Platelets Stimulate Liver Regeneration in a Rat Model of Partial Liver Transplantation.

Living donor liver transplantation (LDLT) is sometimes associated with impaired regeneration and severe ischemia/reperfusion injury (IRI) in the graft, resulting in small-for-size syndrome (SFSS). Platelets were previously reported to stimulate liver regeneration in models of hepatectomy, but the evidence in partial liver transplantation (LT) is lacking. In this study, a rat model of partial LT was used, and the impact of thrombopoietin (TPO)-induced perioperative thrombocytosis on graft regeneration, IRI, and survival was investigated. In experiment 1, a 30% partial LT was performed. Under thrombocytosis, SFSS was attenuated, as shown by decreased levels of serum aminotransferases, bilirubin, and ascites. Serum hepatocyte regeneration-related cytokines, including insulin-like growth factor-1, hepatocyte growth factor, interleukin 6 (IL6), and tumor necrosis factor α (TNF-α), were elevated. In addition, the proliferative signaling pathways, Ki-67-labeling index, proliferating cell nuclear antigen (PCNA)-labeling index, mitotic index, and liver/body weight ratio were increased under thrombocytosis. The platelet-induced regeneration was independent of TPO because increases in the Ki-67-labeling and PCNA-labeling indexes were eliminated after reducing platelet counts by antiplatelet serum in rats administered with TPO. For IRI, thrombocytosis did not aggravate oxidative stress or downstream signaling pathways, necrosis, or apoptosis in the graft. After Kupffer cell (KC) depletion, the platelet-induced attenuation of serum aminotransferases, increased serum levels of IL6 and TNF-α, and proliferation-related signaling pathways were eliminated. Moreover, platelet accumulation in the graft decreased substantially. In experiment 2, a 20% partial LT was performed, and thrombocytosis improved postoperative survival. In conclusion, our results suggested that thrombocytosis stimulated graft regeneration and prolonged survival without aggregating IRI after partial LT, and KCs vitally contributed to platelet-derived regeneration. Platelet therapies to increase perioperative platelet counts may improve the outcomes after LDLT.

The evidence of a macrophage barrier in the xenotransplantation of human hematopoietic stem cells to severely immunodeficient rats.

BACKGROUND: The human-to-rat hematopoietic stem cell transplantation (HSCT) model is rare, unlike its human-to-mouse counterpart. The rat models are desired, especially in areas of physiology, toxicology, and pharmacology. In addition to lymphocytes, macrophages are also considered to be important for xenotransplantation. We generated a rat xenotransplantation model to prove the role of macrophages as a xenotransplantation barrier. METHODS: Immunodeficiency in SRG rats, which are Sprague-Dawley (SD) rats lacking Rag2 and Il2rg, was confirmed by flow cytometry and spleen immunostaining. Human umbilical cord blood was collected after scheduled cesarean section at the University of Tsukuba Hospital. Cord blood mononuclear cells (CB-MNCs) were transplanted into the SRG rats administered several injections of clodronate liposome (CL), which cause macrophage depletion. Survival of human cells was observed by flow cytometry. Rat macrophage phagocytosis assay was performed to check the species-specific effects of rat macrophages on injected human/rat blood cells. RESULTS: SRG rats were deficient in T/B/NK cells. Without CL pretreatment, human CB-MNCs were removed from SRG rats within 7 hours after transplantation. The rats pretreated with CL could survive after transplantation. Prolonged survival for more than 4 weeks was observed only following a one-time CL injection. Rat macrophages had a species-specific potential for the phagocytosis of human blood cells in vivo. CONCLUSION: In human-to-rat HSCT, the short period of early macrophage control, leading to macrophage immunotolerance, is important for engraftment. The generated model can be useful for the creation of future xenotransplantation models or other clinical research.

Oxidative stress and Liver X Receptor agonist induce hepatocellular carcinoma in Non-alcoholic steatohepatitis model.

