Pioglitazone Reverses Alcohol-Induced Alveolar Macrophage Phagocytic Dysfunction.
Pioglitazone Reverses Alcohol-Induced Alveolar Macrophage Phagocytic Dysfunction.
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DOI：
10.4049/jimmunol.2000565
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发表时间：
2021-07-15
期刊：
影响因子：
--
通讯作者：
Hart CM
中科院分区：
文献类型：
--
作者：
Yeligar SM;Mehta AJ;Harris FL;Brown LAS;Hart CM
酒精使用障碍（AUD）使呼吸道感染的易感性增加2-4倍，部分原因是肺泡巨噬细胞（AM）免疫功能受损。酒精引起AM氧化应激，降低AM吞噬能力和从肺泡腔清除微生物。酒精增加AM NADPH氧化酶（Noxes），AM氧化应激的主要来源，并减少过氧化物酶体增殖物激活受体γ（PPARγ）的表达，AM免疫功能的关键调节因子。为了研究这些酒精诱导的AM紊乱的潜在机制，我们假设酒精刺激CCAAT/增强子结合蛋白β（C/EBPβ）以抑制Nox相关的microRNA（miR），从而增强AM Nox表达、氧化应激和吞噬功能障碍。此外，我们推测吡格列酮（PIO）的药理学PPARγ激活可抑制C/EBPβ并减轻酒精诱导的AM功能障碍。检查从人AUD受试者或其他健康对照受试者分离的AM。与对照AM相比，酒精激活AM C/EBPβ，降低Nox 1相关的miR-1264和Nox 2相关的miR-107，并增加Nox 1、Nox 2和Nox 4的表达和活性。通过抑制C/EBPβ、过表达miR-1264或miR-107或PIO治疗，这些酒精诱导的AM紊乱被消除。这些发现定义了由C/EBPβ和Nox相关miR介导的酒精诱导的AM功能障碍的新分子机制，这些miR适合于用PPARγ配体进行治疗靶向。这些结果表明，PPARγ配体提供了一种新的和快速翻译的策略，以减轻对呼吸道感染的易感性和相关的发病率与AUD的个人。
Alcohol use disorders (AUD) increase susceptibility to respiratory infections by 2–4-fold due in part to impaired alveolar macrophage (AM) immune function. Alcohol causes AM oxidative stress, diminishing AM phagocytic capacity and clearance of microbes from the alveolar space. Alcohol increases AM NADPH oxidases (Noxes), primary sources of AM oxidative stress, and reduces peroxisome proliferator-activated receptor gamma (PPARγ) expression, a critical regulator of AM immune function. To investigate the underlying mechanisms of these alcohol-induced AM derangements, we hypothesized that alcohol stimulates CCAAT/enhancer-binding protein beta (C/EBPβ) to suppress Nox-related microRNAs (miRs) thereby enhancing AM Nox expression, oxidative stress, and phagocytic dysfunction. Further, we postulated that pharmacologic PPARγ activation with pioglitazone (PIO) would inhibit C/EBPβ and attenuate alcohol-induced AM dysfunction. AM isolated from human AUD subjects or otherwise healthy control subjects were examined. Compared to control AM, alcohol activated AM C/EBPβ, decreased Nox1-related miR-1264 and Nox2-related miR-107, and increased Nox1, Nox2, and Nox4 expression and activity. These alcohol-induced AM derangements were abrogated by inhibition of C/EBPβ, by overexpression of miRs-1264 or −107, or by PIO treatment. These findings define novel molecular mechanisms of alcohol-induced AM dysfunction mediated by C/EBPβ and Nox-related miRs that are amenable to therapeutic targeting with PPARγ ligands. These results demonstrate that PPARγ ligands provide a novel and rapidly translatable strategy to mitigate susceptibility to respiratory infections and related morbidity in individuals with AUD.
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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.
DOI：
10.1016/j.alcohol.2016.08.005
发表时间：
2016-09
期刊：
Alcohol (Fayetteville, N.Y.)
影响因子：
--
作者：
Yeligar SM;Chen MM;Kovacs EJ;Sisson JH;Burnham EL;Brown LA
通讯作者：
Brown LA
影响因子：
16.6
作者：
Schlingmann B;Overgaard CE;Molina SA;Lynn KS;Mitchell LA;Dorsainvil White S;Mattheyses AL;Guidot DM;Capaldo CT;Koval M
通讯作者：
Koval M
DOI：
10.1111/j.1530-0277.2009.01017.x
发表时间：
2009-10-01
影响因子：
3.2
作者：
Brown, Sheena D.;Gauthier, Theresa W.;Brown, Lou Ann S.
通讯作者：
Brown, Lou Ann S.