Publications by authors named "Hirofumi Hirao"

28 Publications

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

J Hepatol 2021 Dec 3. Epub 2021 Dec 3.

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jhep.2021.11.026DOI Listing
December 2021

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

Nat Rev Gastroenterol Hepatol 2021 Nov 26. Epub 2021 Nov 26.

The Dumont-UCLA Transplantation Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.

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.
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http://dx.doi.org/10.1038/s41575-021-00549-8DOI Listing
November 2021

Reply.

Hepatology 2021 Sep 3. Epub 2021 Sep 3.

The Dumont-UCLA Transplantation Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

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http://dx.doi.org/10.1002/hep.32136DOI Listing
September 2021

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

Hepatology 2021 11 30;74(5):2759-2773. Epub 2021 Aug 30.

The Dumont-UCLA Transplantation Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA.

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.
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http://dx.doi.org/10.1002/hep.32030DOI Listing
November 2021

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

Transplantation 2021 09;105(9):1989-1997

Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, University of California, Los Angeles, CA.

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.
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http://dx.doi.org/10.1097/TP.0000000000003488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046839PMC
September 2021

The lectin-like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice.

Am J Transplant 2021 02 24;21(2):540-551. Epub 2020 Sep 24.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin-like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion-induced liver damage in a dose-dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage.
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http://dx.doi.org/10.1111/ajt.16269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891328PMC
February 2021

Ischemia-reperfusion injury and its relationship with early allograft dysfunction in liver transplant patients.

Am J Transplant 2021 02 10;21(2):614-625. Epub 2020 Sep 10.

The Dumont-UCLA Liver Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Ischemia-reperfusion injury (IRI) is believed to contribute to graft dysfunction after liver transplantation (LT). However, studies on IRI and the impact of early allograft dysfunction (EAD) in IRI grafts are limited. Histological IRI was graded in 506 grafts from patients who had undergone LT and classified based on IRI severity (no, minimal, mild, moderate, and severe). Of the 506 grafts, 87.4% had IRI (no: 12.6%, minimal: 38.1%, mild: 35.4%, moderate: 13.0%, and severe: 0.8%). IRI severity correlated with the incidence of EAD and graft survival at 6 months. Longer cold/warm ischemia time, recipient/donor hypertension, and having a male donor were identified as independent risk factors for moderate to severe IRI. Among 70 grafts with moderate to severe IRI, 42.9% of grafts developed EAD, and grafts with EAD had significantly inferior survival compared to grafts without EAD. Longer cold ischemia time and large droplet macrovesicular steatosis (≥20%) were identified as independent risk factors for EAD. Our study demonstrated that increased IRI severity was correlated with inferior short-term graft outcomes. Careful consideration of IRI risk factors during donor-recipient matching may assist in optimizing graft utilization and LT outcomes. Furthermore, identification of risk factors of IRI-associated EAD may guide patient management and possible timely graft replacement.
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http://dx.doi.org/10.1111/ajt.16219DOI Listing
February 2021

Microbiota in organ transplantation: An immunological and therapeutic conundrum?

Cell Immunol 2020 05 27;351:104080. Epub 2020 Feb 27.

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA. Electronic address:

The gastrointestinal (GI) tract microbiota is an environmental factor that regulates host immunity in allo-transplantation (allo-Tx). It is required for the development of resistance against pathogens and the stabilization of mucosa-associated lymphoid tissue. The gut-microbiota axis may also precipitate allograft rejection by producing metabolites that activate host cell-mediated and humoral immunity. Here, we discuss new insights into microbial immunomodulation, highlighting ongoing attempts to affect commensal colonization in an attempt to ameliorate allograft rejection cascade. Recent progress on the use of antibiotics to modulate GI microbiota diversity and innate-adaptive immune interface are discussed. Our focus on the microbiota's influence of endoplasmic reticulum (ER) stress and autophagy signaling through hepatic EP4/CHOP/LC3B platforms reveals a novel molecular pathway and potential biomarkers determining the progression of allo-Tx damage. Understanding and harnessing the potential of microbiome/bacteriophage therapies may offer safe and effective means for personalized treatment to reduce risks of infections and immunosuppression in allo-Tx.
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http://dx.doi.org/10.1016/j.cellimm.2020.104080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425695PMC
May 2020

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

Free Radic Biol Med 2020 09 19;157:75-82. Epub 2020 Feb 19.

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434658PMC
September 2020

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

J Clin Invest 2020 05;130(5):2689-2704

Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center.

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.
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http://dx.doi.org/10.1172/JCI133142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190917PMC
May 2020

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

Hepatology 2020 09 17;72(3):1056-1072. Epub 2020 Jul 17.