BACKGROUND AND AIM: The incidence of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is progressively increasing. However, the pathophysiology and etiology of NASH progression to HCC are unknown. We hypothesized that steatosis was the key factor in NASH-related hepatocarcinogenesis and aimed to evaluate the effects of long-term liver X receptor (LXR) agonist stimulation on hepatic steatosis induced by a high-fat diet and oxidative stress. METHODS: We used an LXR agonist (T0901317) and CCl4 to induce hepatic steatosis and oxidative stress, respectively. C57BL/6 mice fed with a high-fat diet were treated with either T0901317 + CCl4 (T09 + CCl4 group) or CCl4 alone (CCl4 group). T0901317 (2.5 mg/kg) and CCl4 (0.1 mL/kg) were intraperitoneally administered twice weekly for 24 weeks. RESULTS: The liver-to-body weight ratio was significantly higher in the T09 + CCl4 group than in the CCl4 group. Mice in the T09 + CCl4 group exhibited abnormal lipid metabolism and NASH-like histopathological features. Additionally, all mice in the T09 + CCl4 group developed liver tumors diagnosed as well-differentiated HCC. The genes identified via microarray analysis were related to NASH and HCC development. CONCLUSIONS: By combining long-term LXR agonist stimulation with oxidative stress and a high-fat diet, we successfully reproduced liver conditions in mice similar to those in humans with NASH and progression to HCC. Our results provide new insight into NASH-related HCC progression and therapy.

Platelet and liver regeneration after liver surgery.

The success of liver surgery, including resection and transplantation, is largely dependent on the ability of the liver to regenerate. Despite substantial improvement in surgical techniques and perioperative care, one of the main concerns is post-hepatectomy liver failure and early allograft dysfunction, both of which are associated with impaired liver regeneration. Recent studies have demonstrated the positive role of platelets in promoting liver regeneration and protecting hepatocytes; however, the underlying mechanisms responsible for these effects are not fully understood. In this review, we updated the accumulated evidence of the role of platelets in promoting liver regeneration, with a focus on liver resection and liver transplantation. The goal of these studies was to support the clinical implementation of platelet agents, such as thrombopoietin receptor agonists, to augment liver regeneration after liver surgery. This "platelet therapy" may become a treatment choice for post-hepatectomy liver failure and early allograft dysfunction.

Remnant pancreatic volume as an indicator of poor prognosis in pancreatic cancer patients after resection.

BACKGROUND: Remnant pancreatic volume (RPV) is a well-known marker for short-term outcomes in pancreatic cancer patients after resection. However, in terms of the long-term outcomes, the significance of the RPV value remains unclear. Here, we address whether the RPV value is a predictor of the long-term outcomes in pancreatic cancer patients after resection by comparing various cancer-, patient-, and surgery-related prognostic factors and systemic inflammatory response markers in a retrospective cohort. METHODS: The RPV was measured on a three-dimensional (3D) image, revealing the actual pancreatic parenchymal remnant volume. Ninety-one patients who underwent pancreaticoduodenectomy were retrospectively enrolled. We divided the cohort into high- and low-RPV groups based on a cut-off value (>31.5 cm3, n = 66 and ≤31.5 cm3, n = 25, respectively). The median survival times (MSTs) were compared between the two groups. Using multivariate analysis, the RPV and other well-known prognostic factors were independently assessed. RESULTS: The MSTs (days) were significantly different between the two groups (high, 823 vs. low, 482, p = 0.001). Multivariate analysis identified the RPV (≤31.5 cm3) (hazard ratio [HR], 2.015; p = 0.011), lymph node metastasis (HR, 8.415; p = 0.002), lack of adjuvant chemotherapy (HR, 5.352; p < 0.001), stage III/IV disease (HR, 2.352; p = 0.029), and pathological fibrosis (HR, 1.771; p = 0.031) as independent prognostic factors. CONCLUSIONS: The present study suggests that the RPV value is also useful for predicting long-term outcomes in pancreatic cancer patients after resection.

Prevalence and characteristics of hepatitis E virus infection in kidney transplant recipients: A single-center experience in Japan.

