A case of progressive xanthogranulomatous pancreatitis with splenic abscess.

Xanthogranulomatous inflammation is a chronic inflammatory reaction microscopically characterized by aggregation of foamy histiocytes, fibrous tissue, and infiltration of various inflammatory cells. In contrast to xanthogranulomatous inflammation in the gallbladder or kidney, xanthogranulomatous pancreatitis is rare. We herein present a case of xanthogranulomatous pancreatitis in a patient who underwent distal pancreatectomy with splenectomy under preoperative suspicion of a pancreatic pseudocyst or pancreatic tumor. A 77-year-old woman with a 1 month history of epigastric pain, anorexia, and general fatigue was admitted to our hospital. Contrast-enhanced computed tomography revealed a cystic mass with ill-defined margins at the pancreatic tail together with a splenic abscess. Contrast-enhanced endoscopic ultrasound detected a hyperechoic cystic lesion at the tail of the pancreas with heterogeneous internal echogenicity, and part of the intra-cystic content was enhanced by the contrast agent. Endoscopic retrograde cholangiopancreatography showed a cystic lesion at the tail of the pancreas that continued into the main pancreatic duct, and the main pancreatic duct was slightly narrowed downstream of the cystic lesion. Pancreatic juice cytology revealed suspicious cells, leading to the possibility of intraductal papillary mucinous carcinoma. Distal pancreatectomy with splenectomy was performed, and the histopathological diagnosis was xanthogranulomatous pancreatitis with no malignant findings.

A case of spindle and giant cell-type undifferentiated carcinoma of the extrahepatic bile duct.

Spindle and giant cell type undifferentiated carcinoma of the extrahepatic bile duct is an uncommon malignancy. We report a case involving the common bile duct in a 72-year-old male with jaundice who was admitted to our hospital. Diagnostic imaging, including abdominal computed tomography and magnetic resonance imaging, revealed a mass in the distal common bile duct, accompanied by dilatation of both intra- and extrahepatic bile ducts and regional lymph node enlargement. Endoscopic retrograde cholangiography demonstrated stenosis in the distal common bile duct, with a biopsy confirming adenocarcinoma. The patient underwent endoscopic retrograde biliary drainage followed by a subtotal stomach-preserving pancreaticoduodenectomy with regional lymphadenectomy. Microscopic examination revealed that the tumor predominantly comprised spindle and giant atypical cells within the stroma. Immunohistochemical analysis showed the tumor cells expressing cytokeratins and mesenchymal markers, confirming the diagnosis of spindle and giant cell type undifferentiated carcinoma of the common bile duct. Ki-67 labeling index was observed to be above 80%. Postoperatively, intra-abdominal lymph node recurrence was noted at two months, and multiple liver metastases were identified at three months. The patient died seven months post-surgery. The literature pertaining to this rare disease is reviewed and discussed.

Vascular Reconstruction with the Cuff Technique in Mouse Orthotopic Liver Transplantation.

Mouse orthotopic liver transplantation is an effective methodology for investigating the underlying mechanisms of liver ischemia and reperfusion injury. However, the technical challenges pose a barrier to utilizing this valuable experimental model and passing on these skills to the next generation. The most challenging aspect of this procedure is vascular reconstruction, including the portal vein (PV), infrahepatic inferior vena cava (IHIVC), and suprahepatic inferior vena cava. The use of plastic cuffs, rather than sutures, allows for smoother PV and IHIVC reconstruction. Vessels are reconstructed by attaching a cuff made from an intravenous catheter to the tip of the graft vessel and interposing the cuff into the recipient vessel. The two most crucial aspects are properly visualizing the inner lumen of the vessel and avoiding the use of excessive force. Our aim is to provide a technical overview of vascular reconstructions using the cuff technique in recipient surgery. These technical tips for the cuff technique are expected to help microsurgeons facilitate vascular reconstruction and advance their research.

SIRT1 regulates hepatocyte programmed cell death via GSDME - IL18 axis in human and mouse liver transplantation.