The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA.

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.
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http://dx.doi.org/10.1002/hep.31093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330638PMC
September 2020

Impact of Rifaximin Therapy on Ischemia/Reperfusion Injury in Liver Transplantation: A Propensity Score-Matched Analysis.

Liver Transpl 2019 12 4;25(12):1778-1789. Epub 2019 Nov 4.

The Dumont-UCLA Transplantation Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.

Intestinal microbiota is thought to play an important role in hepatic ischemia/reperfusion injury (IRI) after liver transplantation (LT). Rifaximin, a nonabsorbable antibiotic used to treat encephalopathy, exhibits antibacterial activity within the gut. We report the first study examining the impact of pre-LT rifaximin use on reducing hepatic IRI and inflammatory cell infiltration after LT. This retrospective single-center study included adult LT recipients from January 2013 through June 2016. Patients were divided into 2 groups based on duration of rifaximin use before LT: rifaximin group (≥28 days) and control group (none or <28 days). Patients receiving other antibiotics within 28 days of LT and re-LTs were excluded. Outcomes and messenger RNA (mRNA) expression in the graft were compared by 1:1 propensity score-matching and multivariate analyses. On 1:1 matching (n = 39/group), rifaximin patients had lower postoperative serum transaminase levels and lower early allograft dysfunction (EAD; 10.3% versus 33.3%; P = 0.014). Of the matched patients, 8 patients (n = 4/group) had postreperfusion liver biopsies (approximately 2 hours after reperfusion) available for mRNA analysis. Hepatic expression of CD86 (macrophage marker) and cathepsin G (neutrophil marker) was significantly lower in rifaximin patients than controls (P < 0.05). The multivariate analysis included 458 patients. Rifaximin treatment <28 days was identified as an independent risk factor EAD in all patients and those with high Model for End-Stage Liver Disease (MELD) score (MELD ≥35; n = 230). In conclusion, the propensity score-matched and multivariate analyses suggest a therapeutic role of rifaximin in reducing EAD. Pre-LT rifaximin administration exerted a protective function against early liver injury, potentially by suppressing inflammatory cell activation in the graft.
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http://dx.doi.org/10.1002/lt.25633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887108PMC
December 2019

Antibiotic pretreatment alleviates liver transplant damage in mice and humans.

J Clin Invest 2019 07 22;129(8):3420-3434. Epub 2019 Jul 22.

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx <10 days; n = 108) and Abx treatment (Abx ≥10days; n = 156) groups; OLT biopsy (Bx) samples were collected 2 hours after OLT (n = 52). Abx in mice mitigated IRI-stressed OLT (IRI-OLT), decreased CCAAT/enhancer-binding protein homologous protein (CHOP) (endoplasmic reticulum [ER] stress), enhanced LC3B (autophagy), and inhibited inflammation, whereas it increased serum prostaglandin E2 (PGE2) and hepatic PGE2 receptor 4 (EP4) expression. PGE2 increased EP4, suppressed CHOP, and induced autophagosome formation in hepatocyte cultures in an EP4-dependent manner. An EP4 antagonist restored CHOP, suppressed LC3B, and recreated IRI-OLT. Remarkably, human recipients of Abx treatment plus OLT (Abx-OLT), despite severe pretransplantation clinical acuity, had higher EP4 and LC3B levels but lower CHOP levels, which coincided with improved hepatocellular function (serum aspartate aminotransferase/serum aspartate aminotransferase [sALT/sAST]) and a decreased incidence of early allograft dysfunction (EAD). Multivariate analysis identified "Abx-free/Abx <10 days" as a predictive factor of EAD. This study documents the benefits of Abx pretreatment in liver transplant recipients, identifies ER stress and autophagy regulation by the PGE2/EP4 axis as a homeostatic underpinning, and points to the microbiome as a therapeutic target in OLT.
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http://dx.doi.org/10.1172/JCI127550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668671PMC
July 2019

Heme Oxygenase-1 dictates innate - adaptive immune phenotype in human liver transplantation.

Arch Biochem Biophys 2019 08 9;671:162-166. Epub 2019 Jul 9.