BACKGROUND: Hepatitis E virus (HEV) infection can lead to chronic hepatitis in solid organ transplant recipients. To investigate whether HEV infection influences outcomes following kidney transplantation, we examined the prevalence of HEV infection and clinical characteristics of kidney transplant recipients in our hospital. METHODS: Our cross-sectional study included 184 kidney transplant recipients. Blood samples were obtained from all patients to detect anti-HEV immunoglobulin (Ig)A, IgM, and IgG by enzyme-linked immunosorbent assay and HEV RNA by reverse transcription polymerase chain reaction. Clinical data were collected from medical charts for all patients. RESULTS: The prevalence of anti-HEV IgG was 8/184 (4.3%). Anti-HEV IgA, anti-HEV IgM, and HEV RNA were not detected in any patients. Compared to their anti-HEV IgG-negative counterparts, anti-HEV IgG-positive patients were significantly older at the time of transplantation, and they were more likely to receive kidneys from deceased donors. No significant differences in other characteristics such as the prevalence of primary cause of end-stage renal disease, blood transfusion, and immunosuppressive therapy use; liver and renal function; and the frequencies of hepatitis B and hepatitis C virus infection were observed according to the patients' anti-HEV IgG status. CONCLUSION: HEV infection had no significant influence on the outcomes of kidney transplantation at our institution. However, HEV infection should be recognized in kidney transplant recipients similarly as hepatitis B and hepatitis C virus infection in cases of liver dysfunction.

Albumin-Indocyanine Green Evaluation Grading System Predicts Post-Hepatectomy Liver Failure for Biliary Tract Cancer.

BACKGROUND: In biliary tract cancer treatment, a precise preoperative evaluation of the patient's liver function is essential to avoid post-hepatectomy liver failure (PHLF) and mortality. The present study aimed to evaluate the role of the Albumin-Indocyanine Green Evaluation (ALICE) grading system in predicting PHLF in biliary tract cancer patients. METHODS: Data from 166 patients who underwent hepatectomy for biliary tract cancer between 2000 and 2016 were retrospectively analyzed. Univariate and multivariate analyses were performed to identify the risk factors for PHLF. RESULTS: Among the 166 patients, major hepatectomy was performed in 101 (61%) and bile duct resection was performed in 99 (60%) patients. Thirteen (8%) patients developed PHLF. Furthermore, PHLF, major complications, and mortality were significantly higher in patients with high ALICE grades (≥2b) than in those with low ALICE grades (<2b) (PHLF, 42 vs. 18%, p = 0.002; major complications, 35 vs. 19%, p = 0.036; mortality, 9.3 vs. 0%, p = 0.001). In multivariate analysis, high ALICE grade (p = 0.016) and blood loss ≥1,500 mL (p = 0.009) were identified as independent risk factors for PHLF. CONCLUSIONS: The ALICE grading system effectively stratified the risks for PHLF for biliary tract cancer.

Novel non-alcoholic steatohepatitis model with histopathological and insulin-resistant features.

Although several non-alcoholic steatohepatitis (NASH) models have been reported to date, few of these models fully reflect the histopathology and pathophysiology of human NASH. The aim of this study was to establish a novel NASH model by feeding a high-fat (HF) diet and administering both carbon tetrachloride (CCl4 ) and the Liver X receptor agonist T0901317. Male C57BL/6J mice were divided into four groups (each n = 5): HF, HF + CCl4 , HF + T0901317, and the novel NASH model (HF + CCl4 + T0901317). CCl4 (0.1 mL/kg) and T0901317 (2.5 mg/kg) were intraperitoneally administered four times and five times, respectively. The livers of the novel NASH model group presented a whitish colour. The serum levels of TNF-α and IL-6 were significantly increased in the novel NASH model group, and mice in this group exhibited histopathological features and insulin resistance reflective of NASH, i.e., macrovesicular hepatic steatosis, ballooning hepatocytes, Mallory-Denk bodies, lobular inflammation and fibrosis. The novel NASH model group presented significantly upregulated expression levels of mRNAs related to lipogenesis, oxidative stress, fibrosis and steatosis and significantly downregulated expression levels of mRNAs related to triglyceride export. We successfully established a novel experimental NASH model that exhibits similar histopathology and pathophysiology to human NASH.

