Role of extracellular regulated kinase signal transduction pathway in the pathogenesis of acute necrotizing pancreatitis

Abstract

Objective To investigate the changes of extraceUular regulated kinase 1/2 (ERK1/2) phosphorylation and assess the effects of blocking the ERK1/2 phosphorylation on rats with acute necrotizing pancreatitis (ANP). Methods The ANP model was induced by retrograde injection of 5% sodium tanrocholate into the biliary and pancreatic duct. 5 rats were treated as normal control. Other 75 Sprague-Dawley (SD) rots were randomly divided into sham operations(SO) group (n =25), ANP group (n =25) and PD98059 group (n =25). The rats were sacrificed at 15 min, 30 min, 1 h, 3 h and 6 h after ANP induction, the blood and pancreatic sample were taken. Pathological changes of pancreas were observed with light microscope and scored. The serum level of TNF-α and IL-1β was determined by ELISA. MPO activities in pancreas were measured by enzyme chemistry assay. Western blotting was performed to determine the phosphorylations of ERK1/2 in the pancreas homogenates. Results There was no significant pathologic changes in rats of SO group;but significant injuries occurred in ANP group, the pathologic score at 3 h was 9.9 ± 0.4;the extent of injuries attenuated in PD98059 group, the pathologic score at 3 h was 4.0 ± 0.4 (P < 0.05). The serum levels of TNF-α at 3 h in SO, ANP and PD98059 groups were (65.8 ± 20.5) pg/ml, (286.5 ± 50.3) pg/ml, (180.4±32.9)pg/ml, respectively;the serum levels of IL-1β at 3 h in SO, ANP and PD98059groups were (85.8 ± 25.5) pg/ml, (293.8 ± 46.3) pg/ml, (200. 5 ± 33.6) pg/ml, respectively;MPOactivities in pancreas were (0. 19 ± 0.02)U/g, (0.61±0.05)U/g, (0.52±0.03) U/g, and the values in ANP and PD98059 groups were significantly higher than those in SO group, while the values in PD98059 group were significantly lower than those in ANP group (P < 0.01). The expression of ERK1/2 phosphorylation in normal pancreas was 1100 ± 141, the expressions of ERK1/2 phosphorylation in ANP group at 15 min, 30 min were 5300 ± 486, 5621 ± 384, respectively;the expressions began to decrease 1 h later and returned the similar level as SO group at 6 h;the expressions of ERK1/2 phosphorylation in PD98059 group at 15 min, 30 rain were 4200 ± 370, 3600 ± 290, respectively;which were signifieanfly lower than those in ANP group (all P value < 0. 01). Conclusions The ERK1/2 signal transduetion pathway plays an important role in the pathogenesis of ANP. Inhibition of ERK1/2 phosphorylation by PD98059 may decrease the production of IL-1β, TNF-α and pancreatic MPO, attenuate the extent of pancreatic pathologic injuries. Key words: Pancreatitis,acute necrotizing; Extracellular signal-regulated kinases; Pancreatic injury