{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:13:22Z","timestamp":1791843202605,"version":"4.3.4"},"reference-count":112,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T00:00:00Z","timestamp":1485475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma.The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms\/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currentlyonly partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aimsto introduce the reader to the concept of alcohol\u2010mediated liver damage and the mechanisms driving injury.<\/jats:p>","DOI":"10.3390\/biom7010009","type":"journal-article","created":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T11:23:02Z","timestamp":1485516182000},"page":"9","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Key Events Participating in the Pathogenesis of  Alcoholic Liver Disease"],"prefix":"10.3390","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4121-6743","authenticated-orcid":false,"given":"Fernando","family":"Magdaleno","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Illinois at Chicago, 840 S. 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Liver Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.jhep.2016.08.011","article-title":"The genetics of alcohol dependence and alcohol-related liver disease","volume":"66","author":"Stickel","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1038\/ng.3417","article-title":"A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis","volume":"47","author":"Buch","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1748-1716.2009.01970.x","article-title":"AMP-activated protein kinase in the regulation of hepatic energy metabolism: From physiology to therapeutic perspectives","volume":"196","author":"Viollet","year":"2009","journal-title":"Acta Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/j.jhep.2016.01.035","article-title":"The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis","volume":"64","author":"Bala","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.fct.2011.11.030","article-title":"Garlic oil alleviated ethanol-induced fat accumulation via modulation of SREBP-1, PPAR-\u03b1, and CYP2E1","volume":"50","author":"Zeng","year":"2012","journal-title":"Food Chem. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/nrgastro.2011.134","article-title":"Alcoholic liver disease: Pathogenesis and new targets for therapy","volume":"8","author":"Altamirano","year":"2011","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.jnutbio.2014.10.016","article-title":"Enhanced AMPK phosphorylation contributes to the beneficial effects of Lactobacillus rhamnosus GG supernatant on chronic-alcohol-induced fatty liver disease","volume":"26","author":"Zhang","year":"2015","journal-title":"J. Nutr. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.biochi.2007.09.019","article-title":"Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP-activated protein kinase in rat liver","volume":"90","author":"Guillen","year":"2008","journal-title":"Biochimie"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/biom6010001","article-title":"Alcoholic liver disease: Update on the role of dietary fat","volume":"6","author":"Kirpich","year":"2016","journal-title":"Biomolecules"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/S0140-6736(95)91685-7","article-title":"Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver","volume":"346","author":"Teli","year":"1995","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/978-3-319-09614-8_7","article-title":"Alcoholic cirrhosis and hepatocellular carcinoma","volume":"815","author":"Stickel","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1002\/hep.25614","article-title":"Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis","volume":"55","author":"Altamirano","year":"2012","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1136\/gutjnl-2014-308410","article-title":"Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis","volume":"64","author":"Dubuquoy","year":"2015","journal-title":"Gut"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"35610","DOI":"10.1038\/srep35610","article-title":"LPS-TLR4 pathway mediates ductular cell expansion in alcoholic hepatitis","volume":"6","author":"Odena","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1111\/apm.12568","article-title":"The damage-associated molecular pattern HMGB1 is elevated in human alcoholic hepatitis, but does not seem to be a primary driver of inflammation","volume":"124","author":"Laursen","year":"2016","journal-title":"APMIS"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lackner, C., Spindelboeck, W., Haybaeck, J., Douschan, P., Rainer, F., Terracciano, L., Haas, J., Berghold, A., Bataller, R., and Stauber, R.E. (2016). Histological parameters and alcohol abstinence determine long-term prognosis in patients with alcoholic liver disease. J. Hepatol.","DOI":"10.1016\/j.jhep.2016.11.011"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Garcia-Saenz-de-Sicilia, M., Duvoor, C., Altamirano, J., Chavez-Araujo, R., Prado, V., de Lourdes Candolo-Martinelli, A., Holanda-Almeida, P., Becerra-Martins-de-Oliveira, B., Fernandez-de-Almeida, S., and Bataller, R. (2016). A Day-4 Lille Model Predicts Response to Corticosteroids and Mortality in Severe Alcoholic Hepatitis. Am. J. Gastroenterol.","DOI":"10.1038\/ajg.2017.76"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.jhep.2013.03.007","article-title":"Global