Surgical resection of hepatic and rectal metastases of pancreatic acinar cell carcinoma (PACC): a case report.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC), a rare variant of pancreatic malignancy, is generally managed the same way as pancreatic ductal adenocarcinoma (PDAC). Surgical resection is the gateway to curing it; however, once it metastasizes (usually to the liver, lungs, lymph nodes, or peritoneal cavity), systemic chemotherapy has been the only option, but with unfavorable results. CASE PRESENTATION: A 67-year-old man with symptoms of loss of appetite and weight underwent surgery for malignancy of the pancreatic tail extending into the entire pancreas. The pathological diagnosis was PACC following total pancreatectomy. Twenty-four months after the pancreatectomy, a solitary liver metastasis was treated by partial hepatectomy, and, subsequently, 4 months later, he presented with melena. Further examination revealed a type-2 rectal tumor. Histological examination following biopsy revealed it to be rectal metastasis of PACC, and it was treated by abdominoperineal resection. Subsequently, the patient did not have tumor recurrence as of 40 months after pancreatectomy. CONCLUSIONS: This is a rare case of PACC presenting with metachronal metastases in the liver and rectum, and we successfully treated them by surgical resections. Since the malignant behavior of PACC is usually less than that of PDAC, surgical resection could be an option even for metastatic lesions when the number and extent of metastases are limited.

Development of Implantable Wireless Sensor Nodes for Animal Husbandry and MedTech Innovation.

In this paper, we report the development, evaluation, and application of ultra-small low-power wireless sensor nodes for advancing animal husbandry, as well as for innovation of medical technologies. A radio frequency identification (RFID) chip with hybrid interface and neglectable power consumption was introduced to enable switching of ON/OFF and measurement mode after implantation. A wireless power transmission system with a maximum efficiency of 70% and an access distance of up to 5 cm was developed to allow the sensor node to survive for a duration of several weeks from a few minutes' remote charge. The results of field tests using laboratory mice and a cow indicated the high accuracy of the collected biological data and bio-compatibility of the package. As a result of extensive application of the above technologies, a fully solid wireless pH sensor and a surgical navigation system using artificial magnetic field and a 3D MEMS magnetic sensor are introduced in this paper, and the preliminary experimental results are presented and discussed.

Unique clinical courses of transfusion-transmitted hepatitis E in patients with immunosuppression.

BACKGROUND: The high prevalence of specific immunoglobulin G for hepatitis E virus (HEV) in Japanese people raises the possibility of a high incidence of HEV-viremic blood donors and therefore frequent transfusion-transmitted HEV (TT-HEV). STUDY DESIGN AND METHODS: TT-HEV cases established in Japan through hemovigilance and those published in the literature were collected. Infectivity of HEV-contaminated blood components and disease severity in relation to immunosuppression were investigated. RESULTS: Twenty established TT-HEV cases were recorded over the past 17 years. A lookback study verified that five of 10 patients transfused with known HEV-contaminated blood components acquired HEV infection. The minimal infectious dose of HEV through transfusion was 3.6 × 104 IU. Nine of the 19 TT-HEV cases analyzed had hematologic diseases. Only two cases showed the maximal alanine aminotransferase level of more than 1000 U/L. Two patients with hematologic malignancy and two liver transplant recipients had chronic liver injury of moderate severity. CONCLUSION: The infectivity of HEV-contaminated components was 50%. Immunosuppression likely causes the moderate illness of TT-HEV, but it may lead to the establishment of chronic sequelae. Transfusion recipients, a population that is variably immunosuppressed, are more vulnerable to chronic liver injury as a result of TT-HEV than the general population is as a result of food-borne infection.

Survival of surgery for recurrent biliary tract cancer: a single-center experience and systematic review of literature.

