SMALL-MOLECULE INHIBITION OF TUMOR-NECROSIS-FACTOR GENE PROCESSING DURING ACUTE-PANCREATITIS PREVENTS CYTOKINE CASCADE PROGRESSION AND ATTENUATES PANCREATITIS SEVERITY

Citation
W. Denham et al., SMALL-MOLECULE INHIBITION OF TUMOR-NECROSIS-FACTOR GENE PROCESSING DURING ACUTE-PANCREATITIS PREVENTS CYTOKINE CASCADE PROGRESSION AND ATTENUATES PANCREATITIS SEVERITY, The American surgeon, 63(12), 1997, pp. 1045-1049
Citations number
25
Journal title
ISSN journal
00031348
Volume
63
Issue
12
Year of publication
1997
Pages
1045 - 1049
Database
ISI
SICI code
0003-1348(1997)63:12<1045:SIOTGP>2.0.ZU;2-8
Abstract
The morbidity and mortality associated with acute pancreatitis are pri marily a result of pancreatic parenchymal necrosis and the development of marked pulmonary dysfunction. Recent evidence suggests that both o f these conditions are propagated by interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha; which are produced in large quantities w ithin these organs. Because the generation of these cytokines occurs i n a predictable manner early in the development of acute pancreatitis, we aimed to determine whether cytokine gene processing could be inhib ited ill vivo and what effects this would have on pancreatitis severit y. Mild [caerulein, 50 mu g/kg/hour intraperitoneally (IF) x 4; n = 40 ] or severe (choline-deficient diet; n = 40) necrotizing pancreatitis was induced in NIH swiss mice. Animals were randomly given a novel sma ll molecule (CNI-1493; 10 mg/kg IF) known to inhibit macrophage produc tion of TNF and IL-1 in vitro by inhibiting translation of TNF mRNA in to protein. Control animals received IP vehicle. All animals with acut e pancreatitis showed dramatic up-regulation of the IL-1 beta and TNF- alpha genes. Those animals receiving CNI-1493 demonstrated attenuated production of both species of mRNA in pancreatic as well as pulmonary tissue (P < 0.01). Markers of pancreatitis severity such as serum amyl ase and lipase, as well as pancreatic necrosis, were decreased in anim als treated with CNI-1493 (all P < 0.05). Posttranscriptional blockade of TNF production precludes induction of the proinflammatory cytokine cascade that normally occurs during acute pancreatitis. This lack of cytokine gene processing in the pancreas and lungs results in dramatic reductions in tissue damage and pancreatitis severity, which is not m odel dependent. This is the first time that a small molecule has been shown to influence this disease.