The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address:

Liver transplantation (LT) has become the standard of care for patients with end-stage liver disease and those with hepatic malignancies, while adaptive immune-dominated graft rejection remains a major challenge. Despite potent anti-inflammatory and cytoprotective functions of heme oxygenase-1 (HO-1) overexpression upon innate immune-driven hepatic ischemia reperfusion injury, its role in adaptive immune cell-driven responses remains to be elucidated. We analyzed human biopsies from LT recipients (n = 55) to determine putative association between HO-1 levels and adaptive/co-stimulatory gene expression programs in LT. HO-1 expression negatively correlated with innate (CD68, Cathepsin G, TLR4, CXCL10), adaptive (CD4, CD8, IL17) and co-stimulatory (CD28, CD80, CD86) molecules at the graft site. LT recipients with high HO-1 expression showed a trend towards improved overall survival. By demonstrating the association between graft HO-1 levels and adaptive/co-stimulatory gene programs, our study provides important insights to the role of HO-1 signaling in LT patients.
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http://dx.doi.org/10.1016/j.abb.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688971PMC
August 2019

Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury.

Proc Natl Acad Sci U S A 2019 07 13;116(27):13533-13542. Epub 2019 Jun 13.

Division of Hepato-Pancreato-Biliary and Transplantation Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, 606-8501 Kyoto, Japan.

Liver ischemia and reperfusion injury (IRI) is a major challenge in liver surgery. Diet restriction reduces liver damage by increasing stress resistance; however, the underlying molecular mechanisms remain unclear. We investigated the preventive effect of 12-h fasting on mouse liver IRI. Partial warm hepatic IRI model in wild-type male C57BL/6 mice was used. The control ischemia and reperfusion (IR) group of mice was given food and water ad libitum, while the fasting IR group was given water but not food for 12 h before ischemic insult. In 12-h fasting mice, serum liver-derived enzyme level and tissue damages due to IR were strongly suppressed. Serum β-hydroxybutyric acid (BHB) was significantly raised before ischemia and during reperfusion. Up-regulated BHB induced an increment in the expression of FOXO1 transcription factor by raising the level of acetylated histone. Antioxidative enzyme heme oxigenase 1 (HO-1), a target gene of FOXO1, then increased. Autophagy activity was also enhanced. Serum high-mobility group box 1 was remarkably lowered by the 12-h fasting, and activation of NF-κB and NLRP3 inflammasome was suppressed. Consequently, inflammatory cytokine production and liver injury were reduced. Exogenous BHB administration or histone deacetylase inhibitor administration into the control fed mice ameliorated liver IRI, while FOXO1 inhibitor administration to the 12-h fasting group exacerbated liver IRI. The 12-h fasting exerted beneficial effects on the prevention of liver IRI by increasing BHB, thus up-regulating FOXO1 and HO-1, and by reducing the inflammatory responses and apoptotic cell death via the down-regulation of NF-κB and NLRP3 inflammasome.
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http://dx.doi.org/10.1073/pnas.1820282116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613133PMC
July 2019

Human Atrial Natriuretic Peptide in Cold Storage of Donation After Circulatory Death Rat Livers: An Old but New Agent for Protecting Vascular Endothelia?

Transplantation 2019 03;103(3):512-521

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Current critical shortage of donor organs has increased the use of donation after circulatory death (DCD) livers for transplantation, despite higher risk for primary nonfunction or ischemic cholangiopathy. Human atrial natriuretic peptide (hANP) is a cardiovascular hormone that possesses protective action to vascular endothelia. We aimed to clarify the therapeutic potential of hANP in cold storage of DCD livers.

Methods: Male Wistar rats were exposed to 30-minute warm ischemia in situ. Livers were then retrieved and cold-preserved for 6 hours with or without hANP supplementation. Functional and morphological integrity of the livers was evaluated by oxygenated ex vivo reperfusion at 37°C.

Results: hANP supplementation resulted in significant reduction of portal venous pressure (12.2 ± 0.5 versus 22.5 ± 3.5 mm Hg, P < 0.001). As underlying mechanisms, hANP supplementation significantly increased tissue adenosine concentration (P = 0.008), resulting in significant upregulation of endothelial nitric oxide synthase and significant downregulation of endothelin-1 (P = 0.01 and P = 0.004 vs. the controls, respectively). Consequently, hANP significantly decreased transaminase release (P < 0.001) and increased bile production (96.2 ± 18.2 versus 36.2 ± 15.2 μL/g-liver/h, P < 0.001). Morphologically, hepatocytes and sinusoidal endothelia were both better maintained by hANP (P = 0.021). Electron microscopy also revealed that sinusoidal ultrastructures and microvilli formation in bile canaliculi were both better preserved by hANP supplementation. Silver staining also demonstrated that hANP significantly preserved reticulin fibers in Disse space (P = 0.017), representing significant protection of sinusoidal frameworks/architectures.

Conclusions: Supplementation of hANP during cold storage significantly attenuated cold ischemia/warm reperfusion injury of DCD livers.
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http://dx.doi.org/10.1097/TP.0000000000002552DOI Listing
March 2019

Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury.

