{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:57:29Z","timestamp":1790092649641,"version":"4.0.1"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2344,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,4]]},"abstract":"<jats:sec>\n            <jats:title>Abstract<\/jats:title>\n            <jats:p>The innate immune system has been implicated in the pathogenesis of alcoholic liver disease. Although innate immunity is usually considered an early response to injury, previous work implicating innate immunity in ethanol-induced liver injury focuses primarily on long-term ethanol exposure. We investigated the early period of ethanol exposure to determine whether there were temporal associations between activation of innate immune responses and known correlates of liver injury. Female C57BL\/6 mice were allowed free access to an ethanol-containing Lieber-DeCarli diet or were pair-fed a control diet. Within 4 days of ethanol exposure, we observed a striking spike in expression of hepatic proinflammatory cytokines\u2014including tumor necrosis factor \u03b1 (TNF-\u03b1), interleukin-6, and interferon-\u03b3\u2014prior to hepatic triglyceride accumulation or increased plasma alanine aminotransferase activities, as well as before the induction of cytochrome P450 2E1 or oxidative stress. This early spike in inflammatory cytokines coincided with deposition of C3b-iC3b\/C3c (C3b) in the liver. This deposition, resulting from the cleavage of the third component of the complement system (C3), is evidence for activation of complement in response to ethanol. <jats:italic toggle=\"yes\">C3<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice were protected from the early, ethanol-induced increase in hepatic TNF-\u03b1 expression. Ethanol increased C3b deposition in mice deficient in C3a receptor or C5a receptor, as well as in wild-type mice depleted of hepatic macrophages; however, there was no increase in hepatic TNF-\u03b1 in the absence of C3a receptor, C5a receptor, or hepatic macrophages. In contrast, the absence of Toll-like receptor 4 (TLR-4) had no effect on the early, ethanol-induced increase in either C3b or TNF-\u03b1. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> We have identified a complement- and macrophage-dependent, but TLR-4 independent, phase in the pathogenesis of ethanol-induced liver injury. (Hepatology 2009.)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.22776","type":"journal-article","created":{"date-parts":[[2008,12,9]],"date-time":"2008-12-09T22:29:19Z","timestamp":1228861759000},"page":"1326-1334","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":92,"title":["An early complement-dependent and TLR-4\u2013independent phase in the pathogenesis of ethanol-induced liver injury in mice #"],"prefix":"10.1097","volume":"49","author":[{"given":"Sanjoy","family":"Roychowdhury","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan R.","family":"McMullen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele T.","family":"Pritchard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy G.","family":"Hise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"van Rooijen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M.","family":"Medof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abram B.","family":"Stavitsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-30-20241201","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1159\/000201257","article-title":"Molecular mechanisms of liver fibrogenesisa homage to the role of activated fatstoring cells.","volume":"56","author":"Gressner","year":"1995","journal-title":"Digestion"},{"key":"R2-30-20241201","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/hep.1840200227","article-title":"Inactivation of Kupffer cells prevents early alcoholinduced liver injury.","volume":"20","author":"Adachi","year":"1994","journal-title":"HEPATOLOGY"},{"key":"R3-30-20241201","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1056\/NEJM200011163432007","article-title":"Cytokines in alcoholic and nonalcoholic steatohepatitis.","volume":"343","author":"Tilg","year":"2000","journal-title":"N Engl J Med"},{"key":"R4-30-20241201","first-page":"G605","article-title":"Mechanisms of hepatic toxicity II. 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