After PD, RPV and status of postoperative infection paradoxically influenced the development of NAFLD.
Background & Aims: Organ shortage has led to the use of steatotic livers in transplantation, despite their elevated susceptibility to ischemia/reperfusion injury (IRI). Matrix metalloproteinase-9 (MMP-9), an inducible gelatinase, is emerging as a central mediator of leukocyte traffic into inflamed tissues. However, its role in steatotic hepatic IRI has yet to be demonstrated. Methods: We examined the function of MMP-9 in mice fed with a high-fat diet (HFD), which developed approximately 50% hepatic steatosis, predominantly macrovesicular, prior to partial hepatic IRI. Results: The inability of MMP-9−/− deficient steatotic mice to express MMP-9 significantly protected these mice from liver IRI. Compared to fatty controls, MMP-9−/− steatotic livers showed significantly reduced leukocyte infiltration, proinflammatory cytokine expression, and liver necrosis. Loss of MMP-9 activity preserved platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, a modulator of vascular integrity at the endothelial cell–cell junctions in steatotic livers after IRI. Using in vitro approaches, we show that targeted inhibition of MMP-9 sheltered the extracellular portion of PECAM-1 from proteolytic processing, and disrupted leukocyte migration across this junctional molecule. Moreover, the evaluation of distinct parameters of regeneration, proliferating cell nuclear antigen (PCNA) and histone H3 phosphorylation (pH3), provided evidence that hepatocyte progression into S phase and mitosis was notably enhanced in MMP-9−/− steatotic livers after IRI. Conclusion: MMP-9 activity disrupts vascular integrity at least partially through a PECAM-1 dependent mechanism and interferes with regeneration of steatotic livers after IRI. Our novel findings establish MMP-9 as an important mediator of steatotic liver IRI.
Hepatic ischemia/reperfusion (IRI) injury remains a major challenge in clinical orthotopic liver transplantation (OLT). Tenascin-C (Tnc) is an extracellular matrix protein (ECM) involved in various aspects of immunity and tissue injury. Using a Tnc-deficient mouse model, we present data that suggest an active role for Tnc in liver IRI. We show that Tnc-deficient mice have a reduction in liver damage and a significant improvement in liver regeneration after IRI. The inability of Tnc−/− mice to express tenascin-C significantly reduced the levels of active caspase-3/TUNEL apoptotic markers and enhanced the expression of the proliferation cell nuclear antigen (PCNA) after liver IRI. The lack of Tnc expression resulted in impaired leukocyte recruitment and decreased expressions of IL-1β, IL-6 and CXCL2 after liver reperfusion. Tenascin-C deficient livers were characterized by altered expression patterns of vascular adhesion molecules, such as VCAM-1 and PECAM-1 post-IRI. Moreover, matrix metalloproteinase-9 (MMP-9) synthesis, which facilitates leukocyte transmigration across vascular barriers in liver IRI, was markedly downregulated in the absence of tenascin-C. We also show that tenascin-C is capable of inducing MMP-9 expression in isolated neutrophils through Toll-like receptor 4 (TLR4). Therefore, our data suggest that tenascin-C is a relevant mediator of the pathogenic events underlying liver IRI. The data also support the view that studies aimed at further understanding how newly synthesized ECM molecules, such as tenascin-C, participate in inflammatory responses are needed to improve therapeutic approaches in liver IRI.
Hepatic ischemia and reperfusion injury (IRI) remains an important challenge in clinical orthotopic liver transplantation (OLT). Tissue inhibitor of metalloproteinase-1 (TIMP-1) is the major endogenous regulator of matrix metalloproteinase-9 (MMP-9). In this study, we investigated the functional significance of TIMP-1 expression in a well-established mouse model of partial liver IRI. Compared to wild-type mice, TIMP-1−/− mice showed further impaired liver function and histological preservation after IRI. Notably, TIMP-1 deficiency led to lethal liver IRI, as over 60% of the TIMP-1−/− mice died post-reperfusion, whereas all TIMP-1+/+ mice recovered and survived surgery. Lack of TIMP-1 expression was accompanied by markedly high levels of MMP-9 activity, which facilitates leukocyte transmigration across vascular barriers in hepatic IRI. Indeed, TIMP-1−/− livers were characterized by massive leukocyte infiltration and by upregulation of proinflammatory mediators, including TNF-α, IFN-γ, and iNOS, post-IRI. The inability of TIMP-1−/− mice to express TIMP-1 increased the levels of active caspase-3 and depressed the expression of Bcl-2 and the phosphorylation of Akt, emphasizing an important role for TIMP-1 expression on hepatocyte survival. Using independent parameters of regeneration, 5-bromodeoxyuridine (BrdU) incorporation, proliferating cell nuclear antigen (PCNA) expression, and histone H3 phosphorylation, we provide evidence that hepatocyte progression into S phase and mitosis was impaired in TIMP-1 deficient livers after IRI. Inhibition of the cell cycle progression by TIMP-1 deficiency was linked to depressed levels of cyclins-D1 and -E and to disrupted c-Met signaling pathway, as evidenced by reduced phosphorylated c-Met expression and elevated c-Met ectodomain shedding post-liver IRI. In conclusion, these results support a critical protective function for TIMP-1 expression on promoting survival and proliferation of liver cells and on regulating leukocyte recruitment and activation in liver IRI.