Sirtuin 1 (SIRT1) is a histone/protein deacetylase in the cellular response to inflammatory, metabolic, and oxidative stressors. We previously reported that myeloid SIRT1 regulates the inflamed liver's canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain. Here, we undertook translational studies in human and mouse orthotopic liver transplantation (OLT) to interrogate the significance of hepatocyte-specific SIRT1 in cold-stored donor livers and liver grafts after reperfusion. In the clinical arm of sixty human OLT patients, hepatic SIRT1 levels in cold-preserved donor livers correlated with the anti-apoptotic Bcl-2 expression. After reperfusion, improved OLT function was accompanied by hepatic SIRT1 levels negatively associated with cleaved caspase-3 expression. In the experimental arm, we compared FLOX-control with hepatocyte-specific SIRT1-KO livers after orthotopic transplantation into WT mouse recipients, parallel with primary murine hepatocyte cultures subjected to cold activation with/without knockdown of SIRT1, GSDME, and IL18Rß. Indeed, hepatocyte SIRT1 deficiency upregulated apoptosis and GSDME-mediated programmed cell death, deteriorating hepatocellular function and shortening OLT survival. Augmented GSDME processing, accompanied by increased secretion of IL18 by stressed hepatocytes, was prominent in SIRT1-deficient, cold-stored livers. Hepatocyte SIRT1 expression regulated anti-apoptotic Bcl-2/XIAP proteins, suppressed cold stress-triggered apoptosis, and mitigated GSDME licensing to release IL18. Notably, consistent with the ability of IL18 to depress hepatocyte SIRT1 and Bcl-2/XIAP in vitro, IL18 neutralization in vivo prevented hepatocellular damage and restored the anti-apoptotic phenotype in otherwise injury-prone SIRT1-deficient OLTs. In conclusion, this translational study identifies a novel hepatocyte SIRT1-IL18 molecular circuit as a therapeutic target in the mechanism underpinning hepatocyte death pathways in human and mouse liver transplantation.

SIRT1 Regulates Hepatocyte Programmed Cell Death via GSDME - IL18 Axis in Human and Mouse Liver Transplantation.

Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. We previously reported that myeloid SIRT1 signaling regulates the inflamed liver's canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain. Here, we undertook translational studies in human and mouse orthotopic liver transplantation (OLT) to interrogate the significance of hepatocyte-specific SIRT1 signaling in cold-stored donor livers and liver grafts after reperfusion. In the clinical arm of sixty human OLT patients, hepatic SIRT1 levels in cold-preserved donor livers correlated with anti-apoptotic Bcl-2 expression. After reperfusion, improved OLT function was accompanied by hepatic SIRT1 levels negatively associated with cleaved caspase-3 expression. In the experimental arm, we compared FLOX-control with hepatocyte-specific SIRT1-KO livers after orthotopic transplantation into WT mouse recipients, parallel with primary murine hepatocyte cultures subjected to cold activation with/without knockdown of SIRT1, GSDME, and IL18Rß signaling. Hepatocyte SIRT1 deficiency upregulated apoptosis and GSDME-mediated programmed cell death, which in turn deteriorated the hepatocellular function and shortened OLT survival. Augmented GSDME processing, accompanied by increased secretion of IL18 by stressed hepatocytes, was prominent in SIRT1-deficient, cold-stored livers. Hepatocyte SIRT1 signaling regulated anti-apoptotic Bcl-2/XIAP proteins, suppressed cold stress-triggered apoptosis, and mitigated GSDME licensing to release IL18. Notably, while crosslinking IL18R depressed SIRT1 and Bcl-2/XIAP signaling in vitro, IL18 neutralization in vivo prevented hepatocellular damage and restored the anti-apoptotic phenotype in otherwise injury-prone SIRT1-deficient OLTs. In conclusion, this translational study identifies a novel hepatocyte SIRT1-IL18 signaling circuit as a therapeutic target in the mechanism underpinning hepatocyte death in human and mouse liver transplantation.

Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation.

Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in orthotopic liver transplantation (OLT). Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CC1, or CD66a) is essential in neutrophil activation and serves as a checkpoint regulator of innate immune-driven IRI cascade in OLT. Although CC1 alternative splicing generates two functionally distinct short and long cytoplasmic isoforms, their role in neutrophil activation remains unknown. Here, we undertook molecular and functional studies to interrogate the significance of neutrophil CC1 signaling in mouse and human OLT recipients. In the experimental arm, we employed a mouse OLT model to document that ablation of recipient-derived neutrophil CC1-long (CC1-L) isotype aggravated hepatic IRI by promoting neutrophil extracellular traps (NETs). Notably, by regulating the S1P-S1PR2/S1PR3 axis, neutrophil CC1-L determined susceptibility to NET formation via autophagy signaling. In the clinical arm, liver grafts from 55 transplant patients selectively enriched for neutrophil CC1-L showed relative resistance to ischemia-reperfusion (IR) stress/tissue damage, improved hepatocellular function, and clinical outcomes. In conclusion, despite neutrophils being considered a principal villain in peritransplant tissue injury, their CC1-L isoform may serve as a regulator of IR stress resistance/NETosis in human and mouse OLT recipients.

