{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:09:35Z","timestamp":1791331775997,"version":"4.3.1"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1584,"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":[[2011,5]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      <jats:bold>Hepatic ischemia and reperfusion (IR) injury is a major clinical problem that leads to frequent extrahepatic complications including intestinal dysfunction and acute kidney injury (AKI). In this study we aimed to determine the mechanisms of hepatic IR-induced extrahepatic organ dysfunction. Mice subjected to 60 minutes of hepatic IR not only developed severe hepatic injury but also developed significant AKI and small intestinal injury. Hepatic IR induced small intestinal Paneth cell degranulation and increased interleukin-17A (IL-17A) levels in portal vein plasma and small intestine. We also detected increased levels of IL-17A messenger RNA (mRNA) and protein in Paneth cells after hepatic IR with laser capture dissection. IL-17A-neutralizing antibody treatment or genetic deletion of either IL-17A or IL-17A receptors significantly protected against hepatic IR-induced acute liver, kidney, and intestinal injury. Leukocyte IL-17A does not contribute to organ injury, as infusion of wildtype splenocytes failed to exacerbate liver and kidney injury in IL-17A-deficient mice after hepatic IR. Depletion of Paneth cell numbers by pharmacological (with dithizone) or genetic intervention (SOX9 flox\/flox Villin cre+\/\u2212 mice) significantly attenuated intestinal, hepatic, and renal injury following liver IR. Finally, depletion of Paneth cell numbers significantly decreased small intestinal IL-17A release and plasma IL-17A levels after liver IR.<\/jats:bold>\n                      <jats:bold>Conclusion:<\/jats:bold>\n                      <jats:bold>Taken together, the results show that Paneth cell-derived IL-17A plays a critical role in hepatic IR injury and extrahepatic organ dysfunction. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from hepatic IR. (Hepatology 2011;)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.24253","type":"journal-article","created":{"date-parts":[[2011,2,26]],"date-time":"2011-02-26T10:51:58Z","timestamp":1298717518000},"page":"1662-1675","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":97,"title":["Paneth cell-derived interleukin-17A causes multiorgan dysfunction after hepatic ischemia and reperfusion injury"],"prefix":"10.1097","volume":"53","author":[{"given":"Sang Won","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihwa","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivette D.","family":"D'Agati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-27-20250207","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/j.transproceed.2005.03.134","article-title":"Ischemia and reperfusion injury in liver transplantation.","volume":"37","author":"KupiecWeglinski","year":"2005","journal-title":"Transplant Proc"},{"key":"R2-27-20250207","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1053\/jlts.2002.31516","article-title":"Pathophysiology of renal disease associated with liver disorders: implications for liver transplantation.","volume":"8","author":"Davis","year":"2002","journal-title":"Part I Liver Transpl"},{"key":"R3-27-20250207","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nri2800","article-title":"Innate IL17producing cells: the sentinels of the immune system.","volume":"10","author":"Cua","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"R4-27-20250207","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1084\/jem.20080588","article-title":"IL17 produced by Paneth cells drives TNFinduced shock.","volume":"205","author":"Takahashi","year":"2008","journal-title":"J Exp Med"},{"key":"R5-27-20250207","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cyto.2008.12.024","article-title":"IL17F: regulation, signaling and function in inflammation.","volume":"46","author":"Chang","year":"2009","journal-title":"Cytokine"},{"key":"R6-27-20250207","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0083-6729(06)74010-9","article-title":"The IL17 cytokine family.","volume":"74","author":"Gaffen","year":"2006","journal-title":"Vitam Horm"},{"key":"R7-27-20250207","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/labinvest.2010.151","article-title":"Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy.","volume":"91","author":"Park","year":"2011","journal-title":"Lab Invest"},{"key":"R8-27-20250207","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2006.07.035","article-title":"The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL17 T helper cells.","volume":"126","author":"Ivanov","year":"2006","journal-title":"Cell"},{"key":"R9-27-20250207","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1053\/j.gastro.2007.05.020","article-title":"SOX9 is required for the differentiation of paneth cells in the intestinal epithelium.","volume":"133","author":"MoriAkiyama","year":"2007","journal-title":"Gastroenterology"},{"key":"R10-27-20250207","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/labinvest.2008.124","article-title":"Acute kidney injury after hepatic ischemia and reperfusion injury in mice.","volume":"89","author":"Lee","year":"2009","journal-title":"Lab Invest"},{"key":"R11-27-20250207","first-page":"407","article-title":"Selective killing of Paneth cells by intravenous administration of dithizone in rats.","volume":"72","author":"Sawada","year":"1991","journal-title":"Int J Exp Pathol"},{"key":"R12-27-20250207","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1080\/003655202753416803","article-title":"Involvement of tumor necrosis factor alpha in intestinal epithelial cell proliferation following Paneth cell destruction.","volume":"37","author":"Seno","year":"2002","journal-title":"Scand J Gastroenterol"},{"key":"R13-27-20250207","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3109\/00365516509077065","article-title":"Plasma creatinine determination. 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