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The Protective Effect and Mechanism of HMGB1Monoclonal Antibody in Acute Necrotizing Pancreatits

Author: XiaMin
Tutor: ChenWeiChang
School: Suzhou University
Course: Department of Gastroenterology,
Keywords: Acute pancreatitis HMGB1protein interleukin-6 tumor necrosisfactor-α Inflammation mediatorsHigh-mobility group box protein-1 acute necrotizing pancreatitis Pancreatic apoptosis antibody NF-κB
CLC: R576
Type: PhD thesis
Year: 2012
Downloads: 119
Quote: 0
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Abstract


Objectives: To observe the serum level of IL-6, TNF-α and high mobility groupbox-1protein (HMGB1) in patients with acute pancreatitis (AP), to investigate the thecontributions of HMB1in the pathogenesis of AP and to assess the value in earlyjudgement of severity.Methods:33severe acute pancreatitis (SAP) patients and38mild acute pancretitispatients were selected as study objects; and51healthy individuals were set as controlgroup. Serum IL-6, TNF-α and HMGB1concentrations were determined by enzyme-linkedimmunosorbent assay (ELISA), and the association of them and the scores of Rason,APACHE Ⅱ, Balthazar CTwas analyzed.Results: The serum level HMGB1of three groups were (11.48±4.94) μg/L、(6.13±3.80) μg/L and (1.82±0.64) μg/L respectively. The mean level of HMGB1in SAPgroup was significantly higher than that in MAP group, while the level of MAP group wasobviously higher than that in control group (P＜0.05).The serum IL-6level in SAP group,MAP group and healthy control group were (553.72±175.76) pg/ml、(265.73±109.95)pg/ml and (16.43±3.32) pg/m. The mean level of IL-6in SAP group was significantlyhigher than that in MAP group, while the level of MAP group was obviously higher thanthat in control group (P＜0.01). The level of TNF-α in SAP, MAP and healthy group was(13.32±5.60) pg/ml、(12.37±5.63) pg/ml、(12.65±4.25) pg/ml respectively and there was nosignificant difference among three groups. The serum HMGB1levels had no remarkable relationships with sex, age and etiology. The correlation coefficient of serum HMGB1withIL-6and TNF-α were0.896and0.724(P<0.01) respectively. The HMGB1concentrationhad positive correction with scores of Ranson and Balthazar CT. The IL-6concentrationwas significantly positively correlated with scores of Ranson, APACHE Ⅱand BalthazarCT. The TNF-α concentration had positive correction with APACHE Ⅱ score.The IL-6levels of patients with systemic and/or local complications were significantly higher thanthose in patients without complications(P＜0.05), but there were no significant differencein TNF-α and HMGB1levels between two groups (P>0.05).Conclusions: The serum level of IL-6, TNF-α and HMGB1had closed correctionwith severity in AP. The high level of serium IL-6has closed correlation with complicationin pancreatitis. The serum HMGB1level had positive correction with serum IL-6andTNF-α and they were involved in the inflammation of AP. Objective: To investigate the pathogenesis of high-mobility group box protein1(HMGB1) in acute necrotizing pancreatitis(ANP) and discuss the protective effect ofHMGB1monoclonal antibody.Methods: ANP model was induced by intraperitoneal injection of20%L-2arginine(200mg/g body weight) twice with an interval of an hour. Male ICR mice were randomlyallocated into sham group, the acute necrotizing pancreatitis group and HMGB1monoclonal antibody group. The number of each group is36. The level of serum HMGB1were measured using enzyme-linked immunosorbent assay and HMGB1mRNA levels inthe liver and pancreas were studied by real time fluorescence quantitative PCR. The pathologic score of pancreas was observed. The apoptosis of pancreas cells was examinedby Annexin V/PI binding staining. The expression of the nuclear factor-κB was determinedby immunohistochemical analysis.Results: The serum HMGB1level and HMGB1mRNA expression in pancreas andliver increased remarkably at the12h, reached a peak at24h, and maintained up to48hafter mice ANP model. HMGB1antibody could decrease expression of HMGB1-mRNA inpancreas and liver and serum HMGB1concentration, which can improve the pancreatichistological changes. Compared to the normal pancreatic cell, the percentage of necrosiswas increased and the ratio of apoptosis was decreased in ANP mice. There was positivecorrelation between the expression of NF-κB and HMGB1levels at48h after theestablishment of ANP model. With the treatment of monoclonal antibody, the apoptosiscells were elevated and the expression of NF-κB was declined.Conclusions: High-mobility group box protein-1was involved in late inflammationof ANP and the serum levels were related with the severity of pancreatic lesions. HMGB1monoclonal antibody obviously inhibited the expression of HMGB1-mRNA in pancreasand liver of ICR in ANP, decreased the serum HMGB1level and improve the pancreaticpathology score. The pathogenesis of HMGB1in ANP mice may be relevant to inducingapoptosis evasion and NF-κB expression in pancreas cells.

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