Chronic ethanol exposure alters the lung proteome and leads to mitochondrial dysfunction in alveolar type 2 cells

Alli, Abdel A.; Brewer, Elizabeth M.; Montgomery, Darrice; Ghant, Marcus; Eaton, Douglas C.; Brown, Lou Ann S.; Helms, My N.

doi:10.1152/ajplung.00287.2013

Cited by 11 publications

(7 citation statements)

References 56 publications

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“…Ethanol exposure has also been shown to promote inducible nitric oxide synthase (iNOS) expression and the subsequent production of NO [24] , [25] . Together, the ROS, reactive nitrogen species (RNS), and acetaldehyde produced during chronic ethanol exposure can induce nuclear and mitochondrial DNA damage and initiate ER stress via the accumulation of misfolded proteins [25] , [26] , [27] . Specifically, oxidized mitochondrial DNA and ER stress stimulate signaling pathways such as NF-κB and the NRLP3 inflammasome, but it is not known whether these factors contribute to inflammasome activation during chronic ethanol consumption [28] , [29] .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome

et al. 2017

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Alcohol use disorders are common both in the United States and globally, and are associated with a variety of co-morbid, inflammation-linked diseases. The pathogenesis of many of these ailments are driven by the activation of the NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the pro-inflammatory cytokines IL-1β and IL-18. We hypothesized that protracted exposure of leukocytes to ethanol would amplify inflammasome activation, which would help to implicate mechanisms involved in diseases associated with both alcoholism and aberrant NLRP3 inflammasome activation. Here we show that long-term ethanol exposure of human peripheral blood mononuclear cells and a mouse macrophage cell line (J774) amplifies IL-1β secretion following stimulation with NLRP3 agonists, but not with AIM2 or NLRP1b agonists. The augmented NRLP3 activation was mediated by increases in iNOS expression and NO production, in conjunction with increases in mitochondrial membrane depolarization, oxygen consumption rate, and ROS generation in J774 cells chronically exposed to ethanol (CE cells), effects that could be inhibited by the iNOS inhibitor SEITU, the NO scavenger carboxy-PTIO, and the mitochondrial ROS scavenger MitoQ. Chronic ethanol exposure did not alter K+ efflux or Zn2+ homeostasis in CE cells, although it did result in a lower intracellular concentration of NAD+. Prolonged administration of acetaldehyde, the product of alcohol dehydrogenase (ADH) mediated metabolism of ethanol, mimicked chronic ethanol exposure, whereas ADH inhibition prevented ethanol-induced IL-1β hypersecretion. Together, these results indicate that increases in iNOS and mitochondrial ROS production are critical for chronic ethanol-induced IL-1β hypersecretion, and that protracted exposure to the products of ethanol metabolism are probable mediators of NLRP3 inflammasome hyperactivation.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome

et al. 2017

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“…Transmission electron microscopy. Whole lungs were perfusionfixed with glutaraldehyde and prepared for transmission electron microscopy analysis by standard methods (5). Ultrastructure was visualized using a JEM-1400 transmission electron microscope (JEOL, Peabody, MA) linked to an Olympus SIS Veleta 2K camera (Olympus Soft Imaging Solutions).…”

Section: Methodsmentioning

confidence: 99%

Lethal H1N1 influenza A virus infection alters the murine alveolar type II cell surfactant lipidome

Woods

Doolittle

Rosas

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alveolar type II (ATII) epithelial cells are the primary site of influenza virus replication in the distal lung. Development of acute respiratory distress syndrome in influenza-infected mice correlates with significant alterations in ATII cell function. However, the impact of infection on ATII cell surfactant lipid metabolism has not been explored. C57BL/6 mice were inoculated intranasally with influenza A/WSN/33 (H1N1) virus (10,000 plaque-forming units/mouse) or mock-infected with virus diluent. ATII cells were isolated by a standard lung digestion protocol at 2 and 6 days postinfection. Levels of 77 surfactant lipid-related compounds of known identity in each ATII cell sample were measured by ultra-high-performance liquid chromatography-mass spectrometry. In other mice, bronchoalveolar lavage fluid was collected to measure lipid and protein content using commercial assay kits. Relative to mock-infected animals, ATII cells from influenza-infected mice contained reduced levels of major surfactant phospholipids (phosphatidylcholine, phosphatidylglycerol, and phosphatidylethanolamine) but increased levels of minor phospholipids (phosphatidylserine, phosphatidylinositol, and sphingomyelin), cholesterol, and diacylglycerol. These changes were accompanied by reductions in cytidine 5'-diphosphocholine and 5'-diphosphoethanolamine (liponucleotide precursors for ATII cell phosphatidylcholine and phosphatidylethanolamine synthesis, respectively). ATII cell lamellar bodies were ultrastructurally abnormal after infection. Changes in ATII cell phospholipids were reflected in the composition of bronchoalveolar lavage fluid, which contained reduced amounts of phosphatidylcholine and phosphatidylglycerol but increased amounts of sphingomyelin, cholesterol, and protein. Influenza infection significantly alters ATII cell surfactant lipid metabolism, which may contribute to surfactant dysfunction and development of acute respiratory distress syndrome in influenza-infected mice.

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“…Direct or indirect evidence is emerging for alcohol-induced disruption of mitochondrial protein homeostasis and UPRmt. In alveolar type 2 cells isolated from alcohol fed mice, the boldface mitochondrial proteins are significantly altered in alcohol versus caloric control-fed animals [ 69 ]. In the liver, chronic ethanol-mediated oxidative stress and lipid peroxidation increases the levels of various reactive species including 4-hydroxynonenal (4-HNE).…”

Section: Alcohol and Upr In The Mitochondriamentioning

confidence: 99%

Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage

Cheng

2015

Biomolecules

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Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between biogenesis and turnover of proteins within and outside the cell. A significant amount of published evidence indicates that alcohol and its metabolites directly or indirectly interfere with protein homeostasis in the endoplasmic reticulum (ER) causing an accumulation of unfolded or misfolded proteins, which triggers the unfolded protein response (UPR) leading to either restoration of homeostasis or cell death, inflammation and other pathologies under severe and chronic alcohol conditions. The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function. Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest. Here, I review recent advances in the alcohol-induced ER stress response as well as discuss new concepts on alcohol-induced mitochondrial, Golgi and lysosomal stress responses and injuries.

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Chronic ethanol exposure alters the lung proteome and leads to mitochondrial dysfunction in alveolar type 2 cells

Cited by 11 publications

References 56 publications

Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome

Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome

Lethal H1N1 influenza A virus infection alters the murine alveolar type II cell surfactant lipidome

Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage

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