BACKGROUND: For recurrent biliary tract cancer, chemotherapy is the standard treatment. However, the efficacy of surgery is unknown. Here, the prognostic benefit of surgery for recurrent biliary tract cancer was investigated. METHODS: Data of 206 patients who underwent surgery for biliary tract cancer between 2005 and 2015 were retrospectively analyzed. Of these, 107 recurrent patients were divided into two groups, surgery (n = 14) and non-surgery (n = 93) groups. In the latter group, 45 patients received chemotherapy and 48 received best supportive care. RESULTS: Of the total 121 sites of recurrence, the liver was the most common (n = 41), followed by locoregional recurrence (n = 32) and lymph nodes (n = 18). Surgery was performed in the 14 patients with recurrence, comprising nine patients with intrahepatic cholangiocarcinoma, three with perihilar cholangiocarcinoma, one with distal cholangiocarcinoma and one with gallbladder carcinoma. Survival after recurrence was significantly better after surgery than after chemotherapy or best supportive care (38% vs. 5.3% vs. 0% at 3 years and 19% vs. 5.3% vs. 0% at 5 years; P < 0.0001). Multivariate analysis identified the residual status of the primary tumor (hazard ratio = 1.58, 95% confidence interval = 1.00-2.44; P = 0.047), time to recurrence ≥1 year (hazard ratio = 0.62, 95% confidence interval = 0.39-0.97; P = 0.037) and surgery for recurrence (hazard ratio = 0.32, 95% confidence interval = 0.14-0.62; P < 0.001) as independent prognostic factors. CONCLUSIONS: Surgery for recurrent biliary tract cancer may prolong survival in patients with time to recurrence ≥1 year.

The Effect of Three-Dimensional Preoperative Simulation on Liver Surgery.

BACKGROUND: In the past decade, three-dimensional (3D) simulation has been commonly used for liver surgery. However, few studies have analyzed the usefulness of this 3D simulation. The aim of this study was to evaluate the effect of 3D simulation on the outcome of liver surgery. METHODS: We retrospectively analyzed 240 consecutive patients who underwent liver resection. The patients were divided into two groups: those who received 3D preoperative simulation ("3D group", n = 120) and those who did not undergo 3D preoperative simulation ("without 3D group", n = 120). The perioperative outcomes, including operation time, blood loss, maximum aspartate transaminase level, length of postoperative stay, postoperative complications and postoperative mortality, were compared between the two groups. The predicted resected liver volume was compared with the actual resected volume. RESULTS: The median operation time for the 3D group was 36 min shorter than that for the without 3D group (P = 0.048). There were no significant differences in other outcomes between the two groups. A subgroup analysis revealed that the operation time of repeated hepatectomy and segmentectomy for the 3D group was shorter than that for the without 3D group (P = 0.03). There was a strong correlation between the predicted liver volume and the actual resected liver weight (r = 0.80, P < 0.001). CONCLUSION: These findings demonstrate that 3D preoperative simulation may reduce the operation time, particularly for repeated hepatectomy and segmentectomy.

Novel imaging using a touchless display for computer-assisted hepato-biliary surgery.

PURPOSE: We developed a touchless display system that allows the user to control the medical imaging software via hand gestures in the air. We conducted this study to verify the effectiveness of this novel touchless display system as a tool for assisting with surgical imaging. METHODS: The patient's computed tomography (CT) data are generally observed on a display during surgery. The "Dr. aeroTAP" touchless display system was developed to generate virtual mouse events based on the position of one hand. We conducted comparative analyses of using the Dr. aeroTAP vs. using a regular mouse (control group) by measuring the time to select a 3D image from 24 thumbnail images on a screen (study 1) and to then see the CT image on the DICOM viewer (study 2). RESULTS: We used the Dr. aeroTAP in 31 hepato-biliary operative procedures performed at our hospital. In study 1, which measured the time required to select one of 24 thumbnails, there were significant differences between the mouse and Dr. aeroTAP groups for all five surgeons who participated (P < 0.001). In study 2, there were also significant differences in the time required for CT DICOM images to be displayed (P < 0.001). CONCLUSIONS: The touchless interface proved efficient for allowing the observation of surgical images while maintaining a sterile field during surgery.

A novel three-dimensional print of liver vessels and tumors in hepatectomy.

Creating a three-dimensional (3D)-printed liver model is costly, and the visibility of the inner structures is slightly hindered. We developed a novel structure that simultaneously solves both of these problems. The outer frames were set up along the liver surface. Our structure did not use the transparent loading material because this material increases the printing cost. Therefore, we were able to directly observe the inside of the structure. We performed hepatectomy using this novel 3D-printed liver model. Using this model, we were able to clearly simulate the resection line and safely perform the surgery. Our process was more cost effective, had a shorter production time, and improved the visibility than other processes. We developed a novel 3D-printed liver for hepatectomy, which made the procedure easier, reduced the production cost, and improved the visibility; this approach may be useful for future surgeries.