JCI Insight 2018 10 4;3(19). Epub 2018 Oct 4.

Department of Medicine, Division of Cardiology, and.

Macrophages polarize into heterogeneous proinflammatory M1 and antiinflammatory M2 subtypes. Heme oxygenase 1 (HO-1) protects against inflammatory processes such as ischemia-reperfusion injury (IRI), organ transplantation, and atherosclerosis. To test our hypothesis that HO-1 regulates macrophage polarization and protects against IRI, we generated myeloid-specific HO-1-knockout (mHO-1-KO) and -transgenic (mHO-1-Tg) mice, with deletion or overexpression of HO-1, in various macrophage populations. Bone marrow-derived macrophages (BMDMs) from mHO-1-KO mice, treated with M1-inducing LPS or M2-inducing IL-4, exhibited increased mRNA expression of M1 (CXCL10, IL-1β, MCP1) and decreased expression of M2 (Arg1 and CD163) markers as compared with controls, while BMDMs from mHO-1-Tg mice displayed the opposite. A similar pattern was observed in the hepatic M1/M2 expression profile in a mouse model of liver IRI. mHO-1-KO mice displayed increased hepatocellular damage, serum AST/ALT levels, Suzuki's histological score of liver IRI, and neutrophil and macrophage infiltration, while mHO-1-Tg mice exhibited the opposite. In human liver transplant biopsies, subjects with higher HO-1 levels showed lower expression of M1 markers together with decreased hepatocellular damage and improved outcomes. In conclusion, myeloid HO-1 expression modulates macrophage polarization, and protects against liver IRI, at least in part by favoring an M2 phenotype.
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http://dx.doi.org/10.1172/jci.insight.120596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237471PMC
October 2018

Hydrogen Flush After Cold Storage as a New End-Ischemic Ex Vivo Treatment for Liver Grafts Against Ischemia/Reperfusion Injury.

Liver Transpl 2018 11;24(11):1589-1602

Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation.

Cold storage (CS) remains the gold standard for organ preservation worldwide, although it is inevitably associated with ischemia/reperfusion injury (IRI). Molecular hydrogen (H ) is well known to have antioxidative properties. However, its unfavorable features, ie, inflammability, low solubility, and high tissue/substance permeability, have hampered its clinical application. To overcome such obstacles, we developed a novel reconditioning method for donor organs named hydrogen flush after cold storage (HyFACS), which is just an end-ischemic H flush directly to donor organs ex vivo, and, herein, we report its therapeutic impact against hepatic IRI. Whole liver grafts were retrieved from Wistar rats. After 24-hour CS in UW solution, livers were cold-flushed with H solution (1.0 ppm) via the portal vein (PV), the hepatic artery (HA), or both (PV + HA). Functional integrity and morphological damages were then evaluated by 2-hour oxygenated reperfusion at 37°C. HyFACS significantly lowered portal venous pressure, transaminase, and high mobility group box protein 1 release compared with vehicle-treated controls (P < 0.01). Hyaluronic acid clearance was significantly higher in the HyFACS-PV and -PV + HA groups when compared with the others (P < 0.01), demonstrating the efficacy of the PV route to maintain the sinusoidal endothelia. In contrast, bile production and lactate dehydrogenase leakage therein were both significantly improved in HyFACS-HA and -PV + HA (P < 0.01), representing the superiority of the arterial route to attenuate biliary damage. Electron microscopy consistently revealed that sinusoidal ultrastructures were well maintained by portal HyFACS, while microvilli in bile canaliculi were well preserved by arterial flush. As an underlying mechanism, HyFACS significantly lowered oxidative damages, thus improving the glutathione/glutathione disulfide ratio in liver tissue. In conclusion, HyFACS significantly protected liver grafts from IRI by ameliorating oxidative damage upon reperfusion in the characteristic manner with its route of administration. Given its safety, simplicity, and cost-effectiveness, end-ischemic HyFACS may be a novel pretransplant conditioning for cold-stored donor organs.
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http://dx.doi.org/10.1002/lt.25326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686173PMC
November 2018

Recipient HO-1 inducibility is essential for posttransplant hepatic HO-1 expression and graft protection: From bench-to-bedside.

Am J Transplant 2019 02 24;19(2):356-367. Epub 2018 Aug 24.

Division of Liver and Pancreas Transplantation, Department of Surgery, The Dumont-UCLA Transplantation Center, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.

