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
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.