Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation

Marc A.R.C. Daemen, Cornelis Van't Veer, Geertrui Denecker, Vincent H. Heemskerk, Tim G.A.M. Wolfs, Matthias Clauss, Peter Vandenabeele, Wim A. Buurman

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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.

Original languageEnglish (US)
Pages (from-to)541-549
Number of pages9
JournalJournal of Clinical Investigation
Issue number5
StatePublished - Sep 1999

ASJC Scopus subject areas

  • Medicine(all)

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    Daemen, M. A. R. C., Van't Veer, C., Denecker, G., Heemskerk, V. H., Wolfs, T. G. A. M., Clauss, M., Vandenabeele, P., & Buurman, W. A. (1999). Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation. Journal of Clinical Investigation, 104(5), 541-549.