By documenting potent antioxidative and anti-inflammatory functions, preclinical studies encourage heme oxygenase-1 (HO-1)-inducing regimens in clinical orthotopic liver transplantation (OLT). We aimed to determine the importance of recipient-derived HO-1 in murine and human OLTs. Hepatic biopsies from 51 OLT patients were screened for HO-1 expression (Western blots) prior to put-in (basal) and post reperfusion (stressed) and correlated with the hepatocellular function. In parallel, livers from HO-1 proficient mice (WT; C57/BL6), subjected to ex vivo cold storage (18 hour), were transplanted to syngeneic myeloid HO-1 deficient (mHO-1 KO) or FLOX (control) hosts, and sampled postreperfusion (6 hour). In human OLT, posttransplant but not pretransplant HO-1 expression correlated negatively with ALT levels (P = .0178). High posttransplant but not pretransplant HO-1 expression trended with improved OLT survival. Compared with controls, livers transplanted into mHO-1 KO recipient mice had decreased HO-1 levels, exacerbated hepatic damage/frequency of TUNEL+ cells, increased mRNA levels coding for TNFα/CXCL1/CXCL2/CXCL10, higher frequency of Ly6G+/4HN+ neutrophils; and enhanced MPO activity. Peritoneal neutrophils from mHO-1 KO mice exhibited higher CellRox+ ratio and increased TNFα/CXCL1/CXCL2/CXCL10 expression. By demonstrating the importance of posttransplant recipient HO-1 phenotype in hepatic macrophage/neutrophil regulation and function, this translational study identifies recipient HO-1 inducibility as a novel biomarker of ischemic stress resistance in OLT.
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http://dx.doi.org/10.1111/ajt.15043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349504PMC
February 2019

Preventive Effect of Antioxidative Nutrient-Rich Enteral Diet Against Liver Ischemia and Reperfusion Injury.

JPEN J Parenter Enteral Nutr 2019 01 5;43(1):133-144. Epub 2018 Jun 5.

Division of Hepato-Pancreato-Biliary and Transplantation Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Liver ischemia and reperfusion injury (IRI) is a major problem associated with liver surgery. This study is aimed to compare the preventive effect of an antioxidative nutrient-rich enteral diet (Ao diet) with an ordinal enteral diet (control diet) against liver IRI.

Methods: The Ao diet was an ordinary diet comprising polyphenols (catechin and proanthocyanidin) and enhanced levels of vitamins C and E. Male C57BL/6 mice were fed the Ao or control diet for 7 days before ischemic insult for 60 minutes, followed by reperfusion for 6 hours. The levels of inflammatory cytokines, chemokines, and antioxidant enzymes and oxidative stress were evaluated.

Results: After 7 days of pretreatment with the Ao diet, the serum levels of vitamins C and E in mice were markedly elevated. The levels of serum aspartate aminotransferase and alanine aminotransferase, as well as the scores of liver necrosis caused by ischemia and reperfusion, were significantly lower in the Ao diet group than in the control diet group. The gene expression levels of inflammatory cytokines and chemokines, such as interleukin-6 and CXCL1, were significantly lower in the Ao diet group. In the liver, the levels of antioxidant enzymes superoxide dismutase 1 (SOD1) and SOD2 were significantly higher and the malondialdehyde levels were significantly lower in the Ao diet group. Cell adhesion molecule expression was significantly lower, and neutrophil and macrophage infiltration was less in the Ao diet group.

Conclusions: Antioxidative nutrient supplementation to an ordinary enteral diet may mitigate liver IRI by causing an antioxidant effect and suppressing inflammation.
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http://dx.doi.org/10.1002/jpen.1308DOI Listing
January 2019

Impact of Donor Age on Recipient Survival in Adult-to-Adult Living-donor Liver Transplantation.

Ann Surg 2018 06;267(6):1126-1133

Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Objective: To investigate the influence of donor age on recipient outcome after living-donor partial liver transplantation (LDLT).

Background: Donor age is a well-known prognostic factor in deceased donor liver transplantation; however, its role in LDLT remains unclear.

Methods: We retrospectively analyzed 315 consecutive cases of primary adult-to-adult LDLT in our center between April 2006 and March 2014. Recipients were divided into 5 groups according to the donor age: D-20s (n = 60); D-30s (n = 72); D-40s (n = 57); D-50s (n = 94); and D-60s (n = 32). The recipient survival and the association with various clinical factors were investigated.

