Development of a novel therapy for severe acute pancreatitis by a specific inhibiiton of NF-κB- -Basic analysis using recombinant NLS-I k Bαadenoviral vector-

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In 1999, we have to decelop a recombinant NLS-IκBα adenoviral vector in which IκBα cDNA was bound to a nuclear localizing signal. However, it was difficult to produce the cDNAs of IκBα and SV40 large T antigen with precise nudiotide sequences. We have also examined whether cDNA construct could be incorporated into the adenoviral vector or not, but it was also difficult to obtain satisfatory results. Therefore, we have studied in vivo whether the NF-κB inhibitors such as PDTC) or NAC could alleviate the lung injury in a model of lethal pancreatitis (TCA pancreatitis) and in a model with lung injury which was induced by a trasfer of the supematant of TCA pancreatitis ascites (P-AAF) into the rats with nonlethal edematous pancreatitis (Cn pancreatitis). In both models pretreatment with PDTC or NAC improved significantly the lung injury, and the survival of these rats was improved. The effects were considered to be brought about at least by the inhibition of TNA-α and lL-1 β production in the lung via a blockade of NF-κB activation. In 2000 and 2OO1, we have continued to produce the recombinant NLS-I-κBα adenoviral vector. Additionally, we have examined and verified the preset of some factors in the PAAF that could stimulate directly vascular endothelial cells or mono cytes and upregulate the expression of adhesion molecules and various cytoldnes in vitro in these cells. We have also confirmed that an inhibition of NF-κB could block the expression of these proinflammatory molecules.