{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:22:45Z","timestamp":1792790565972,"version":"4.5.0"},"reference-count":46,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2013,7,1]]},"abstract":"<jats:p> Cell line studies have previously demonstrated that hypoxia-reoxygenation (H\/R) leads to the production of NADPH oxidase 1 and 2 (NOX1 and NOX2)-dependent reactive oxygen species (ROS) required for the activation of c-Src and NF-\u03baB. We now extend these studies into mouse models to evaluate the contribution of hepatocytes to the NOX- and c-Src-dependent TNF-\u03b1 production that follows H\/R in primary hepatocytes and liver ischemia-reperfusion (I\/R). In vitro, c-Src-deficient primary hepatocytes produced less ROS and TNF-\u03b1 following H\/R compared with controls. In vivo, c-Src-KO mice also had impaired TNF-\u03b1 and NF-\u03baB responses following partial lobar liver I\/R. Studies in NOX1 and p47<jats:sup>phox<\/jats:sup> knockout primary hepatocytes demonstrated that both NOX1 and p47<jats:sup>phox<\/jats:sup> are partially required for H\/R-mediated TNF-\u03b1 production. To further investigate the involvement of NADPH oxidases in the production of TNF-\u03b1 following liver I\/R, we performed additional in vivo experiments in knockout mice deficient for NOX1, NOX2, p47<jats:sup>phox<\/jats:sup>, Rac1, and\/or Rac2. Cumulatively, these results demonstrate that NOX2 and its activator subunits (p47<jats:sup>phox<\/jats:sup> and Rac) control the secretion of TNF-\u03b1 by the liver following I\/R. Interestingly, in the absence of Kupffer cells and NOX2, NOX1 played a dominant role in TNF-\u03b1 production following hepatic I\/R. However, NOX1 deletion alone had little effect on I\/R-induced TNF-\u03b1. Thus Kupffer cell-derived factors and NOX2 act to suppress hepatic NOX1-dependent TNF-\u03b1 production. We conclude that c-Src and NADPH oxidase components are necessary for redox-mediated production of TNF-\u03b1 following liver I\/R and that hepatocytes play an important role in this process. <\/jats:p>","DOI":"10.1152\/ajpgi.00430.2012","type":"journal-article","created":{"date-parts":[[2013,5,3]],"date-time":"2013-05-03T06:19:27Z","timestamp":1367561967000},"page":"G84-G94","source":"Crossref","is-referenced-by-count":39,"title":["Hepatocytes produce TNF-\u03b1 following hypoxia-reoxygenation and liver ischemia-reperfusion in a NADPH oxidase- and c-Src-dependent manner"],"prefix":"10.1152","volume":"305","author":[{"given":"Netanya Y.","family":"Spencer","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, 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