Results: Recipient survival proportions were significantly higher in D-20s compared with all the other groups (P = 0.008, < 0.001, < 0.001, and = 0.006, vs D-30s, -40s, -50s, and -60s, respectively), whereas there was no association between recipient survival and their own age. There are 3 typical relationships between donors and recipients in adult-to-adult LDLT: from child-to-parent, between spouses/siblings, and from parent-to-child. The overall survival in child-to-parent was significantly higher than in spouses/siblings (P = 0.002) and in parent-to-child (P = 0.005), despite significantly higher recipient age in child-to-parent [59 (42-69) years, P < 0.001]. Contrastingly, parent-to-child exhibited the lowest survival, despite the youngest recipient age [26 (20-43) years, P < 0.001]. In addition, younger donor age exhibited significantly better recipient survival both in hepatitis C virus-related and in non-hepatitis C virus diseases. Univariate and multivariate analyses both demonstrated that donor age and graft-type (right-sided livers) are independent prognostic factors for recipient survival.

Conclusions: Donor age is an independent, strong prognostic factor in adult-to-adult LDLT.
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http://dx.doi.org/10.1097/SLA.0000000000002194DOI Listing
June 2018

Influence of hepatorenal syndrome on outcome of living donor liver transplantation: A single-center experience in 357 patients.

Hepatol Res 2017 Apr 19;47(5):425-434. Epub 2016 Jul 19.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Aim: Liver transplantation is the only curative treatment for hepatorenal syndrome (HRS); however, the influence of HRS on the patient and renal outcome after living donor liver transplantation (LDLT) is still unclear. The aim of the present study was to evaluate the influence of HRS on the outcome of LDLT.

Methods: We retrospectively analyzed 357 consecutive adult patients who underwent primary LDLT between January 2005 and March 2013 at Kyoto University Hospital. The outcome of the patients with HRS was compared with those without HRS.

Results: A total of 29 patients (8%) were diagnosed as HRS (Group-HRS) preoperatively, and the other 328 patients (92%) were not diagnosed as HRS (Group-Non-HRS). Group-HRS showed a significantly lower preoperative estimated glomerular filtration rate (22.1 vs 78.3 mL/min/1.73m , P < 0.001) and higher Child-Pugh-Turcotte score (13 vs 10, P < 0.001) than Group-non-HRS. After a median follow up of 60 months, the 1-, 3- and 5-year recipients' survival were 60.7%, 57.1% and 57.1% in Group-HRS, and 83.7%, 79.4% and 76.2% in Group-Non-HRS, respectively (P = 0.030). Concomitant HRS significantly elongated postoperative hospital stays (75 vs 50 days, P = 0.003), as well as predisposed patients to higher in-hospital mortality (41% vs 18%, P = 0.005). Multivariate analysis showed that preoperative renal dysfunction (estimated glomerular filtration rate on admission <40 mL/min/1.73m , OR 2.106, P = 0.03) was an independent risk factor for 1-year recipients' survival after LDLT, in addition to donor age ≥38 years (OR 3.114, P < 0.001), Child-Pugh-Turcotte score ≥13 (OR 2.929, P < 0.001) and left lobe graft (OR 2.225, P = 0.004).

Conclusion: Coincidence of HRS is associated with significantly worse outcome after LDLT, especially in the early post-transplant period.
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http://dx.doi.org/10.1111/hepr.12764DOI Listing
April 2017

The protective function of galectin-9 in liver ischemia and reperfusion injury in mice.

Liver Transpl 2015 Jul;21(7):969-81

Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Galectin-9 (Gal-9) has gained attention as a multifaceted player in adaptive and innate immunity. To elucidate the role of Gal-9, we used a mouse model of partial liver ischemia/reperfusion injury (IRI) with wild type (WT) and Gal-9 knockout (KO) mice as well as a recombinant galectin-9 (reGal-9) protein. We found that the expression of Gal-9 was enhanced endogenously in the liver especially by hepatocytes and Kupffer cells during warm IRI for a mouse liver, which causes massive destruction of liver tissue. Gal-9 was released into the extracellular space in the liver and the highest levels in the plasma at 1 hour after reperfusion. The present study elucidates a novel role of Gal-9 signaling in mouse liver IRI, by using Gal-9-deficient mice and a stable form of reGal-9 protein. In the circumstance of Gal-9 absence, liver damage due to ischemia/reperfusion (IR) exacerbated the severity as compared with WT. On the other hand, exogenously administered reGal-9 significantly ameliorated hepatocellular damage. It decreased the local infiltration of the inflammatory cells such as T cells, neutrophils, and macrophages, and it reduced the expression of proinflammatory cytokines/chemokines; then, it strongly suppressed the apoptosis of the liver cells. Interestingly, severe liver damage due to IR in Gal-9 KO mice was improved by the administration of reGal-9. In conclusion, Gal-9 engagement ameliorated local inflammation and liver damage induced by IR, and the present study suggests a significant role of Gal-9 in the maintenance of hepatic homeostasis. In conclusion, targeting Gal-9 represents a novel approach to protect from inflammation such as liver IRI. Exogenous Gal-9 treatment will be a new therapeutic strategy against innate immunity-dominated liver tissue damage.
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http://dx.doi.org/10.1002/lt.24159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744675PMC
July 2015

Intestinal ischemic preconditioning ameliorates hepatic ischemia/reperfusion injury in rats: role of heme oxygenase 1 in the second window of protection.