burden of alcoholic liver diseases","volume":"59","author":"Rehm","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1097\/MCG.0000000000000208","article-title":"The epidemiology of cirrhosis in the united states: A population-based study","volume":"49","author":"Scaglione","year":"2015","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1002\/hep.27318","article-title":"Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles","volume":"61","author":"Lemoinne","year":"2015","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.jhep.2012.08.018","article-title":"CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease","volume":"58","author":"Leung","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bankoglu, E.E., Tschopp, O., Schmitt, J., Burkard, P., Jahn, D., Geier, A., and Stopper, H. (2016). Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166956"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"80223","DOI":"10.18632\/oncotarget.12831","article-title":"Glycine protects against high sucrose and high fat-induced non-alcoholic steatohepatitis in rats","volume":"7","author":"Zhou","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Park, J.H., Lee, D.H., Park, M.S., Jung, Y.S., and Hong, J.T. (2016). CCR5 deficiency exacerbates alcoholic fatty liver disease through pro-inflammatory cytokines and chemokines-induced hepatic inflammation. J. Gastroenterol. Hepatol.","DOI":"10.1111\/jgh.13657"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lee, S.J., Lee, D.E., Kang, J.H., Nam, M.J., Park, J.W., Kang, B.S., Lee, D.S., Lee, H.S., and Kwon, O.S. (2016). New potential biomarker proteins for alcoholic liver disease identified by a comparative proteomics approach. J. Cell. Biochem.","DOI":"10.1002\/jcb.25770"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1111\/acer.12424","article-title":"Modulation of fatty acid and bile acid metabolism by peroxisome proliferator-activated receptor \u03b1 protects against alcoholic liver disease","volume":"38","author":"Li","year":"2014","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1002\/hep.27036","article-title":"Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice","volume":"60","author":"Kwon","year":"2014","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7692","DOI":"10.1074\/jbc.M111.293399","article-title":"Ethanol suppresses ureagenesis in rat hepatocytes: Role of acetaldehyde","volume":"287","author":"Holmuhamedov","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s11010-016-2798-7","article-title":"Antioxidant and anti-inflammatory role of zingerone in ethanol-induced hepatotoxicity","volume":"421","author":"Mani","year":"2016","journal-title":"Mol. Cell. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s12263-009-0159-9","article-title":"Ethanol-induced oxidative stress: Basic knowledge","volume":"5","author":"Comporti","year":"2010","journal-title":"Genes Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.lfs.2016.08.017","article-title":"Protective effect of treatment with thiamine or benfotiamine on liver oxidative damage in rat model of acute ethanol intoxication","volume":"162","author":"Portari","year":"2016","journal-title":"Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.alcohol.2004.12.001","article-title":"Swift increase in alcohol metabolism (SIAM): Understanding the phenomenon of hypermetabolism in liver","volume":"35","author":"Bradford","year":"2005","journal-title":"Alcohol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/j.1751-2980.2011.00569.x","article-title":"Oxidative stress and redox signaling mechanisms of alcoholic liver disease: Updated experimental and clinical evidence","volume":"13","author":"Zhu","year":"2012","journal-title":"J. Dig. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cld.2004.10.005","article-title":"Metabolism of alcohol","volume":"9","author":"Lieber","year":"2005","journal-title":"Clin. Liver Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S0022-2275(20)40613-3","article-title":"Effects of ethanol on lipid metabolism","volume":"20","author":"Baraona","year":"1979","journal-title":"J. Lipid Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/j.1530-0277.2011.01602.x","article-title":"Alcohol disrupts endoplasmic reticulum function and protein secretion in hepatocytes","volume":"36","author":"Howarth","year":"2012","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.cld.2012.08.002","article-title":"Alcohol metabolism","volume":"16","author":"Cederbaum","year":"2012","journal-title":"Clin. Liver Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/j.1530-0277.2001.tb02242.x","article-title":"Gender differences in pharmacokinetics of alcohol","volume":"25","author":"Baraona","year":"2001","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S0168-8278(97)80286-3","article-title":"Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients","volume":"27","author":"Mansouri","year":"1997","journal-title":"J. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0016-5085(95)90024-1","article-title":"Hepatic mitochondrial DNA deletion in alcoholics: Association with microvesicular steatosis","volume":"108","author":"Fromenty","year":"1995","journal-title":"Gastroenterology"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ramirez, T., Li, Y.M., Yin, S., Xu, M.J., Feng, D., Zhou, Z., Zang, M., Mukhopadhyay, P., Varga, Z.V., and Pacher, P. (2016). Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. J. Hepatol., in press.","DOI":"10.1016\/j.jhep.2016.11.004"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1097\/MOG.0000000000000176","article-title":"Aging and liver disease","volume":"31","author":"Kim","year":"2015","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8459","DOI":"10.3748\/wjg.v19.i46.8459","article-title":"Liver physiology and liver diseases in the elderly","volume":"19","author":"Tajiri","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/0531-5565(92)90059-9","article-title":"Effect of aging and caloric restriction on intestinal permeability","volume":"27","author":"Ma","year":"1992","journal-title":"Exp. Gerontol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1046\/j.1440-1746.2003.03032.x","article-title":"Intestinal barrier: An interface between health and disease","volume":"18","author":"Farhadi","year":"2003","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1111\/eci.12032","article-title":"Iron homeostasis in the metabolic syndrome","volume":"43","author":"Datz","year":"2013","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/0378-4274(95)03532-X","article-title":"Toxicity of iron and hydrogen peroxide: The fenton reaction","volume":"82\u201383","author":"Winterbourn","year":"1995","journal-title":"Toxicol. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1172\/JCI114934","article-title":"Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload","volume":"86","author":"Houglum","year":"1990","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.jhep.2016.01.037","article-title":"Mechanisms of iron hepatotoxicity","volume":"65","author":"Pietrangelo","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1017\/S0007114516001197","article-title":"Decreased hepatic iron in response to alcohol may contribute to alcohol-induced suppression of hepcidin","volume":"115","author":"Varghese","year":"2016","journal-title":"Br. J. Nutr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/liv.13020","article-title":"Iron and the liver","volume":"36","author":"Pietrangelo","year":"2016","journal-title":"Liver Int."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4091","DOI":"10.3748\/wjg.v22.i16.4091","article-title":"Adult mouse model of early hepatocellular carcinoma promoted by alcoholic liver disease","volume":"22","author":"Ambade","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Li, M., He, Y., Zhou, Z., Ramirez, T., Gao, Y., Gao, Y., Ross, R.A., Cao, H., Cai, Y., and Xu, M. (2016). MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47phox-oxidative stress pathway in neutrophils. Gut.","DOI":"10.1136\/gutjnl-2016-311861"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/hep.28680","article-title":"Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease","volume":"64","author":"Bukong","year":"2016","journal-title":"Hepatology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"G269","DOI":"10.1152\/ajpgi.00200.2014","article-title":"Cytotoxic t lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis","volume":"308","author":"Stoy","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"G15","DOI":"10.1152\/ajpgi.90512.2008","article-title":"Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis","volume":"296","author":"Stadlbauer","year":"2009","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Andrews, K., Abdelsamed, H., Yi, A.K., Miller, M.A., and Fitzpatrick, E.A. (2013). TLR2 regulates neutrophil recruitment and cytokine production with minor contributions from TLR9 during hypersensitivity pneumonitis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073143"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"16544","DOI":"10.1073\/pnas.1308331110","article-title":"Sting-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease","volume":"110","author":"Petrasek","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/cdd.2011.4","article-title":"TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation","volume":"18","author":"Krysko","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1172\/JCI76887","article-title":"The HMGB1\/rage axis triggers neutrophil-mediated injury amplification following necrosis","volume":"125","author":"Huebener","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"E155","DOI":"10.1073\/pnas.1522288113","article-title":"Critical role of RAGE and HMGB1 in inflammatory heart disease","volume":"113","author":"Bangert","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1002\/hep.28811","article-title":"IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease","volume":"64","author":"Zhou","year":"2016","journal-title":"Hepatology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"315941","DOI":"10.1155\/2012\/315941","article-title":"Danger signals activating the immune response after trauma","volume":"2012","author":"Hirsiger","year":"2012","journal-title":"Mediat. Inflamm."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1007\/s00018-013-1400-7","article-title":"Joining S100 proteins and migration: For better or for worse, in sickness and in health","volume":"71","author":"Gross","year":"2014","journal-title":"Cell Mol. Life Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/cmi.2016.34","article-title":"HMGB1, IL-1\u03b1, IL-33 and S100 proteins: Dual-function alarmins","volume":"14","author":"Bertheloot","year":"2017","journal-title":"Cell. Mol. