Alcohol induces mitochondrial redox imbalance in alveolar macrophages

Ling, Yan; Harris, Frank L.; Jones, Dean P.; Brown, Lou Ann S.

doi:10.1016/j.freeradbiomed.2013.10.010

Cited by 36 publications

(31 citation statements)

References 47 publications

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“…These include altered oxidant-antioxidant balance (24,25) and direct suppressive effects on AMs (26,27). In this study, we describe a mechanism in which EtOH impairs lung lipid homeostasis, associated with altered activation of AMPK, with the net effects of enhanced lipid synthesis and impaired immune function.…”

Section: Discussionmentioning

confidence: 90%

Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

Romero

Shah

Duong

et al. 2014

Am J Respir Cell Mol Biol

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Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. Although alcoholism has been shown to alter hepatic metabolism, leading to lipid accumulation, hepatitis, and, eventually, cirrhosis, the effects of alcohol on pulmonary metabolism remain largely unknown. Because both the lung and the liver actively engage in lipid synthesis, we hypothesized that chronic alcoholism would impair pulmonary metabolic homeostasis in ways similar to its effects in the liver. We reasoned that perturbations in lipid metabolism might contribute to the impaired pulmonary immunity observed in people who chronically consume alcohol. We studied the metabolic consequences of chronic alcohol consumption in rat lungs in vivo and in alveolar epithelial type II cells and alveolar macrophages (AMs) in vitro. We found that chronic alcohol ingestion significantly alters lung metabolic homeostasis, inhibiting AMP-activated protein kinase, increasing lipid synthesis, and suppressing the expression of genes essential to metabolizing fatty acids (FAs). Furthermore, we show that these metabolic alterations promoted a lung phenotype that is reminiscent of alcoholic fatty liver and is characterized by marked accumulation of triglycerides and free FAs within distal airspaces, AMs, and, to a lesser extent, alveolar epithelial type II cells. We provide evidence that the metabolic alterations in alcohol-exposed rats are mechanistically linked to immune impairments in the alcoholic lung: the elevations in FAs alter AM phenotypes and suppress both phagocytic functions and agonist-induced inflammatory responses. In summary, our work demonstrates that chronic alcohol ingestion impairs lung metabolic homeostasis and promotes pulmonary immune dysfunction. These findings suggest that therapies aimed at reversing alcohol-related metabolic alterations might be effective for preventing and/or treating alcohol-related pulmonary disorders.Keywords: chronic alcohol ingestion; AMP-activated protein kinase; surfactant lipids; macrophage Clinical RelevanceChronic alcohol abuse is a risk factor for bacterial pneumonia and acute respiratory distress syndrome; the molecular mechanisms underlying this association are not understood. Our work demonstrates that chronic alcohol exposure induces significant metabolic changes in the lung, including marked accumulation of triglycerides and free fatty acids within distal airspaces and alveolar macrophages (AMs). Furthermore, we provide evidence linking these lipid abnormalities to phenotypic and functional impairments in AMs, suggesting that these metabolic disturbances may contribute to the pathogenesis of alcohol-related inflammatory lung diseases. Together, these observations have broad implications for studying the effects of alcohol on lung homeostasis and immunity, and may be relevant to the pathogenesis of other inflammatory pulmonary disorders.

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Section: Discussionmentioning

confidence: 90%

Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

Romero

Shah

Duong

et al. 2014

Am J Respir Cell Mol Biol

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“…There are also evidences that chronic and acute ethanol consumption increases the NADH/NAD + ratio [33–36]. The elevated NADH/NAD + ratio results in an imbalance in the redox state of the cell contributing to increased ROS production [37]. In addition, increased ratio of NADH/NAD + is also suggested to contribute to the pathogenesis of fatty liver in part by modulating fatty acid metabolism [38].…”

Section: Discussionmentioning

confidence: 99%

Synergistic Interaction of Light Alcohol Administration in the Presence of Mild Iron Overload in a Mouse Model of Liver Injury: Involvement of Triosephosphate Isomerase Nitration and Inactivation