Liver Transpl 2015 Jan;21(1):112-22

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Ehime, Japan.

Preconditioning by brief ischemia protects not only the concerned organ but also other distant organs against subsequent lethal damage; this is called remote ischemic preconditioning (RIPC). This study was designed to investigate the impact of intestinal RIPC on hepatic ischemia/reperfusion injury (IRI) with a special interest in heme oxygenase 1 (HO-1) induction in the second window of protection (SWOP). Male Wistar rats were randomly assigned to 1 of 2 groups: an RIPC group or a sham group. Before hepatic IRI, either intestinal RIPC, consisting of 2 cycles of 4-minute superior mesenteric artery clamping separated by 11 minutes of declamping (RIPC group), or a sham procedure (sham group) was performed. After 48 hours of recovery, the rats were exposed to 30 minutes of total hepatic IRI. Transaminase releases and proinflammatory cytokines were determined at several time points after reperfusion. Histopathological analysis and animal survival were also investigated. Intestinal RIPC significantly lowered transaminase release (alanine aminotransferase at 2 hours: 873.3 ± 176.4 IU/L for the RIPC group versus 3378.7 ± 871.1 IU/L for the sham group, P < .001) as well as proinflammatory cytokine production (tumor necrosis factor α at 2 hours: 930 ± 42 versus 387 ± 17 pg/μL, P < .001). The morphological integrity of the liver and the ileum was maintained significantly better with intestinal RIPC; this reached statistical significance not only in Suzuki's liver injury score (3.5 ± 0.2 versus 0.7 ± 0.5, P = .007) but also in Park's score for intestinal damage (4.0 ± 0.4 versus 2.0 ± 0.2, P = .007). Animal survival was also markedly improved (83.1% versus 15.4%, P < .001). As a mechanism underlying this protection, HO-1 was substantially induced in liver tissue, especially in hepatocytes, with remarkable up-regulation of bradykinin in the portal blood, whereas HO-1 protein induction in enterocytes was not significant. In conclusion, intestinal RIPC remarkably attenuates hepatic IRI in the SWOP, presumably by HO-1 induction in hepatocytes.
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http://dx.doi.org/10.1002/lt.24006DOI Listing
January 2015

Association of anti-human leukocyte antigen and anti-angiotensin II type 1 receptor antibodies with liver allograft fibrosis after immunosuppression withdrawal.

Transplantation 2014 Nov;98(10):1105-11

1 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 2 Department of Gastroenterological Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan. 3 Terasaki Foundation Laboratory, Los Angeles, CA. 4 Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan. 5 Address correspondence to: Hidenori Ohe, M.D., Ph.D., Terasaki Foundation Laboratory, 11570 W. Olympic Blvd, Los Angeles, CA 90064.

Background: Many pediatric patients who receive a living-donor liver transplant undergo withdrawal of immunosuppression (IS). For them, the high incidence of long-term progressive graft fibrosis is of particular concern.

Methods: We conducted a cross-sectional study including 81 pediatric patients who underwent IS withdrawal after living-donor liver transplant at Kyoto University Hospital and whose serum samples and pathological data could be obtained during the analysis period. We examined the association of donor-specific anti-human leukocyte antigen (HLA) antibody (DSA) and angiotensin II type 1 receptor antibody (anti-AT1R Ab) with posttransplant graft fibrosis. Normalized mean fluorescence intensity (MFI) 5,000 or higher and anti-AT1R Ab concentrations 17 U/mL or higher were both considered high level. The patients were classified into an advanced fibrosis group (AFG) (Ishak score ≥ 3) and a control group (CG) (Ishak score ≤ 2).

Results: Only one patient demonstrated DSA class I. Among those who demonstrated DSA class II, more AFG patients than CG patients demonstrated high-level mean fluorescence intensity, although the difference was not significant (64% vs. 39%; P=0.053). The incidence of high-level DSA-DRB1, however, was significantly higher in the AFG than that in the CG (40% vs. 4%; P<0.001), but there was no significant difference in DSA-DQB1 or DSA-DRB345. High-level anti-AT1R Ab was significantly more frequent in the AFG than in the CG (65% vs. 36%; P=0.02). All patients with both high-level DSA-DRB1 and high-level anti-AT1R Ab were found to have advanced fibrosis (P<0.001).