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4835","DOI":"10.4049\/jimmunol.1102048","article-title":"IL-1\u03b1 and IL-1\u03b2 recruit different myeloid cells and promote different stages of sterile inflammation","volume":"187","author":"Rider","year":"2011","journal-title":"J. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nrd3800","article-title":"Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases","volume":"11","author":"Dinarello","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1080\/15548627.2015.1058473","article-title":"Macrophage autophagy protects against liver fibrosis in mice","volume":"11","author":"Lodder","year":"2015","journal-title":"Autophagy"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4771","DOI":"10.4049\/jimmunol.1502490","article-title":"Highly dynamic transcriptional signature of distinct macrophage subsets during sterile inflammation, resolution, and tissue repair","volume":"196","author":"Varga","year":"2016","journal-title":"J. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1002\/hep.26429","article-title":"Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice","volume":"58","author":"Pradere","year":"2013","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1053\/j.gastro.2011.09.002","article-title":"Alcoholic liver disease: Pathogenesis and new therapeutic targets","volume":"141","author":"Gao","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Arriazu, E., Ge, X., Leung, T.M., Magdaleno, F., Lopategi, A., Lu, Y., Kitamura, N., Urtasun, R., Theise, N., and Antoine, D.J. (2016). Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut.","DOI":"10.1136\/gutjnl-2015-310752"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1002\/hep.26931","article-title":"Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-\u03b1 and prevents early alcohol-induced liver injury in mice","volume":"59","author":"Ge","year":"2014","journal-title":"Hepatology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"G929","DOI":"10.1152\/ajpgi.00014.2013","article-title":"Milk osteopontin, a nutritional approach to prevent alcohol-induced liver injury","volume":"304","author":"Ge","year":"2013","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/labinvest.2013.134","article-title":"Induction of chemokines and cytokines before neutrophils and macrophage recruitment in different regions of rat liver after TAA administration","volume":"94","author":"Amanzada","year":"2014","journal-title":"Lab. Investig."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4308","DOI":"10.4049\/jimmunol.180.6.4308","article-title":"Neutrophil chemokines KC and macrophage-inflammatory protein-2 are newly synthesized by tissue macrophages using distinct TLR signaling pathways","volume":"180","author":"Henderson","year":"2008","journal-title":"J. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"31697","DOI":"10.1074\/jbc.M804779200","article-title":"The Kinase Activity of IL-1 Receptor-associated Kinase 4 is Required for Interleukin-1 Receptor\/Toll-like Receptor-induced TAK1-dependent NF\u03baB Activation","volume":"283","author":"Fraczek","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1084\/jem.20061825","article-title":"A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity","volume":"204","author":"Kim","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6075","DOI":"10.1074\/jbc.M609039200","article-title":"Interleukin-1 (IL-1)-induced TAK1-dependent versus MEKK3-dependent NF\u03baB activation pathways bifurcate at IL-1 receptor-associated kinase modification","volume":"282","author":"Yao","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/ni.1703","article-title":"The inflammasome: A caspase-1-activation platform that regulates immune responses and disease pathogenesis","volume":"10","author":"Franchi","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nrgastro.2015.94","article-title":"Inflammasome activation and function in liver disease","volume":"12","author":"Szabo","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S1097-2765(02)00599-3","article-title":"The Inflammasome: A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of proIL-\u03b2","volume":"10","author":"Martinon","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1053\/j.gastro.2014.03.014","article-title":"Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity","volume":"146","author":"Hoque","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Prochnicki, T., Mangan, M.S., and Latz, E. (2016). Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000Research, 5.","DOI":"10.12688\/f1000research.8614.1"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.jhep.2014.12.027","article-title":"Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1\u03b2 in mice","volume":"62","author":"Cui","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.1998.tb08307.x","article-title":"Interleukin-1\u03b2, interleukin-18, and the interleukin-1\u03b2 converting enzyme","volume":"856","author":"Dinarello","year":"1998","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Mehta, R., Neupane, A., Wang, L., Goodman, Z., Baranova, A., and Younossi, Z.M. (2014). Expression of NALPs in adipose and the fibrotic progression of non-alcoholic fatty liver disease in obese subjects. BMC Gastroenterol., 