Ischemia-reperfusion injury in rat steatotic liver is dependent on NFκB P65 activation.

BACKGROUND: Steatotic liver grafts tolerate ischemia-reperfusion (I/R) injury poorly, contributing to increased primary graft nonfunction following transplantation. Activation of nuclear factor kappa-B (NFκB) following I/R injury plays a crucial role in activation of pro-inflammatory responses leading to injury. METHODS: We evaluated the role of NFκB in steatotic liver injury by using an orthotopic liver transplant (OLT) model in Zucker rats (lean to lean or obese to lean) to define the mechanisms of steatotic liver injury. Obese donors were treated with bortezomib to assess the role of NF-κB in steatotic liver I/R injury. Hepatic levels of NF-κB and pro-inflammatory cytokines were analyzed by ELISA. Serum transaminase levels and histopathological analysis were performed to assess associated graft injury. RESULTS: I/R injury in steatotic liver results in significant increases in activation of NF-κB (40%, p<0.003), specifically the p65 subunit following transplantation. Steatotic donor pretreatment with proteasome inhibitor bortezomib (0.1mg/kg) resulted in significant reduction in levels of activated NF-κB (0.58±0.18 vs. 1.37±0.06O.D./min/10 µg protein, p<0.003). Bortezomib treatment also reduced expression of pro-inflammatory cytokines MIP-2 compared with control treated steatotic and lean liver transplants respectively (106±17.5 vs. 443.3±49.9 vs. 176±10.6 pg/mL, p=0.02), TNF-α (223.8±29.9 vs. 518.5±66.5 vs. 264.5±30.1 pg/2 µg protein, p=0.003) and IL-1ß (6.0±0.91 vs. 19.8±5.2 vs. 5±1.7 pg/10 µg protein, p=0.02) along with a significant reduction in ALT levels (715±71 vs. 3712.5±437.5 vs. 606±286 U/L, p=0.01). CONCLUSION: These results suggest that I/R injury in steatotic liver transplantation are associated with exaggerated activation of NFκB subunit p65, leading to an inflammatory mechanism of reperfusion injury and necrosis. Proteasome inhibition in steatotic liver donor reduces NFκB p65 activation and inflammatory I/R injury, improving transplant outcomes of steatotic grafts in a rat model.

Incidence of residual choledocholithiasis detected by intraoperative cholangiography at the time of laparoscopic cholecystectomy in patients having undergone preoperative ERCP.

INTRODUCTION: The purpose of this study is to determine the incidence of residual common bile duct (CBD) stones after preoperative ERCP for choledocholithiasis and to evaluate the utility of routine intraoperative cholangiography (IOC) during laparoscopic cholecystectomy (LC) in this patient population. METHODS: All patients who underwent preoperative ERCP and interval LC with IOC from 5/96 to 12/05 were reviewed under an Institutional Review Board (IRB)-approved protocol. Data collected included all radiologic imaging, laboratory values, clinical and pathologic diagnoses, and results of preoperative ERCP and LC with IOC. Standard statistical analyses were used with significance set at p < 0.05. RESULTS: A total of 227 patients (male:female 72:155, mean age 51.9 years) underwent preoperative ERCP for suspicion of choledocholithiasis. One hundred and eighteen patients were found to have CBD stones on preoperative ERCP, and of these, 22 had choledocholithiasis diagnosed on IOC during LC. However, two patients had residual stones on completion cholangiogram after ERCP and were considered to have retained stones. Therefore, 20 patients overall were diagnosed with either interval passage of stones into the CBD or a false-negative preoperative ERCP. In the 109 patients without CBD stones on preoperative ERCP, nine patients had CBD stones on IOC during LC, an 8.3% incidence of interval passage of stones or false-negative preoperative ERCP. In both groups, there was no correlation (p > 0.05) between an increased incidence of CBD stones on IOC and a longer time interval between ERCP and LC, performance of sphincterotomy, incidence of cystic duct stones, or pathologic diagnosis of cholelithiasis. CONCLUSIONS: The overall incidence of retained or newly passed CBD stones on IOC during LC after a preoperative ERCP is 12.9%. Although the natural history of residual CBD stones after preoperative ERCP is not known, the routine use of IOC should be considered in patients with CBD stones on preoperative ERCP undergoing an interval LC.