AIM:To prevent pancreatic leakage after pancreaticojejunostomy, we designed a new standardized technique that we term the "Pair-Watch suturing technique". METHODS:Before anastomosis, we imagine the faces of a pair of watches on the jejunal hole and pancreatic duct. The first stitch was put between 9 o'clock of the pancreatic side and 3 o'clock of the jejunal side, and a total of 7 stitches were put on the posterior wall, followed by the 5 stitches on the anterior wall. Using this technique, twelve stitches can be sutured on the first layer anastomosis regardless of the caliber of the pancreatic duct. In all cases the amylase activity of the drain were measured. A postoperative pancreatic fistula was diagnosed using postoperative pancreatic fistula grading. RESULTS:From March 2007 to July 2008, 29 consecutive cases underwent pancreaticojejunostomy using this technique. Pathologic examination results showed pancreatic carcinoma (n = 14), intraductal papillary-mucinous neoplasm (n = 10), intraductal papillary-mucinous carcinoma (n = 1), carcinoma of ampulla of Vater (n=1), carcinoma of extrahepatic bile duct (n = 1), metastasis of renal cell carcinoma (n = 1), and duodenal carcinoma (n = 1). Pancreaticojejunal anastomoses using this technique were all watertight during the surgical procedure. The mean diameter of main pancreatic duct was 3.4 mm (range 2-7 mm). Three patients were recognized as having an amylase level greater than 3 times the serum amylase level, but all of them were diagnosed as grade A postoperative pancreatic fistula grading and required no treatment. None of the cases developed complications such as hemorrhage, abdominal abscess, and pulmonary infection. There was no postoperative mortality. CONCLUSION:Our technique is less complicated than other methods and very secure, providing reliable anastomosis for any size of pancreatic duct.
To achieve R0 resection for pancreatic ductal adenocarcinoma (PDAC) of the pancreatic head, complete resection of the retropancreatic nerve plexus around the superior mesenteric artery (SMA) is thought to be required. Twenty-five patients with borderline resectable right-sided PDAC were divided into two groups after neoadjuvant chemoradiotherapy: those with portal vein (PV) invasion alone (n = 12), and those with invasion of both PV and SMA (n = 13). A tape for guidance was passed in a space ventral to the SMA and behind the pancreatic parenchyma, followed by resection of the pancreatic parenchyma with the splenic vein. Another tape was passed behind the nerve plexus lateral to the hepatic artery and the SMA ventral to the inferior vena cava and the nerve plexus was dissected, resulting in complete resection of the nerve plexus around the SMA. Pathological findings revealed that the rates of R0, R01 (a margin less than 1 mm) and R1 were 58.3 %, 41.7 % and 0 % in PV group, and 53.8 %, 30.8 % and 15.4 % in PV/A group, respectively. The median survival time was 23.3 and 22.8 months in PV and PV/A groups, respectively. The plexus hanging maneuver for PDAC of the pancreatic head achieved complete resection of the retropancreatic nerve plexus around the SMA, helping to secure a negative surgical margin.
BackgroundIn adult living donor liver transplantation (ALDLT), graft-to-recipient weight ratio of less than 0.8 is incomplete for predicting portal hypertension (>20 mm Hg) after reperfusion. We aimed to identify preoperative factors contributing to portal venous pressure (PVP) after reperfusion and to predict portal hypertension, focusing on spleen volume-to-graft volume ratio (SVGVR).MethodsIn 73 recipients with ALDLT between 2002 and 2013, first we analyzed survival according to PVP of 20 mm Hg as the threshold, evaluating the efficacy of splenectomy. Second, we evaluated various preoperative factors contributing to portal hypertension after reperfusion.ResultsAll of the recipients with PVP greater than 20 mm Hg (n = 19) underwent PVP modulation by splenectomy, and their overall survival was favorable compared with 54 recipients who did not need splenectomy (PVP ≤ 20 mm Hg). Graft-to-recipient weight ratio had no correlation with PVP.Multivariate analysis revealed that estimated graft and spleen volume were significant factors contributing to PVP after reperfusion (P < 0.0001 and P < 0.0001, respectively). Furthermore, estimated SVGVR showed a significant negative correlation to PVP after reperfusion (R = 0.652), and the best cutoff value for portal hypertension was 0.95.ConclusionsIn ALDLT, preoperative assessment of SVGVR is a good predictor of portal hypertension after reperfusion can be used to indicate the need for splenectomy before reperfusion.
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