14.","DOI":"10.1186\/s12876-014-0208-8"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"19571","DOI":"10.1074\/jbc.M114.550624","article-title":"Mitochondrial NLRP3 protein induces reactive oxygen species to promote Smad protein signaling and fibrosis independent from the inflammasome","volume":"289","author":"Bracey","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jhep.2014.08.027","article-title":"Absent in melanoma 2 triggers a heightened inflammasome response in ascitic fluid macrophages of patients with cirrhosis","volume":"62","author":"Bachiller","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"288","DOI":"10.3389\/fimmu.2014.00288","article-title":"Mcl and mincle: C-type lectin receptors that sense damaged self and pathogen-associated molecular patterns","volume":"5","author":"Richardson","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.jhep.2016.07.002","article-title":"The inflammasome in liver disease","volume":"65","author":"Wree","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.jhep.2015.06.013","article-title":"Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice","volume":"63","author":"Petrasek","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1194\/jlr.M053785","article-title":"Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH","volume":"56","author":"Ioannou","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Hendrikx, T., Bieghs, V., Walenbergh, S.M., van Gorp, P.J., Verheyen, F., Jeurissen, M.L., Steinbusch, M.M., Vaes, N., Binder, C.J., and Koek, G.H. (2013). Macrophage specific caspase-1\/11 deficiency protects against cholesterol crystallization and hepatic inflammation in hyperlipidemic mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078792"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1002\/hep.28736","article-title":"A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice","volume":"64","author":"Lundback","year":"2016","journal-title":"Hepatology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.jhep.2011.12.019","article-title":"Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity","volume":"56","author":"Antoine","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"479","DOI":"10.2119\/molmed.2010.00126","article-title":"Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity","volume":"16","author":"Antoine","year":"2010","journal-title":"Mol. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1053\/j.gastro.2013.12.015","article-title":"Intracellular HMGB1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice","volume":"146","author":"Kang","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.bbrc.2015.01.159","article-title":"Nuclear DAMP Complex-mediatedRAGE-Dependent Macrophage Cell Death","volume":"458","author":"Chen","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"357","DOI":"10.2119\/molmed.2013.00099","article-title":"Emerging role of high-mobility group box 1 (HMGB1) in liver diseases","volume":"19","author":"Chen","year":"2013","journal-title":"Mol. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.jss.2011.02.026","article-title":"LPS induces HMGB1 relocation and release by activating the NF-\u03baB-CBP signal transduction pathway in the murine macrophage-like cell line RAW264.7","volume":"175","author":"Wu","year":"2012","journal-title":"J. Surg. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.intimp.2016.11.002","article-title":"Ethyl pyruvate inhibits the acetylation and release of HMGB1 via effects on SIRT1\/STAT signaling in LPS-activated RAW264.7 cells and peritoneal macrophages","volume":"41","author":"Kim","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"22672","DOI":"10.1074\/jbc.M114.552141","article-title":"High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD)","volume":"289","author":"Ge","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"G732","DOI":"10.1152\/ajpgi.00073.2014","article-title":"Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a \u03b2-arrestin-2 pathway","volume":"307","author":"Farooq","year":"2014","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/hep.23258","article-title":"Alcoholic liver disease","volume":"51","author":"Dasarathy","year":"2010","journal-title":"Hepatology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.bbagen.2015.12.013","article-title":"Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice","volume":"1860","author":"Mir","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Ferrere, G., Wrzosek, L., Cailleux, F., Turpin, W., Puchois, V., Spatz, M., Ciocan, D., Rainteau, D., Humbert, L., and Hugot, C. (2016). Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice. J. Hepatol.","DOI":"10.1016\/j.jhep.2016.11.008"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1002\/hep.23009","article-title":"Endotoxemia and gut barrier dysfunction in alcoholic liver disease","volume":"50","author":"Rao","year":"2009","journal-title":"Hepatology"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/7\/1\/9\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:27:08Z","timestamp":1760207228000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/7\/1\/9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,27]]},"references-count":112,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,3]]}},"alternative-id":["biom7010009"],"URL":"https:\/\/doi.org\/10.3390\/biom7010009","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,27]]}}}