title: Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation.
abstract: Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of tissue injury in organs subjected to ischemia. The mechanism that triggers inflammation and organ injury after ischemia remains to be elucidated, although different causes have been postulated. We investigated the role of apoptosis in the induction of inflammation and organ damage after renal ischemia. Using a murine model, we demonstrate a relationship between apoptosis and subsequent inflammation. At the time of reperfusion, administration of the antiapoptotic agents IGF-1 and ZVAD-fmk (a caspase inactivator) prevented the early onset of not only renal apoptosis, but also inflammation and tissue injury. Conversely, when the antiapoptotic agents were administered after onset of apoptosis, these protective effects were completely abrogated. The presence of apoptosis was directly correlated with posttranslational processing of the endothelial monocyte-activating polypeptide II (EMAP-II), which may explain apoptosis-induced influx and sequestration of leukocytes in the reperfused kidney. These results strongly suggest that apoptosis is a crucial event that can initiate reperfusion-induced inflammation and subsequent tissue injury. The newly described pathophysiological insights provide important opportunities to effectively prevent clinical manifestations of reperfusion injury in the kidney, and potentially in other organs.
authors.affiliation: Department of General Surgery, University of Maastricht, 6200 MD Maastricht, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Daemen
authors.forename: C
authors.initials: C
authors.lastname: van 't Veer
authors.forename: G
authors.initials: G
authors.lastname: Denecker
authors.forename: V H
authors.initials: VH
authors.lastname: Heemskerk
authors.forename: T G
authors.initials: TG
authors.lastname: Wolfs
authors.forename: M
authors.initials: M
authors.lastname: Clauss
authors.forename: P
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: W A
authors.initials: WA
authors.lastname: Buurman
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001806:Blood Urea Nitrogen; D020169:Caspases / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines; D003864:Depression, Chemical; D004334:Drug Administration Schedule; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007511:Ischemia / Q000150:complications / Q000473:pathology*; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D009393:Nephritis / Q000209:etiology / Q000517:prevention & control*; D009195:Peroxidase / Q000097:blood; D011499:Protein Processing, Post-Translational; D016601:RNA-Binding Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C077219:small inducible cytokine subfamily E, member 1; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D009195:Peroxidase; D020169:Caspases