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.