{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T03:34:46Z","timestamp":1790134486898,"version":"4.0.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,1,1]],"date-time":"2019-01-01T00:00:00Z","timestamp":1546300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hepatic ischemia reperfusion (I\/R) is a clinically relevant model of acute sterile inflammation leading to a reverberating, self-sustaining inflammatory response with resultant necrosis. We hypothesized that computerized dynamic network analysis (DyNA) of 20 inflammatory mediators could help dissect the sequence of post-I\/R mediator interactions that induce injury. Although the majority of measured inflammatory mediators become elevated in the first 24 h, we predicted that only a few would be secreted early in the process and serve as organizational centers of downstream intermediator complexity. In support of this hypothesis, DyNA inferred a central organizing role for IL-17A during the first 3 h of reperfusion. After that, DyNA revealed connections among almost all the inflammatory mediators, representing an ongoing cytokine storm. Blocking IL-17A immediately after reperfusion disassembled the inflammatory networks and protected the liver from injury. Disassembly of the networks was not achieved if IL-17A blockage was delayed two or more hours postreperfusion. Network disassembly was accompanied by decrease in neutrophil infiltration and neutrophil extracellular trap (NET) formation. By contrast, administration of recombinant IL-17A increased neutrophil infiltration, NET formation, and liver necrosis. The administration of DNase, a NET inhibitor, significantly reduced hepatic damage despite prior administration of IL-17A, and DNase also disassembled the inflammatory networks. In vitro, IL-17A was a potent promoter of NET formation. Therefore, computational analysis identified IL-17A\u2019s early, central organizing role in the rapid evolution of a network of inflammatory mediators that induce neutrophil infiltration and NET formation responsible for hepatic damage after liver I\/R.<\/jats:p>","DOI":"10.4049\/jimmunol.1800454","type":"journal-article","created":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T21:35:24Z","timestamp":1543613724000},"page":"268-277","source":"Crossref","is-referenced-by-count":49,"title":["Computational Analysis Supports IL-17A as a Central Driver of Neutrophil Extracellular Trap\u2013Mediated Injury in Liver Ischemia Reperfusion"],"prefix":"10.1093","volume":"202","author":[{"given":"Samer","family":"Tohme","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza O","family":"Yazdani","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1505-9684","authenticated-orcid":false,"given":"Vikas","family":"Sud","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9375-1724","authenticated-orcid":false,"given":"Patricia","family":"Loughran","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213"},{"name":"Center for Biologic Imaging, Department of Cell Biology, University of Pittsburgh , Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3882-9087","authenticated-orcid":false,"given":"Ruben","family":"Zamora","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213"},{"name":"Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine , Pittsburgh, PA 15219"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L","family":"Simmons","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4389-8768","authenticated-orcid":false,"given":"Yoram","family":"Vodovotz","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213"},{"name":"Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine , Pittsburgh, PA 15219"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3916-8965","authenticated-orcid":false,"given":"Allan","family":"Tsung","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,1,1]]},"reference":[{"key":"2025030417555756100_r1","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nri2873","article-title":"Sterile inflammation: sensing and reacting to damage","volume":"10","author":"Chen","year":"2010","journal-title":"Nat. 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