Senescent hepatocytes enhance natural killer cell activity via the CXCL-10/CXCR3 axis.

Cellular senescence and natural killer (NK) cells play an important role in liver diseases. Chemokines, a component of the senescence-associated secretory phenotype, can recruit NK cells and are involved in the development of various liver diseases. The effect of the C-X-C motif chemokine ligand (CXCL)-9, -10, -11/C-X-C motif chemokine receptor (CXCR)3 axis in senescent hepatocytes remains unknown. The chemokines secreted by senescent hepatocytes, the contribution of the CXCL-9, -10, -11/CXCR3 axis to the migration of NK cells, and the effect of senescent hepatocytes on the function of NK cells were investigated in the present study. The results demonstrated significantly increased levels of C-C motif chemokine ligand 2 and CXCL-1, -2 and -10 in the supernatant of senescent AML12 cells. Despite increased mRNA expression of CXCL-9, -10, and -11 in these cells, western blotting revealed significantly enhanced expression of only CXCL-10. The expression of CXCR3 on the surface of NK cells stimulated by senescent AML12 cells was upregulated (fold change, >3). Following incubation with the supernatant of senescent hepatocytes, both CD107a and interferon γ expression in NK cells increased by >2.5-fold. The cytotoxic effect of NK cells was notably higher stimulated by senescent AML12 cells. Chemotaxis and blocking assays demonstrated that the senescent hepatocytes enhanced the migration of NK cells via the CXCL-10/CXCR3 axis. The present study suggests that senescent hepatocytes secrete various chemokines, including CXCL-10, resulting in the upregulation and activation of CXCR3 in NK cells and the enhancement of NK cell migration via the CXCL-10/CXCR3 axis.

Senescent hepatocyte secretion of matrix metalloproteinases is regulated by nuclear factor-κB signaling.

AIMS: Cellular senescence and matrix metalloproteinases (MMPs) play an important role in liver diseases. The source and regulating factors of MMPs in senescent hepatocytes are not known. We investigated whether senescent hepatocytes secreted MMPs and if this was regulated by nuclear factor (NF)-κB. MATERIALS AND METHODS: The TGF-α transgenic mouse hepatocyte line AML12 was treated with H2O2 to induce senescence. NF-κB signaling was examined by Western blotting and luciferase reporter assays. Quantitative reverse transcription polymerase chain reaction was used to evaluated expression of MMP-2, -9 and -13. KEY FINDINGS: AML12 cells treated with H2O2 showed the characteristic morphology of senescence. The activity of NF-κB and expression of MMP-2, -9 and -13 were increased in senescent AML12 cells. The NF-κB inhibitor BAY 11-7082 decreased the levels of MMPs. SIGNIFICANCE: These results suggest that senescent hepatocytes are involved in the pathology of liver diseases through remodeling the extracellular matrix.

Elective laparoscopic cholecystectomy without intraoperative cholangiography: role of preoperative magnetic resonance cholangiopancreatography - a retrospective cohort study.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the standard treatment for gallbladder diseases. Intraoperative cholangiography (IOC) can reduce biliary complications of LC; however, with the emergence of magnetic resonance cholangiopancreatography (MRCP), IOC nowadays is faced with unprecedented challenge. The purpose of this study is to evaluate whether preoperative MRCP can safely replace IOC during elective LC in terms of retained common bile duct (CBD) stones and bile duct injury (BDI). METHODS: A retrospective study on candidates for elective LC who underwent IOC or preoperative MRCP between January 2009 and December 2014 was conducted. RESULTS: In the IOC group, 1972 patients underwent LC and 213 required IOC. In the MRCP group, 2268 patients underwent LC and 257 required MRCP. In the IOC group, the rate of retained CBD stones was 0.45 % without IOC and 1.41 % with IOC. In five of 157 patients who underwent IOC, endoscopic retrograde cholangiopancreatography or laparoscopic CBD exploration showed no evidence of CBD stones. In the MRCP group, the rate of retained CBD stones was 0.45 % without MRCP. No patients with normal MRCP findings returned with symptomatic CBD stones during 1-year follow-up. The rate of BDIs was 0.20 % in the IOC group and 0.13 % in the MRCP group. CONCLUSIONS: Selective use of preoperative MRCP is an effective and safe strategy when conducting elective LC to treat gallstones. LC resorting to preoperative MRCP can be performed safely without IOC, with an acceptable rate of retained CBD stones and BDIs.

A Randomized, Clinical Trial Involving Different Surgical Methods Affecting the Sphincter of Oddi in Patients With Choledocholithiasis.

AIM: The purpose of the current study was to compare pressure changes in the sphincter of Oddi (SO) and stone recurrence after surgery in patients with choledocholithiasis who underwent laparoscopic common bile duct exploration during laparoscopic cholecystectomy (LC) or endoscopic sphincterotomy (EST) with LC, which may provide clinical evidence for choledocholithiasis patients to choose the appropriate surgical approach. MATERIALS AND METHODS: Fifty-one patients with choledocholithiasis were randomized to the EST/LC (group A 26 cases) or laparoscopic common bile duct exploration during LC group (group B 25 cases). We performed SO manometry during surgery and 3 months postoperatively on all patients. In addition, the duodenobiliary reflux test was performed during the third month postoperatively. All patients were followed for 24 to 30 months. RESULTS: In group A, the SO basal and contraction pressures were 30.88±16.11 and 77.46±23.62 mm Hg intraoperatively and 10.34±10.27 and 45.65±24.77 mm Hg 3 months postoperatively, respectively. In group B, the SO basal and contraction pressures were 27.80±15.88 and 73.96±23.99 mm Hg intraoperatively and 15.43±7.36 and 59.56±22.61 mm Hg 3 months postoperatively, respectively. During the third month postoperatively, duodenobiliary reflux was demonstrated in 16 of 26 and 7 of 25 patients in groups A and B, respectively (P<0.05). During follow-up, the stone recurrence rates were 6 of 26 in group A and 1 of 25 in group B (P<0.05). CONCLUSIONS: After EST, the SO basal and contraction pressures decreased, and the duodenobiliary reflux and stone recurrence rates increased. Thus, EST should be selected with care.