Conclusion: Anti-AT1R Ab and DSA-DRB1 may be candidates as biomarkers of graft fibrosis; both HLA and non-HLA immunity may be involved in graft fibrosis after IS withdrawal.
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http://dx.doi.org/10.1097/TP.0000000000000185DOI Listing
November 2014

How to successfully resect 70 % of the liver in pigs to model an extended hepatectomy with an insufficient remnant or liver transplantation with a small-for-size graft.

Surg Today 2014 Nov 12;44(11):2201-7. Epub 2014 Feb 12.

Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan,

An insufficient remnant in extended hepatectomy and small-for-size graft in liver transplantation are critical matters in the field of liver surgery, and reliable and reproducible animal models that can provide clinically relevant and reliable data are needed. We herein describe our detailed surgical procedures for performing 70 % hepatectomy in pigs, and discuss the critical anatomical features, key techniques and pitfalls based on our experience. The porcine liver is divided into four lobes. The right lateral lobe (RLL) accounts for 30 % of the liver volume. Important points, such as selective temporal clamping of the arterial branch, confirmation of a related demarcation line, a two-step process to skeletonize Glisson's capsules during liver resection and selective ligation of the portal venous branch to the right medial lobe without inducing any subtle injuries to Glisson's capsules from the RLL to common bile duct, are discussed.
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http://dx.doi.org/10.1007/s00595-014-0862-zDOI Listing
November 2014

Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis.

Hepatol Res 2014 Apr 30;44(4):460-73. Epub 2013 Jun 30.

Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Aim: Liver fibrosis is a common pathway leading to cirrhosis. Cilostazol, a clinically available oral phosphodiesterase-3 inhibitor, has been shown to have antifibrotic potential in experimental non-alcoholic fatty liver disease. However, the detailed mechanisms of the antifibrotic effect and its efficacy in a different experimental model remain elusive.

Methods: Male C57BL/6J mice were assigned to five groups: mice fed a normal diet (groups 1 and 2); 0.1% or 0.3% cilostazol-containing diet (groups 3 and 4, respectively); and 0.125% clopidogrel-containing diet (group 5). Two weeks after feeding, groups 2-5 were intraperitoneally administered carbon tetrachloride (CCl4 ) twice a week for 6 weeks, while group 1 was treated with the vehicle alone. To investigate the effects of cilostazol on hepatic cells, in vitro studies were conducted using primary hepatic stellate cells (HSC), Kupffer cells and hepatocytes with cilostazol supplementation.

Results: Sirius red staining revealed that groups 3 and 4 exhibited a lesser fibrotic area (2.49 ± 0.43% and 2.31 ± 0.30%, respectively) than group 2 (3.17 ± 0.67%, P < 0.05 and P < 0.001, respectively). In vitro studies showed cilostazol dose-dependently suppressed HSC activation (assessed by morphological change, cell proliferation, and the expression of HSC activation markers), suggesting the therapeutic effect of cilostazol is mediated by its direct action on HSC.

Conclusion: Cilostazol could alleviate CCl4 -induced hepatic fibrogenesis in vivo, presumably due, at least partly, to its direct effect to suppress HSC activation. Given its clinical availability and safety, it may be a novel therapeutic intervention for chronic liver diseases.
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http://dx.doi.org/10.1111/hepr.12140DOI Listing
April 2014

[A case of long-term survival after undergoing S-1 treatment and splenectomy for liver, lung and splenic metastases following curative distal gastrectomy for gastric cancer].

Gan To Kagaku Ryoho 2010 Jun;37(6):1125-9

Department of Surgery, Asahi General Hospital.

A 7 0-year-old female underwent distal gastrectomy for gastric cancer in November 2001. She did not wish to receive postoperative adjuvant chemotherapy. In May 2002, her serum carcinoembryonic antigen(CEA)level rose. CT demonstrated liver(S5/6)and lung(S9)metastases in August 2002. We started to treat her with S-1(100mg/day day 1-14 orally), and restaging CT showed complete regression of liver and lung metastases in August 2003. In spite her complete response(CR), we continued S-1 treatment for the successive two years. No adverse reaction to chemotherapy occurred. Although CR was maintained for about 4 years, she was found to have a 9-mm solitary lesion in the upper pole of the spleen in June 2007. After 6 months, this tumor increased to 15mm in size, and we considered it as a solitary metastasis to the spleen from gastric cancer. S-1 chemotherapy was restarted, but tumor size gradually increased. Tumor size finally reached 25mm in December 2008. She underwent splenectomy in January 2009. From then until now, she has not received any chemotherapy, and has been followed well without any recurrence.
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June 2010
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