Ja. Dunn et al., THERAPEUTIC MODIFICATION OF NUCLEAR FACTOR KAPPA-B BINDING-ACTIVITY AND TUMOR-NECROSIS-FACTOR-ALPHA GENE-EXPRESSION DURING ACUTE BILIARY PANCREATITIS, The American surgeon, 63(12), 1997, pp. 1036-1043
The role of cytokines has been well documented in the pathogenesis of
acute pancreatitis. Antibodies against specific cytokines have been us
ed to treat pancreatitis, with mixed results. The transcription factor
nuclear factor (NF)-kappa B is a pleiotropic regulator of many genes
involved in stress and inflammatory responses. The aim of this study w
as to prevent the NF-kappa B binding activity and tumor necrosis facto
r (TNF)-alpha gene overexpression as a possible therapeutic interventi
on for acute pancreatitis. Reversible acute biliary pancreatitis was i
nduced in male Sprague Dawley rats as established in this laboratory.
The animals were sacrificed at 0, 5, 15, 30 min and 1, 2, 3, 4, 6, 8,
10, 12, and 24 hours after the induction of pancreatitis. NF-kappa B b
inding activity was determined by electrophoretic mobility shift assay
, and TNF-alpha gene expression was assayed by reverse transcription-P
CR. NF-kappa B binding activity was markedly higher around 4 hours and
persisted up to 24 hours after pancreatitis induction in animals with
acute pancreatitis, whereas TNF-alpha mRNA levels peaked at 24 hours.
When amobarbital (to block NF-kappa B activation) was given (60 mg/kg
body weight, I.P.) 3 hours before induction of pancreatitis, the acti
vation of NF-kappa B and the overexpression of TNF-alpha gene was prev
ented, with significantly decreased severity of pancreatitis as assess
ed by amylase and clinical recovery. We conclude that 1) preventing th
e activation of NF-kappa B eliminates the induced overexpression of in
flammatory cytokines (TNF-alpha) in acute pancreatitis, 2) such interv
ention correlates with clinical improvement in pancreatitis, and 3) th
is genetic modification offers a possible therapeutic intervention in
acute pancreatitis.