Guidewire-assisted transpancreatic sphincterotomy for difficult biliary cannulation: a prospective randomized controlled trial.

PURPOSE: Precut techniques have been used to facilitate biliary cannulation during difficult endoscopic retrograde cholangiopancreatography. Presently, needle-knife sphincterotomy (NKS) is a commonly used precut technique. Since its first description, transpancreatic sphincterotomy, as an alternative method for bile duct entry when conventional biliary cannulation failed, has been debated on its success rate of cannulation and its complications, such as increased incidence of pancreatitis. Guidewire techniques are another effective method to improve the success rate of selective bile duct cannulation. This is a single-center prospective randomized controlled trial aimed to compare success rate, cannulation time, and complications of guidewire-assisted transpancreatic sphincterotomy (GATS) and NKS for difficult biliary cannulation. METHODS: Between July 2010 and October 2013, consecutive patients who failed in the standard biliary cannulation were randomly assigned to the GATS and NKS groups. The outcome measures included success rate, cannulation time, and complications. RESULTS: A total of 149 patients were enrolled and analyzed: 73 in the GATS group and 79 in the NKS group. The characteristics of the 2 groups were similar. Bile duct cannulation was successful in 70 patients (95.9%) in the GATS group and 64 (84.2%) in the NKS group (P=0.018). The median cannulation time spent in precut was 193 seconds in the GATS group and 485 seconds in the NKS group (P<0.001). There was no difference between the groups for the incidence of complications, pancreatitis, and hemorrhage (9.6% vs. 10.5%, 6.8% vs. 6.6%, 1.4% vs. 3.9%, respectively). No perforation occurred. CONCLUSIONS: GATS compared with NKS increases biliary cannulation rate and requires less cannulation time during difficult biliary access. This technique is not associated with an increased risk for complications. It seems to be an effective and safe alternative for biliary access during difficult endoscopic retrograde cholangiopancreatography.

Endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy during the same session: feasibility and safety.

AIM: To explore the feasibility and safety of endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy (LC) performed during the same session. METHODS: Between July 2010 and May 2013, 156 patients with gallstones and common bile duct (CBD) stones were enrolled in this retrospective study. According to the sequence of endoscopic procedures and LC, patients were classified into two groups: in group 1, patients underwent endoscopic stone extraction and LC during the same session, and in group 2, patients underwent LC at least 3 d after endoscopic stone extraction. Outcomes of the endoscopic procedures and LC were compared between the two groups, respectively. RESULTS: There were 91 patients in group 1 and 65 patients in group 2. The characteristics of the two groups were similar. The mean duration of the endoscopic procedures was 34.9 min in group 1 and 35.3 min in group 2. There were no significant differences in the success rate of the endoscopic procedures (97.8% for group 1 vs 98.5% for group 2), the total rate of endoscopic complications (4.40% for group 1 vs 4.62% for group 2) and CBD stone clearance rate (96.7% for group 1 vs 96.9% for group 2). Duration of LC was 53.6 min in group 1 and 52.8 min in group 2. There were no significant differences in the overall LC-related morbidity and postoperative hospital stay. CONCLUSION: Endoscopic stone extraction and LC performed during the same session was feasible and safe in patients with gallstones and concomitant CBD stones.

Early laparoscopic cholecystectomy after endoscopic common bile duct stone extraction: the experience from a developing country.

PURPOSE: The optimal timing of laparoscopic cholecystectomy (LC) after endoscopic common bile duct stone extraction remains controversial. The aim of this China-based retrospective study was to investigate the outcomes of patients who underwent early LC after endoscopic procedures. METHODS: The retrospective study enrolled patients who underwent LC after endoscopic common bile duct stone extraction between January 2007 and February 2010. On the basis of intervals between LC and endoscopic procedures, patients were classified into 2 groups: early LC group, including patients receiving LC within 3 days; and delayed LC group, including patients receiving LC after 3 days. Operation time, surgical complications, postoperative hospital stay, and the cost of hospitalization were compared between 2 groups. RESULTS: There were 92 patients in the early LC group and 115 patients in the delayed LC group. The characteristics and endoscopic procedures of the 2 groups were similar. There were no differences between the 2 groups in operative duration, incidence of surgical complications, restoration of bowel motion, postoperative hospital stay, and LC-related cost. However, total hospital cost of early LC was less than that of delayed LC. CONCLUSIONS: Early LC after endoscopic common bile duct stone extraction in developing countries is feasible and safe. Moreover, it can reduce the total hospital cost effectively. Thus, early LC after endoscopic procedures should be recommended in developing countries.