[Mechanism of liver injury in severe acute pancreatitis rats and role of melatonin].
OBJECTIVE
To investigate the activation level of nuclear factor-kappaB (NF-kappaB) in liver injury caused by severe acute pancreatitis (SAP) and the protective role of melatonin against liver injury.


METHODS
Ninety-six Sprague-Dawley (SD) rats were randomly divided into 3 equal groups: SAP group undergoing injection of sodium taurocholate to establish SAP models, melatonin (Mel) treatment group undergoing intraperitoneal injection 50 mg/kg 30 minutes before the establishment of SAP models, and sham operation group (Sham group). 4, 12, 24, and 48 hours after the onset of operation, blood samples were collected from the inferior vena casa of 8 rats from each group to measure the serum level of amylase (AMY) and alanine transaminase (ALT) by iodine colorimetry, and to detect the serum level of tumor necrosis factor-alpha (TNF-alpha) by ELISA. The livers were taken out to undergo pathological examination. Immunohistochemistry was used to examine the percentage of nuclear factor (NF)-kappaB in the hepatocytes. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) was used to determine the extent of hepatic apoptosis.


RESULTS
The AMY and ALT levels at different time points of the SAP and Mel subgroups were all significantly higher than those of the sham operation subgroups (all P<0.05), and the AMY and ALT levels at different time points of the Mel subgroup were all significantly lower than those of the SAP subgroups (all P<0.05). The liver NF-kappaB activation level and hepatocellular apoptosis index of the SAP group increased since the fourth hour after the operation, and peaked at the time point of 24 hour, all significantly higher than those of the sham operation group (all P<0.05), and then declined. The TNF-alpha level at the time points of 12, 24, and 48 h in the SAP group were all significantly higher than those of the other 2 groups (all P<0.05). The levels of TNF-alpha, AMY, and ALT, the activity of NF-kappaB, and the extent of hepatocellular apoptosis at any time points of the Mel group were all significantly lower than those of the SAP group, but significantly higher than those of the sham operation group. Microscopy showed that the liver pathological damages of the Mel group were milder than those of the SAP group.


CONCLUSIONS
SAP with liver injury is associated with the hepatic NF-kappaB activation leading to the production of NF-kappaB dependent cytokines and chemokines such as TNF-alpha. Melatonin reduces the apoptosis and necrosis in liver by inhibiting the activity of NF-kappaB and decreasing the expression of TNF-alpha.
Ni
Yin
Y
Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, China. niyin108@163.com
Wu
Jian-sheng
JS
Fang
Pei-pei
PP
Wu
Xiu-ling
XL
Sun
Xue-cheng
XC
Jia
Guo-bao
GB
Zhang
Ren-zai
RZ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D009336:Necrosis; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D008550:Melatonin