{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:32:01Z","timestamp":1778571121017,"version":"3.51.4"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":427,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31270929, 30930086, and 81220108024"],"award-info":[{"award-number":["31270929, 30930086, and 81220108024"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Innovation Team Foundation of Ministry of Education of China","award":["PCSIRT 1052"],"award-info":[{"award-number":["PCSIRT 1052"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Viral fulminant hepatitis (FH) remains a serious clinical problem with very high mortality. Lacking understanding of FH pathogenesis has in essence hindered efficient clinical treatment. Inferring from a correlation observed between the genetic differences in the complement component 5 (C5) and the susceptibility of mouse strains to murine hepatitis virus strain-3 (MHV-3) infections, we propose that excessive complement activation plays a critical role in the development of FH. We show that MHV-3 infection causes massive complement activation, along with a rapid increase in serum C5a levels and quick development of FH in susceptible strains. Mice deficient in the C5a receptor (C5aR) or the susceptible strains treated with C5aR antagonists (C5aRa) exhibit significant attenuation of the disease, accompanied by a remarkable reduction of hepatic fibrinogen-like protein 2 (Fgl2), a hallmark protein that causes necrosis of infected livers. In accordance, biopsy of FH patients shows a dramatic increase of Fgl2 expression, which correlates with C5aR up-regulation in the liver.<\/jats:bold>\n                                 <jats:bold>\n                                    In vitro\n                                 <\/jats:bold>\n                                 <jats:bold>C5a administration accelerates MHV-3-induced Fgl2 secretion by macrophages. Furthermore, inhibiting ERK1\/2 and p38 efficiently blocks C5a-mediated Fgl2 production during viral infections.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion :<\/jats:title>\n            <jats:p>\n                                 <jats:bold>These data provide evidence that mouse susceptibility to MHV-3-induced FH may rely on C5a\/C5aR interactions, for which ERK1\/2 and p38 pathways participate in up-regulating Fgl2 expression. Inhibition of C5a\/C5aR interactions is expected to be beneficial in the clinical treatment of FH patients. (Hepatology 2014;60:114\u2013124)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.27114","type":"journal-article","created":{"date-parts":[[2014,3,7]],"date-time":"2014-03-07T06:30:48Z","timestamp":1394173848000},"page":"114-124","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":42,"title":["C5a\/C5aR Pathway Is Essential for the Pathogenesis of Murine Viral Fulminant Hepatitis by Way of Potentiating Fgl2\/Fibroleukin Expression"],"prefix":"10.1097","volume":"60","author":[{"given":"Gui-lian","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gui-qing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-xin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-zhang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-18-20250207","doi-asserted-by":"crossref","first-page":"18621872","DOI":"10.1056\/NEJM199312163292508","article-title":"Acute liver failure.","volume":"329","author":"Lee","year":"1993","journal-title":"N Engl J Med"},{"key":"R3-18-20250207","doi-asserted-by":"crossref","first-page":"649660","DOI":"10.1002\/hep.1840050422","article-title":"Acute and chronic changes in the microcirculation of the liver in inbred strains of mice following infection with mouse hepatitis virus type 3.","volume":"5","author":"MacPhee","year":"1985","journal-title":"Hepatology"},{"key":"R4-18-20250207","doi-asserted-by":"crossref","first-page":"24352440","DOI":"10.1016\/S0021-9258(19)39817-5","article-title":"Deficiency of the murine fifth complement component (C5). 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