Alcohol induces mitochondrial derangements in alveolar macrophages by upregulating NADPH oxidase 4.
Alcohol induces mitochondrial derangements in alveolar macrophages by upregulating NADPH oxidase 4.
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DOI：
10.1016/j.alcohol.2020.11.004
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Yeligar SM
中科院分区：
文献类型：
--
作者：
Morris NL;Harris FL;Brown LAS;Yeligar SM
过量饮酒者患呼吸道感染的风险增加，部分原因是氧化应激诱导的肺泡巨噬细胞（AM）吞噬功能障碍。慢性乙醇暴露通过上调NADPH氧化酶（Nox）4增加AM中的细胞氧化应激，并且用过氧化物酶体增殖物激活受体γ（PPARγ）配体罗格列酮治疗可降低乙醇诱导的Nox 4。然而，乙醇诱导Nox 4表达和PPARγ配体逆转该缺陷的机制尚未阐明。由于microRNA（miR）-92a已被预测为靶向Nox 4去稳定，我们假设乙醇暴露降低miR-92 a表达并导致Nox 4上调。以前的研究表明，AM功能障碍与脑源性氧化应激有关。我们进一步假设，乙醇通过miR-92 a增加了脑源性AM氧化应激和功能障碍，并且用PPARγ配体吡格列酮治疗可以逆转这些紊乱。为了验证这些假设，将小鼠AM细胞系MH-S细胞在体外暴露于乙醇，并从慢性乙醇消耗的小鼠模型中分离原代AM以测量Nox 4、线粒体靶mRNA（qRT-PCR）和蛋白质水平（共聚焦显微镜），大肠杆菌衍生的活性氧物质（共聚焦免疫荧光）、线粒体分裂（电子显微镜）和线粒体生物能量学（细胞外通量分析仪）。乙醇暴露增加了Nox 4，增强了线粒体衍生的氧化应激，增强了线粒体分裂，并损害了线粒体生物能量学。在体外用miR-92 a模拟物转染或在体内用吡格列酮处理降低了Nox 4水平，导致这些乙醇介导的紊乱的改善。这些发现支持吡格列酮可能提供一种新的治疗方法，以减轻乙醇诱导的AM线粒体紊乱。
Excessive alcohol users have increased risk of developing respiratory infections in part due to oxidative stress-induced alveolar macrophage (AM) phagocytic dysfunction. Chronic ethanol exposure increases cellular oxidative stress in AM via upregulation of NADPH oxidase (Nox) 4, and treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) ligand, rosiglitazone, decreased ethanol-induced Nox4. However, the mechanism by which ethanol induces Nox4 expression and PPARγ ligand reverses this defect has not been elucidated. Since microRNA (miR)-92a has been predicted to target Nox4 for destabilization, we hypothesized that ethanol exposure decreases miR-92a expression and leads to Nox4 upregulation. Previous studies have implicated mitochondrial-derived oxidative stress in AM dysfunction. We further hypothesized that ethanol increases mitochondrial-derived AM oxidative stress and dysfunction via miR-92a and that treatment with the PPARγ ligand, pioglitazone, could reverse these derangements. To test these hypotheses, a mouse AM cell line, MH-S cells, were exposed to ethanol in vitro and primary AM were isolated from a mouse model of chronic ethanol consumption to measure Nox4, mitochondrial target mRNA (qRT-PCR) and protein levels (confocal microscopy), mitochondria-derived reactive oxygen species (confocal immunofluorescence), mitochondrial fission (electron microscopy), and mitochondrial bioenergetics (extracellular flux analyzer). Ethanol exposure increased Nox4, enhanced mitochondria-derived oxidative stress, augmented mitochondrial fission, and impaired mitochondrial bioenergetics. Transfection with miR-92a mimic in vitro or pioglitazone treatment in vivo diminished Nox4 levels, resulting in improvements in these ethanol-mediated derangements. These findings provide support that pioglitazone may provide a novel therapeutic approach to mitigate ethanol-induced AM mitochondrial derangements.
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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：
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影响因子：
12.4
作者：
通讯作者：
--
DOI：
10.1073/pnas.1002178107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Kuroda, Junya;Ago, Tetsuro;Sadoshima, Junichi
通讯作者：
Sadoshima, Junichi
影响因子：
168.9
作者：
Dormandy, JA;Charbonnel, B;Taton, J
通讯作者：
Taton, J