Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction.
Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction.
复制标题
DOI：
10.1016/j.alcohol.2022.10.003
复制
发表时间：
2023-02
期刊：
影响因子：
2.3
通讯作者：
Hart, Michael
中科院分区：
文献类型：
--
作者：
Yeligar, Samantha M.;Harris, Frank L.;Brown, Lou Ann S.;Hart, Michael
酒精使用障碍（AUD）引起肺泡巨噬细胞（AM）免疫功能障碍，增加肺部感染的风险。过量饮酒导致AM氧化应激，从而损害AM吞噬和肺泡间隙的病原体清除。酒精诱导NADPH氧化酶（Noxes）的表达，这是AM氧化应激的主要来源。相反，酒精降低AM过氧化物酶体增殖激活受体γ (PPARγ)，这是AM免疫功能的关键调节因子。为了探索酒精这些作用的潜在分子机制，我们假设乙醇促进CCAAT/增强子结合蛋白β (C/EBPβ)介导的Nox相关microrna （miRs）的抑制，进而增强AM Nox的表达、氧化应激和吞噬功能障碍。我们还假设吡格列酮（PIO）激活PPARγ可以逆转酒精诱导的C/EBPβ表达，减轻AM氧化应激和吞噬功能障碍。将小鼠AM细胞系（MH-S）的细胞体外暴露于乙醇中，或从饲喂乙醇的小鼠中分离原代AM。乙醇增强了C/EBPβ的表达，降低了Nox1相关的miR-1264和Nox2相关的miR-107水平，增加了体外MH-S细胞和小鼠AM中Nox1， Nox2和Nox 4的表达。这些酒精诱导的AM紊乱可通过C/EBPβ缺失、miRs-1264或- 107过表达或PIO处理而消除。这些发现确定了C/EBPβ和nox相关的miRs是PPARγ配体的新治疗靶点，这可能为减轻AUD病史患者对肺部感染的易感性提供可转化的策略。这些研究进一步阐明了先前使用短期PIO治疗提高AUD患者AM免疫的临床试验的分子基础。
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.
登录
查看更多内容
影响因子：
--
作者：
Liang Y;Harris FL;Brown LA
通讯作者：
Brown LA
DOI：
10.1164/rccm.201301-0061oc
发表时间：
2013-09-15
影响因子：
24.7
作者：
Mehta, Ashish J.;Yeligar, Samantha M.;Guidot, David M.
通讯作者：
Guidot, David M.
肺泡巨噬细胞中酒精诱导的糖酵解转移是由缺氧诱导因子-1α介导的。
影响因子：
7.3
作者：
Morris, Niya L.;Michael, David N.;Crotty, Kathryn M.;Chang, Sarah S.;Yeligar, Samantha M.
通讯作者：
Yeligar, Samantha M.
影响因子：
6.1
作者：
Abdelhafez，Alaa T.;Gomaa，Asmaa M. S.;Ahmed，Marwa A.
通讯作者：
Ahmed，Marwa A.
DOI：
10.1165/rcmb.2016-0166oc
发表时间：
2017-01-01
影响因子：
6.4
作者：
Kang, Bum-Yong;Park, Kathy;Hart, C. Michael
通讯作者：
Hart, C. Michael