Gao¹,

Zhao²,

Gao³

et al. 2017

PLoS ONE

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It is well known that iron overload promotes alcoholic liver injury, but the doses of iron or alcohol used in studies are usually able to induce liver injury independently. Little attention has been paid to the coexistence of low alcohol consumption and mild iron overload when either of them is insufficient to cause obvious liver damage, although this situation is very common among some people. We studied the interactive effects and the underlining mechanism of mild doses of iron and alcohol on liver injury in a mouse model. Forty eight male Kunming mice were randomly divided into four groups: control, iron (300 mg/kg iron dextran, i.p.), alcohol (2 g/kg/day ethanol for four weeks i.g.), and iron plus alcohol group. After 4 weeks of treatment, mice were sacrificed and blood and livers were collected for biochemical analysis. Protein nitration level in liver tissue was determined by immunoprecipitation and Western blot analysis. Although neither iron overload nor alcohol consumption at our tested doses can cause severe liver injury, it was found that co-administration of the same doses of alcohol and iron resulted in liver injury and hepatic dysfunction, accompanied with elevated ratio of NADH/NAD+, reduced antioxidant ability, increased oxidative stress, and subsequent elevated protein nitration level. Further study revealed that triosephosphate isomerase, an important glycolytic enzyme, was one of the targets to be oxidized and nitrated, which was responsible for its inactivation. These data indicate that even under low alcohol intake, a certain amount of iron overload can cause significant liver oxidative damage, and the modification of triosephosphate isomerasemight be the important underlining mechanism of hepatic dysfunction.

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“…The current study demonstrated direct toxicity of FAEEs such as EO to the MT of the neonatal AM in the absence of ethanol exposure. These results suggested that FAEEs contribute to the well-described MT oxidative stress induced by chronic ethanol exposure (Liang et al., 2013). …”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Ethyl Esters Disrupt Neonatal Alveolar Macrophage Mitochondria and Derange Cellular Functioning

Mohan

Ping

Harris

et al. 2015

Alcohol Clin Exp Res

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BackgroundChronic alcohol exposure alters the function of alveolar macrophages (AM), impairing immune defenses in both adult and neonatal lungs. Fatty acid ethyl esters (FAEEs) are biological markers of prenatal alcohol exposure in newborns. FAEEs contribute to alcohol-induced mitochondrial (MT) damage in multiple organs. We hypothesized that in utero ethanol exposure would increase FAEEs in the neonatal lung and that direct exposure of neonatal AM to FAEEs would contribute to MT injury and cellular dysfunction.MethodsFAEEs were measured in neonatal guinea pig lungs after ± in utero ethanol exposure via gas chromatography/mass spectrometry. The NR8383 cell line and freshly isolated neonatal guinea pig AM were exposed to ethyl oleate (EO) in vitro. MT membrane potential, MT reactive oxygen species generation (mROS), phagocytosis, and apoptosis were evaluated after exposure to EO ± the MT-specific antioxidant mito-TEMPO (mitoT) or ± the pan-caspase inhibitor Z-VAD-FMK. Whole lung FAEEs were compared using the Mann–Whitney U-test. Cellular results were analyzed using 1-way analysis of variance, followed by the Student–Newman–Keuls Method for post hoc comparisons.ResultsIn utero ethanol significantly increased ethyl linoleate and the combinations of ethyl oleate + linoleate + linolenate (OLL), and OLL + stearate in the neonatal lung. In vitro EO caused significant MT dysfunction in both NR8383 and primary neonatal AM, as indicated by increased mROS and loss of MT membrane potential. Impaired phagocytosis and apoptosis were significantly increased in both the cell line and primary AM after EO exposure. MitoT conferred significant but only partial protection against EO-induced MT injury, as did caspase inhibition with Z-VAD-FMK.ConclusionsIn utero ethanol exposure increased FAEEs in the neonatal guinea pig lung. Direct exposure to the FAEE EO significantly contributed to AM dysfunction, in part via oxidant injury to the MT and in part via secondary apoptosis.

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Alcohol induces mitochondrial redox imbalance in alveolar macrophages

Cited by 36 publications

References 47 publications

Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

Synergistic Interaction of Light Alcohol Administration in the Presence of Mild Iron Overload in a Mouse Model of Liver Injury: Involvement of Triosephosphate Isomerase Nitration and Inactivation

Fatty Acid Ethyl Esters Disrupt Neonatal Alveolar Macrophage Mitochondria and Derange Cellular Functioning

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