolar space. Alcohol induces expression of NADPH oxidases (Noxes), primary sources of oxidative stress in AM. In contrast, alcohol decreases AM peroxisome proliferator-activated receptor gamma (PPARγ), a critical regulator of AM immune function. To explore the underlying molecular mechanisms for these effects of alcohol, we hypothesized that ethanol promotes CCAAT/enhancer-binding protein beta (C/EBPβ)-mediated suppression of Nox-related microRNAs (miRs), in turn enhancing AM Nox expression, oxidative stress, and phagocytic dysfunction. We also hypothesized that PPARγ activation with pioglitazone (PIO) would reverse alcohol-induced C/EBPβ expression and attenuate AM oxidative stress and phagocytic dysfunction. Cells from the mouse AM cell line (MH-S) were exposed to ethanol in vitro or primary AM were isolated from mice fed ethanol in vivo. Ethanol enhanced C/EBPβ expression, decreased Nox 1-related miR-1264 and Nox 2-related miR-107 levels, and increased Nox1, Nox2, and Nox 4 expression in MH-S cells in vitro and mouse AM in vivo. These alcohol-induced AM derangements were abrogated by loss of C/EBPβ, overexpression of miRs-1264 or −107, or PIO treatment. These findings identify C/EBPβ and Nox-related miRs as novel therapeutic targets for PPARγ ligands, which could provide a translatable strategy to mitigate susceptibility to lung infections in people with a history of AUD. These studies further clarify the molecular underpinnings for a previous clinical trial using short-term PIO treatment to improve AM immunity in AUD individuals. 2023-02 2022-11-01 /pmc/articles/PMC10080543/ /pubmed/36328183 http://dx.doi.org/10.1016/j.alcohol.2022.10.003 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Yeligar, Samantha M.
Harris, Frank L.
Brown, Lou Ann S.
Hart, C. Michael
Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction
title Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction
title_full Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction
title_fullStr Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction
title_full_unstemmed Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction
title_short Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction
title_sort pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080543/
https://www.ncbi.nlm.nih.gov/pubmed/36328183
http://dx.doi.org/10.1016/j.alcohol.2022.10.003
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