Clinically relevant model of oxaliplatin-induced sinusoidal obstruction syndrome.

AIM: Sinusoidal obstruction syndrome (SOS) induced by oxaliplatin-including chemotherapies (OXCx) is associated with impaired hepatic reserve and higher morbidity after hepatic resection. However, in the absence of an appropriate animal experimental model, little is known about its pathophysiology. This study aimed to establish a clinically relevant reproducible model of FOLFOX-induced SOS and to compare the clinical/histopathological features between the clinical and animal SOS settings. METHODS: We performed clinical/pathological analyses of colorectal liver metastasis (CRLM) patients who underwent hepatectomy with/without preoperative treatment of FOLFOX (n = 22/18). Male micro-minipigs were treated with 50% of the standard human dosage of the FOLFOX regimen. RESULTS: In contrast to the monocrotaline-induced SOS model in rats, hepatomegaly, ascites, congestion, and coagulative necrosis of hepatocytes were absent in patients with CRLM with OXCx pretreatment and OXCx-treated micro-minipigs. In parallel to CRLM cases with OXCx pretreatment, OXCx-challenged micro-minipigs exhibited deteriorated indocyanine green clearance, morphological alteration of liver sinusoidal endothelial cells, and upregulated matrix metalloproteinase-9. Using our novel porcine SOS model, we identified the hepatoprotective influence of recombinant human soluble thrombomodulin in OXCx-SOS. CONCLUSIONS: With distinct differences between monocrotaline-induced rat SOS and human/pig OXCx-SOS, our pig OXCx-SOS model serves as a preclinical platform for future investigations to dissect the pathophysiology of OXCx-SOS and seek preventive strategies.

Rapid transformation of branched pancreatic duct-derived intraductal tubulopapillary neoplasm into an invasive carcinoma: A case report.

BACKGROUND: Intraductal tubulopapillary neoplasm (ITPN) is a rare disease accounting for approximately 3% of all intraductal pancreatic tumors, with intraductal papillary mucinous neoplasm (IPMN) being one of the most common differential diagnoses. Both ITPN and IPMN display slow growth. A branched pancreatic duct type is commonly observed in IPMN, whereas ITPN derived from the branched pancreatic duct has been reported in a limited number of cases; hence, its pathogenesis remains unclear. CASE SUMMARY: Here, we present the case of a patient with ITPN localized in a branched pancreatic duct, with poorly controlled irritable bowel syndrome. A contrast-enhanced computed tomography scan of the abdomen incidentally revealed a 5-mm oligemic nodule-like change in the body of the pancreas. Endoscopic ultrasound (EUS) indicated a 10-mm hypoechoic mass without any cystic structures that had grown within 2 mo. EUS-guided fine needle aspiration was performed for definitive diagnosis, and the findings suggested ductal papillary carcinoma. Distal pancreatectomy was performed, and the tumor was pathologically diagnosed as ITPN with an invasive cancerous component, pT3N1aM0, pStage IIB (International Cancer Control, 8th edition). The patient underwent treatment with postoperative adjuvant chemotherapy (S-1 monotherapy); however, relapse was observed 1 year and 10 mo after surgical resection, and subsequent treatment involving a combination of chemotherapy and radiotherapy was administered. Maintenance therapy has since facilitated a stable disease state. CONCLUSION: Regardless of the microscopic size of the neoplasm, early diagnosis of ITPN with EUS-guided fine needle aspiration and surgical resection are crucial.

Myeloid Ikaros-SIRT1 signaling axis regulates hepatic inflammation and pyroptosis in ischemia-stressed mouse and human liver.

