{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:55:41Z","timestamp":1791492941974,"version":"4.3.4"},"reference-count":57,"publisher":"American Physiological Society","issue":"1","funder":[{"DOI":"10.13039\/100000027","name":"HHS | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAA)","doi-asserted-by":"publisher","award":["P50AA024333"],"award-info":[{"award-number":["P50AA024333"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"HHS | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAA)","doi-asserted-by":"publisher","award":["U01AA020821"],"award-info":[{"award-number":["U01AA020821"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"HHS | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAA)","doi-asserted-by":"publisher","award":["K99AA025386"],"award-info":[{"award-number":["K99AA025386"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"HHS | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAA)","doi-asserted-by":"publisher","award":["R37AA011876"],"award-info":[{"award-number":["R37AA011876"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["T32 DK00731935"],"award-info":[{"award-number":["T32 DK00731935"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Clinical and Translational Science Collaborative Case Western Reserve University","award":["UL1RR024989"],"award-info":[{"award-number":["UL1RR024989"]}]},{"DOI":"10.13039\/100000097","name":"HHS | NIH | National Center for Research Resources (NCRR)","doi-asserted-by":"publisher","award":["1S10RR026820"],"award-info":[{"award-number":["1S10RR026820"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2018,7,1]]},"abstract":"<jats:p>Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL\/6J [wild type (WT)], C1q-deficient ( C1qa<jats:sup>\u2212\/\u2212<\/jats:sup>, lacking classical pathway activation), complement protein 4-deficient ( C4<jats:sup>\u2212\/\u2212<\/jats:sup>, lacking classical and lectin pathway activation), complement factor D-deficient ( FD<jats:sup>\u2212\/\u2212<\/jats:sup>, lacking alternative pathway activation), and C1qa\/FD<jats:sup>\u2212\/\u2212<\/jats:sup>(lacking classical and alternative pathway activation) mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 or 25 days. Following chronic ethanol exposure, liver injury, steatosis, and proinflammatory cytokine expression were increased in WT but not C1qa<jats:sup>\u2212\/\u2212<\/jats:sup>, C4<jats:sup>\u2212\/\u2212<\/jats:sup>, or C1qa\/FD<jats:sup>\u2212\/\u2212<\/jats:sup>mice. In contrast, liver injury, steatosis, and proinflammatory mediators were robustly increased in ethanol-fed FD<jats:sup>\u2212\/\u2212<\/jats:sup>mice compared with WT mice. Complement activation, assessed by hepatic accumulation of C1q and complement protein 3 (C3) cleavage products (C3b\/iC3b\/C3c), was evident in livers of WT mice in response to both short-term and chronic ethanol. While C1q accumulated in ethanol-fed FD<jats:sup>\u2212\/\u2212<\/jats:sup>mice (short term and chronic), C3 cleavage products were detected after short-term but not chronic ethanol. Consistent with impaired complement activation, chronic ethanol induced the accumulation of apoptotic cells and fibrogenic responses in the liver of FD<jats:sup>\u2212\/\u2212<\/jats:sup>mice. These data highlight the protective role of complement factor D (FD) and suggest that FD-dependent amplification of complement is an adaptive response that promotes hepatic healing and recovery in response to chronic ethanol.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY Complement, a component of the innate immune system, is an important pathophysiological contributor to ethanol-induced liver injury. We have identified a novel role for factor D, a component of the alternative pathway, in protecting the liver from ethanol-induced inflammation, accumulation of apoptotic hepatocytes, and profibrotic responses. These data indicate a dual role of complement with regard to inflammatory and protective responses and suggest that accumulation of apoptotic cells impairs hepatic healing\/recovery during alcoholic liver disease.<\/jats:p>","DOI":"10.1152\/ajpgi.00334.2017","type":"journal-article","created":{"date-parts":[[2018,3,29]],"date-time":"2018-03-29T18:53:32Z","timestamp":1522349612000},"page":"G66-G79","source":"Crossref","is-referenced-by-count":46,"title":["Complement Factor D protects mice from ethanol-induced inflammation and liver injury"],"prefix":"10.1152","volume":"315","author":[{"given":"Rebecca L.","family":"McCullough","sequence":"first","affiliation":[{"name":"Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan R.","family":"McMullen","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan M.","family":"Sheehan","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle L.","family":"Poulsen","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjoy","family":"Roychowdhury","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dian J.","family":"Chiang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Swedish Medical Group, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0095-0685","authenticated-orcid":false,"given":"Michele T.","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Caballeria","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biomediques August Pi iSunyer, Hospital Clinic of Barcelona, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio"},{"name":"Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2011-301146"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64039-4"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2013.04.005"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ng0598-56"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1080\/07853890600664608"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2007.05.008"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20051"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.6064\/2012\/402783"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.04.041"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2014.10.017"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/acer.13370"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c120026"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00371.x"},{"key":"B14","doi-asserted-by":"crossref","first-page":"549","DOI":"10.4049\/jimmunol.157.2.549","volume":"157","author":"Fischer MB","year":"1996","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0212099"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.09.002"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00537.2010"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2004.02627.x"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2015.05.006"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406921200"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29645"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i42.11893"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.06.005"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.06.014"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070166"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2003.10.019"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2016.05.006"},{"key":"B28","first-page":"237","volume":"37","author":"Nagy LE","year":"2015","journal-title":"Alcohol Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1556\/EuJMI.2.2012.2.2"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.12030"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2013.04.003"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2013.10.019"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.01.053"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80669-X"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23228"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1923"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2016.70"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathmechdis.3.121806.151456"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28676"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22776"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29144"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i44.16474"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/nri957"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2012.08.001"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0110053"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2014.09.004"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2016.02.008"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M034892"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2011.02.021"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0162228"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.3.1305"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2007.09.008"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.1.541"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.4291\/wjgp.v7.i1.17"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21223"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.261428398"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1111\/acer.12956"}],"container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpgi.00334.2017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T21:04:39Z","timestamp":1693602279000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpgi.00334.2017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,1]]},"references-count":57,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,7,1]]}},"alternative-id":["10.1152\/ajpgi.00334.2017"],"URL":"https:\/\/doi.org\/10.1152\/ajpgi.00334.2017","relation":{},"ISSN":["0193-1857","1522-1547"],"issn-type":[{"value":"0193-1857","type":"print"},{"value":"1522-1547","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,1]]}}}