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2007 Program and Abstracts | 2007 Posters
Heme Oxygenase-1 (Ho-1) Generated Carbon Monoxide Und Biliverdin: Simple Principle to Treat Acute Necrotising Pancreatitis
Pascal O. Berberat*1,2, Tomas Mitkus1, Philipp Nuhn1, Fischer Lars1, GüRalp O. Ceyhan1, Nathalia Giese1, Thomas Giese2, Stefan C. Meuer2, Markus W. Buechler1, Helmut M. Friess1
1Department of General Surgery, University of Heidelberg, Heidelberg, Germany; 2Insitut of Immunology, University of Heidelberg, Heidelberg, Germany

Background: The so-called protective gene heme oxygenase-1 (HO-1) plays a key role in the defense against all kind of cellular stress, because of its anti-inflammatory and anti-apoptotic function. In acute pancreatitis HO-1 becomes highly up regulated during the course of the disease. A recent study showed that the induction of HO-1 in macrophages significantly reduces the mortality in pancreatitis in mice. It is believed that the anti-inflammatory effects of HO-1 are mainly mediated by its enzymatic products biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin. We tested the hypothesis that the metabolites of HO-1 may serve as potential new therapeutic products in acute necrotizing pancreatitis.
Methods: Acute necrotizing pancreatitis was induced by retrograde intraductal natrium-taurocholat injection (4%) on Sprague Dawley rats. Biliverdin (50µmol/kg sc), the iron chelator desferrioxamine (DFO, 125mg/kg sc) or methylen chloride (MC, 500mg/kg per os), which is metabolised to CO, were administered in a therapeutic manner starting with the first dose 4h after the induction of the disease. After 24h the pancreatitis was evaluated by measuring serum amylase, development of oedema and ascites, myeloperoxidase- and NF-κB-activity, and histo- morphological changes. Furthermore, the 5-day-survival-rate was determined (n=20).
Results: When replicating the therapeutic appliance in acute necrotizing pancreatitis all three HO-1 metabolites showed significant reduction of the inflammatory activity in comparison to the controls leading to less oedema and ascites and preserving tissue integrity (p<0.05). Consequently, the 5-day-survival-rate was significantly higher when applying biliverdin or CO therapy (70% and 75% versus 40%, p<0.05). The iron chelation by DFO showed similar results but without significant prolongation of the survival (60%). The protective effect of the metabolites is based on the inhibition of NF-κB activity in the pancreas (p<0.05). Furthermore, Biliverdin revealed a significant inhibition of trypsin activation in vitro (p<0.05).
Conclusions: The metabolites biliverdin and CO may mediate the protective effect of HO-1 in acute pancreatitis through the inhibition of NF-κB and trypsin activation. Both, biliverdin and CO showed a marked reduction of mortality by using them in a therapeutic application. Therefore, they may present new and easy therapeutics to treat severe acute pancreatitis.

2007 Program and Abstracts | 2007 Posters
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