BACKGROUND & AIMS: Although Ikaros (IKZF1) is a well-established transcriptional regulator in leukocyte lymphopoiesis and differentiation, its role in myeloid innate immune responses remains unclear. Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. Whether SIRT1 signaling is essential in myeloid cell activation remains uncertain, while the molecular communication between Ikaros and SIRT1, two major transcriptional regulators, has not been studied. METHODS: We undertook molecular and functional studies to interrogate the significance of the myeloid Ikaros-SIRT1 axis in innate immune activation and whether it may serve as a homeostatic sentinel in human liver transplant recipients (hepatic biopsies) and murine models of sterile hepatic inflammation (liver warm ischemia-reperfusion injury in wild-type, myeloid-specific Sirt1-knockout, and CD11b-DTR mice) as well as primary bone marrow-derived macrophage (BMM) cultures (Ikaros silencing vs. overexpression). RESULTS: In our clinical study, we identified increased post-reperfusion hepatic Ikaros levels, accompanied by augmented inflammasome signaling yet depressed SIRT1, as a mechanism of hepatocellular damage in liver transplant recipients. In our experimental studies, we identified infiltrating macrophages as the major source of Ikaros in IR-stressed mouse livers. Then, we demonstrated that Ikaros-regulated pyroptosis - induced by canonical inflammasome signaling in BMM cultures - was SIRT1 dependent. Consistent with the latter, myeloid-specific Ikaros signaling augmented hepatic pyroptosis to aggravate pro-inflammatory responses in vivo by negatively regulating SIRT1 in an AMPK-dependent manner. Finally, myeloid-specific SIRT1 was required to suppress pyroptosis, pro-inflammatory phenotype, and ultimately mitigate hepatocellular injury in ischemia-stressed murine livers. CONCLUSION: These findings identify the Ikaros-SIRT1 axis as a novel mechanistic biomarker of pyroptosis and a putative checkpoint regulator of homeostasis in response to acute hepatic stress/injury in mouse and human livers. LAY SUMMARY: This report describes how crosstalk between Ikaros and SIRT1, two major transcriptional regulators, influence acute hepatic inflammation in murine models of liver ischemia-reperfusion injury and liver transplant recipients. We show that the myeloid Ikaros-SIRT1 axis regulates inflammasome-pyroptotic cell death and hepatocellular damage in stressed livers. Thus, the Ikaros-SIRT1 axis may serve as a novel checkpoint regulator that is required for homeostasis in response to acute liver injury in mice and humans.

Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity.

Liver ischaemia-reperfusion injury (LIRI), a local sterile inflammatory response driven by innate immunity, is one of the primary causes of early organ dysfunction and failure after liver transplantation. Cellular damage resulting from LIRI is an important risk factor not only for graft dysfunction but also for acute and even chronic rejection and exacerbates the shortage of donor organs for life-saving liver transplantation. Hepatocytes, liver sinusoidal endothelial cells and Kupffer cells, along with extrahepatic monocyte-derived macrophages, neutrophils and platelets, are all involved in LIRI. However, the mechanisms underlying the responses of these cells in the acute phase of LIRI and how these responses are orchestrated to control and resolve inflammation and achieve homeostatic tissue repair are not well understood. Technological advances allow the tracking of cells to better appreciate the role of hepatic macrophages and platelets (such as their origin and immunomodulatory and tissue-remodelling functions) and hepatic neutrophils (such as their selective recruitment, anti-inflammatory and tissue-repairing functions, and formation of extracellular traps and reverse migration) in LIRI. In this Review, we summarize the role of macrophages, platelets and neutrophils in LIRI, highlight unanswered questions, and discuss prospects for innovative therapeutic regimens against LIRI in transplant recipients.

Successful En Bloc Resection of Locally Advanced Pancreatic Tail Cancer with Colonic Perforation Following Neoadjuvant Chemotherapy: A Case Report.

BACKGROUND Distal pancreatic cancers may be unresectable at the time of diagnosis because these cancers are asymptomatic and readily infiltrate neighboring organs. Radical resection of a pancreatic tail cancer with colonic perforation is rare. We describe successful resection of a locally advanced pancreatic tail cancer with colonic perforation using a multidisciplinary approach. CASE REPORT A 66-year-old man presented to our hospital with a chief concern of high fever. Abdominal computed tomography revealed a pancreatic tail tumor infiltrating the neighboring organs and causing colonic obstruction with perforation, which resulted in an intra-abdominal abscess. Colonoscopy revealed obstruction of the descending colon by extramural invasion. Laboratory tests showed high tumor marker concentrations (carcinoembryonic antigen, 11.6 ng/dL; pancreatic cancer-associated antigen-2, >1600 U/mL). We clinically diagnosed locally advanced pancreatic tail cancer with an intra-abdominal abscess caused by colonic perforation. First, we performed transverse colostomy and percutaneous drainage. We then started neoadjuvant chemotherapy with FOLFIRINOX for tumor shrinkage and prevention of distant metastases. The therapeutic effect was a partial response, and no distant metastases was found. We therefore performed radical surgery comprising distal pancreatectomy with partial resection of neighboring organs. Although pathological examination revealed a pancreatic tail tubular adenocarcinoma with direct invasion of the neighboring organs, R0 resection was achieved. The patient was discharged with no perioperative complications. Tegafur/gimeracil/oteracil potassium were administered as adjuvant chemotherapy. The patient remained recurrence-free for 19 months after surgery. CONCLUSIONS We achieved successful en bloc resection of a locally advanced distal pancreatic cancer with colonic perforation by using a multidisciplinary approach.

