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In the present study, we investigated the role of geranylgeranyltransferase in AP. Male C57BL\/6 mice were treated with a geranylgeranyltransferase inhibitor GGTI-2133 (20 mg\/kg) prior to induction of pancreatitis by infusion of taurocholate into the pancreatic duct. Pretreatment with GGTI-2133 reduced plasma amylase levels, pancreatic neutrophil recruitment, hemorrhage, and edema formation in taurocholate-evoked pancreatitis. Moreover, administration of GGTI-2133 decreased the taurocholate-induced increase of MPO activity in the pancreas and lung. Treatment with GGTI-2133 markedly reduced levels of CXCL2 in the pancreas and IL-6 in the plasma in response to taurocholate challenge. Notably, geranylgeranyltransferase inhibition abolished neutrophil expression of Mac-1 in mice with pancreatitis. Finally, inhibition of geranylgeranyltransferase had no direct effect on secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. A significant role of geranylgeranyltransferase was confirmed in an alternate model of AP induced by L-arginine challenge. Our findings show that geranylgeranyltransferase regulates neutrophil accumulation and tissue damage via expression of Mac-1 on neutrophils and CXCL2 formation in AP. Thus, these results reveal new signaling mechanisms in pancreatitis and indicate that targeting geranylgeranyltransferase might be an effective way to ameliorate severe AP.<\/jats:p>","DOI":"10.1189\/jlb.1112546","type":"journal-article","created":{"date-parts":[[2013,6,7]],"date-time":"2013-06-07T04:30:07Z","timestamp":1370579407000},"page":"493-502","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition of geranylgeranyltransferase attenuates neutrophil accumulation and tissue injury in severe acute pancreatitis"],"prefix":"10.1093","volume":"94","author":[{"given":"Mohammed","family":"Merza","sequence":"first","affiliation":[{"name":"Department of Surgery, Clinical Sciences, Malm\u00f6, Sk\u00e5ne University Hospital, Lund University , Malm\u00f6, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"Wetterholm","sequence":"additional","affiliation":[{"name":"Department of Surgery, Clinical Sciences, Malm\u00f6, Sk\u00e5ne University Hospital, Lund University , Malm\u00f6, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Clinical Sciences, Malm\u00f6, Sk\u00e5ne University Hospital, Lund University , Malm\u00f6, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Regner","sequence":"additional","affiliation":[{"name":"Department of Surgery, Clinical Sciences, Malm\u00f6, Sk\u00e5ne University Hospital, Lund University , Malm\u00f6, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Thorlacius","sequence":"additional","affiliation":[{"name":"Department of Surgery, Clinical Sciences, Malm\u00f6, Sk\u00e5ne University Hospital, Lund University , Malm\u00f6, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,6,6]]},"reference":[{"key":"2023032711580312400_","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1097\/MPA.0b013e31802e01ec","article-title":"Late development of pancreas necrosis during acute pancreatitis: an underestimated phenomenon associated with high morbidity and mortality","volume":"34","author":"Wijffels","year":"2007","journal-title":"Pancreas"},{"key":"2023032711580312400_","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1159\/000085265","article-title":"Pathophysiology of acute pancreatitis","volume":"5","author":"Bhatia","year":"2005","journal-title":"Pancreatology"},{"key":"2023032711580312400_","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.3748\/wjg.15.1427","article-title":"Acute pancreatitis: etiology and common pathogenesis","volume":"15","author":"Wang","year":"2009","journal-title":"World J. 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