Gallbladder cancer spreading into the aberrant cystic duct: First literature report.

INTRODUCTION AND IMPORTANCE: Although variations from the standard anatomy of the extrahepatic bile ducts are common, duplication of the cystic duct draining a single gallbladder is an extremely rare variant. We herein describe the first report of gallbladder cancer spreading into the aberrant cystic duct. CASE PRESENTATION: A 60-year-old female presented with upper abdominal pain, and she was diagnosed with gallbladder cancer. Intraoperatively, she was found to have a duplicated cystic duct draining a single gallbladder, and her cancer had spread into the aberrant cystic duct entering the anterior right hepatic duct. Right hepatectomy with extrahepatic bile duct resection was performed to achieve R0 resection. CLINICAL DISCUSSION: In the English literature, 28 cases of duplicated cystic duct draining a single gallbladder have been reported. However, no cases of gallbladder cancer have been described in these previous reports. CONCLUSION: We report the first case of gallbladder cancer spreading into the aberrant cystic duct. To perform an oncologically adequate operation, exact assessment of the biliary tree is essential not only preoperatively but also intraoperatively.

Donor Hepatic Occult Collagen Deposition Predisposes to Peritransplant Stress and Impacts Human Liver Transplantation.

BACKGROUND AND AIMS: Environmentally triggered chronic liver inflammation can cause collagen deposits, whereas early stages of fibrosis without any specific symptoms could hardly be detectable. We hypothesized that some of the human donor grafts in clinical liver transplantation (LT) might possess unrecognizable fibrosis, affecting their susceptibility to LT-induced stress and hepatocellular damage. This retrospective study aimed to assess the impact of occult hepatic fibrosis on clinical LT outcomes. APPROACH AND RESULTS: Human (194) donor liver biopsies were stained for collagen with Sirius red, and positive areas (Sirius red-positive area; SRA) were measured. The body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes score was calculated using 962 cases of the donor data at the procurement. LT outcomes, including ischemia-reperfusion injury (IRI), early allograft dysfunction (EAD), and survival rates, were analyzed according to SRA and BARD scores. With the median SRA in 194 grafts of 9.4%, grafts were classified into low-SRA (<15%; n = 140) and high-SRA (≥15%; n = 54) groups. Grafts with high SRA suffered from higher rates of IRI and EAD (P < 0.05) as compared to those with low SRA. Interestingly, high SRA was identified as an independent risk factor for EAD and positively correlated with the donor BARD score. When comparing low-BARD (n = 692) with high-BARD (n = 270) grafts in the same period, those with high BARD showed significantly higher post-LT transaminase levels and higher rates of IRI and EAD. CONCLUSIONS: These findings from the largest clinical study cohort to date document the essential role of occult collagen deposition in donor livers on LT outcomes. High-SRA and donor BARD scores correlated with an increased incidence of hepatic IRI and EAD in LT recipients. This study provides the rationale for in-depth and prospective assessment of occult fibrosis for refined personalized LT management.

Ischemia-reperfusion Injury in Allogeneic Liver Transplantation: A Role of CD4 T Cells in Early Allograft Injury.

BACKGROUND: A major discrepancy between clinical and most experimental settings of liver ischemia-reperfusion injury (IRI) is the allogenicity. METHODS: In the current study, we first established a murine model of allogeneic orthotopic liver transplantation with extended cold ischemia time (18 h). Roles of CD4 T cells in the pathogenesis of IRI in liver allografts were determined using a depleting anti-CD4 antibody. The clinical relevance of CD4 as a marker of liver IRI was analyzed retrospectively in 55 liver transplant patients. RESULTS: CD4 depletion in both donors and recipients resulted in the most effective protection of liver allografts from IRI, as measured by serum transaminase levels and liver histology. CD4 depletion inhibited IR-induced intragraft neutrophil/macrophage infiltration and proinflammatory gene expressions. Quantitative reverse-transcriptase polymerase chain reaction analysis of human liver biopsies (2 h postreperfusion) revealed that posttransplant, rather than pretransplant, CD4 transcript levels correlated positively with proinflammatory gene expression profile. When we divided patients into subgroups according to intragraft CD4 levels, the high CD4 cohort developed a more severe hepatocellular damage than that with low CD4 levels. CONCLUSIONS: CD4 T cells play a key pathogenic role in IRI of allogeneic liver transplants, and intragraft CD4 levels in the early postreperfusion phase may serve as a potential biomarker and therapeutic target to ameliorate liver IRI and improve orthotopic liver transplantation outcomes.

Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-RAS status for unresectable colorectal liver metastasis (BECK study): Long-term results of survival.

BACKGROUND/PURPOSE: To investigate the long-term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy. METHODS: Recurrence and survival data with long-term follow-up were analyzed in the cohort of a multi-institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study). RESULTS: A total of 22/12 patients with K-RAS wild-type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left-sided primary tumors than in right-sided tumors (75.0% vs 30.0%, P = .022). The median follow-up was 72.6 months. The 5-year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5-year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow-up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5-year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1-4). CONCLUSIONS: Conversion hepatectomy achieved a similar long-term survival to the results of previous studies in initially resectable patients, although many of them experienced several post-hepatectomy recurrences. Left-sided primary was found to be the predictor for conversion hepatectomy.

Heme Oxygenase-1 in liver transplant ischemia-reperfusion injury: From bench-to-bedside.

Hepatic ischemia-reperfusion injury (IRI), a major risk factor for early allograft dysfunction (EAD) and acute or chronic graft rejection, contributes to donor organ shortage for life-saving orthotopic liver transplantation (OLT). The graft injury caused by local ischemia (warm and/or cold) leads to parenchymal cell death and release of danger-associated molecular patterns (DAMPs), followed by reperfusion-triggered production of reactive oxygen species (ROS), activation of inflammatory cells, hepatocellular damage and ultimate organ failure. Heme oxygenase 1 (HO-1), a heat shock protein-32 induced under IR-stress, is an essential component of the cytoprotective mechanism in stressed livers. HO-1 regulates anti-inflammatory responses and may be crucial in the pathogenesis of chronic diseases, such as arteriosclerosis, hypertension, diabetes and steatosis. An emerging area of study is macrophage-derived HO-1 and its pivotal intrahepatic homeostatic function played in IRI-OLT. Indeed, ectopic hepatic HO-1 overexpression activates intracellular SIRT1/autophagy axis to serve as a key cellular self-defense mechanism in both mouse and human OLT recipients. Recent translational studies in rodents and human liver transplant patients provide novel insights into HO-1 mediated cytoprotection against sterile hepatic inflammation. In this review, we summarize the current bench-to-bedside knowledge on HO-1 molecular signaling and discuss their future therapeutic potential to mitigate IRI in OLT.

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury.

Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow-derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress-triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

The Impact of Biliary Reconstruction Methods on Small Partial Liver Grafts.

Graft recipient weight ratios are lower in adult-to-adult living-donor liver transplantation than in adult-to-adult deceased-donor liver transplantation. Rapid liver regeneration is essential for increased recipient survival rates in adult-to-adult living-donor liver transplantation. However, the influence of biliary reconstruction methods, including choledocho-choledochostomy and choledocho-jejunostomy, on small partial liver grafts remains unknown. Herein, we investigate the impact of these biliary reconstruction methods on small partial liver grafts. METHODS: Male Lewis rats underwent isogenic arterialized 30% partial liver transplantation with small partial grafts, either via choledocho-jejunostomy or choledocho-choledochostomy. RESULTS: The 7-day survival rates of the choledocho-choledochostomy and choledocho-jejunostomy groups were 100% and 50%, respectively (P = 0.011). Choledocho-jejunostomy provoked reflux cholangitis, as confirmed by neutrophil infiltration around the bile ducts; suppressed and delayed liver regeneration in grafts, as confirmed by significant increases in intrahepatic interleukin-1ß level, significant decreases in the graft weight increase ratios, hepatocyte proliferation, and intrahepatic mRNA expression of vascular endothelial growth factor; and induced graft dysfunction, as confirmed by the presence of massive ascites, significantly decreased bile production, and prolonged elevation of total bilirubin, aspartate aminotransferase, and alanine aminotransferase. CONCLUSIONS: Choledocho-jejunostomy predisposed grafts to cholangitis, impaired liver regeneration, and aggravated animal survival, suggesting that choledocho-choledochostomy may be preferable over choledocho-jejunostomy in adult-to-adult living-donor liver transplantation.

Therapeutic targets for liver regeneration after acute severe injury: a preclinical overview.

Introduction: Liver transplantation is the only viable treatment with a proven survival benefit for acute liver failure (ALF). Donor organ shortage is, however, a major hurdle; hence, alternative approaches that enable liver regeneration and target acute severe hepatocellular damage are necessary.Areas covered: This article sheds light on therapeutic targets for liver regeneration and considers their therapeutic potential. ALF following extensive hepatocyte damage and small-for-size syndrome (SFSS) are illuminated for the reader while the molecular mechanisms of liver regeneration are assessed in accordance with relevant therapeutic strategies. Furthermore, liver background parameters and predictive biomarkers that might associate with liver regeneration are reviewed.Expert opinion: There are established and novel experimental strategies for liver regeneration to prevent ALF resulting from SFSS. Granulocyte-colony stimulating factor (G-CSF) is a promising agent targeting liver regeneration after acute severe injury. Autophagy and hepatocyte senescence represent attractive new targets for liver regeneration in acute severe hepatic injury. Liver support strategies, including tissue engineering, constitute novel regenerative means; the success of this is dependent on stem cell research advances. However, there is no firm clinical evidence that these supportive strategies may alleviate hepatocellular damage until liver transplantation becomes available or successful self-liver regeneration occurs.

Human Antigen R (HuR): A Regulator of Heme Oxygenase-1 Cytoprotection in Mouse and Human Liver Transplant Injury.

BACKGROUND AND AIMS: Ischemia-reperfusion injury (IRI) represents a risk factor in liver transplantation (LT). We have shown that overexpression of heme oxygenase-1 (HO-1) mitigates hepatic IRI in LT recipients. Here, we hypothesized that human antigen R (HuR), the stabilizer of adenylate-uridylate (AU)-rich mRNAs, is required for hepatoprotection in LT. APPROACH AND RESULTS: In an experimental arm, HuR/HO-1 protein expression was correlated with hepatic IRI phenotype. In an in vitro inflammation mimic model of hepatic warm IRI, induction of HuR/HO-1 and cytoplasmic localization following cytokine preconditioning were detected in primary hepatocyte cultures, whereas HuR silencing caused negative regulation of HO-1, followed by enhanced cytotoxicity. Using the HuR-inhibitor, we showed that HuR likely regulates HO-1 through its 3' untranslated region and causes neutrophil activation (CD69+/lymphocyte antigen 6 complex locus G [Ly6-G]). HuR silencing in bone marrow-derived macrophages decreased HO-1 expression, leading to the induction of proinflammatory cytokines/chemokines. RNA sequencing of HuR silenced transcripts under in vitro warm IRI revealed regulation of genes thymus cell antigen 1 (THY1), aconitate decarboxylase 1 (ACOD1), and Prostaglandin E Synthase (PTGES). HuR, but not hypoxia-inducible protein alpha, positively regulated HO-1 in warm, but not cold, hypoxia/reoxygenation conditions. HuR modulated HO-1 in primary hepatocytes, neutrophils, and macrophages under reperfusion. Adjunctive inhibition of HuR diminished microtubule-associated proteins 1A/1B light chain 3B (LC3B), a marker for autophagosome, under HO-1 regulation, suggesting a cytoprotective mechanism in hepatic IR. In a clinical arm, hepatic biopsies from 51 patients with LT were analyzed at 2 hours after reperfusion. Graft HuR expression was negatively correlated with macrophage (CD80/CD86) and neutrophil (Cathepsin G) markers. Hepatic IRI increased HuR/HO-1 expression and inflammatory genes. High HuR-expressing liver grafts showed lower serum alanine aminotransferase/serum aspartate aminotransferase levels and improved LT survival. CONCLUSIONS: This translational study identifies HuR as a regulator of HO-1-mediated cytoprotection in sterile liver inflammation and a biomarker of ischemic stress resistance in LT.