Three-dimensional simulation of pancreatic surgery showing the size and location of the main pancreatic duct.

PURPOSE: We performed three-dimensional (3D) surgical simulation of pancreatic surgery, including the size and location of the main pancreatic duct on the resected pancreatic surface. METHODS: The subjects of this retrospective analysis were 162 patients who underwent pancreatic surgery. This cohort was sequentially divided into a "without-3D" group (n = 81) and a "with-3D" group (n = 81). We compared the pancreatic duct diameter and its location, using nine sections in a grid pattern, with the intraoperative findings. The perioperative outcomes were also compared between patients who underwent pancreaticoduodenectomy (PD) and those who underwent distal pancreatectomy (DP). RESULTS: There were no significant differences in the main pancreatic duct diameter between the 3D-simulated values and the operative findings. The 3D-simulated main pancreatic duct location was consistent with its actual location in 80 % of patients (65/81). In comparing the PD and DP groups, the intraoperative blood loss was 1174 ± 867 and 817 ± 925 ml in the without-3D group, and 828 ± 739 and 307 ± 192 ml in the with-3D group, respectively (p = 0.024, 0.026). CONCLUSION: The 3D surgical simulation provided useful information to promote our understanding of the pancreatic anatomy, including details on the size and location of the main pancreatic duct.

[COMPUTER-ASSISTED SURGERY SIMULATING THE PROCESS OF HEPATECTOMY].

In the last five years, many hospitals in Japan have created three-dimensional (3D) images from computed tomography (CT) data from patients who have undergone liver resection to share the images of liver structures with the surgical team and analyze the liver volume based on portal perfusion. However, using the previous software packages, the 3D liver model was fixed and rigid. Therefore, we developed novel 3D simulation software, called Liversim, to visualize real-time malformations of the liver. There were no marked differences during the process of liver resection between Liversim and actual surgery. Virtual liver resection showing real-time malformations of the liver using Liversim is useful for the safe performance of liver resections.

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer.

Even with current promising antitumor antibodies, their antitumor effects on stroma-rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa-2; moderate, BxPC-3; and abundant, Capan-1 and Ope-xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra-abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa-2 model, moderate (1063) in the BxPC-3 model, and negative in the Capan-1 and Ope-xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8-fold (2980, 3015) in the BxPC-3 model, 2.5- or 4.8-fold (1881, 3615) in the Capan-1 model, and 3.2- or 4.2-fold (1469, 1922) in the Ope-xeno model, respectively. Cetuximab was effective in treating even stroma-rich and k-ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.

Protecting liver sinusoidal endothelial cells suppresses apoptosis in acute liver damage.

AIM: Apoptosis is associated with various types of hepatic disorders. We have developed a novel cell-transfer drug delivery system (DDS) using a multifunctional envelope-type nano device that targets liver sinusoidal endothelial cells (LSECs). The purpose of this study was to determine the efficacy of the novel DDS containing siRNA at suppressing apoptosis in LSECs. METHODS: Bax siRNA was transfected into a sinusoidal endothelial cell line (M1) to suppress apoptosis induced by an anti-Fas antibody and staurosporine. C57BL/6J mice were divided into three groups: (i) a control group, only intravenous saline; (ii) a nonselective group, injections of siRNA sealed in the nonselective DDS; and (iii) an LSEC-transfer efficient group, injections of siRNA sealed in an LSEC-transfer efficient DDS. Hepatic cell apoptosis was induced by an anti-Fas antibody. RESULTS: Bax siRNA had an anti-apoptotic effect on M1 cells. Serum alanine aminotransferase was reduced in the LSEC-transfer efficient group, as were cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive hepatocytes. Silver impregnation staining indicated that the sinusoidal space was maintained in the LSEC-transfer efficient group but not in the other groups. Electron microscopy showed that the LSECs were slightly impaired, although the sinusoidal structure was maintained in the LSEC-transfer efficient group. CONCLUSION: Hepatocyte apoptosis was reduced by the efficient suppression of LSEC apoptosis with a novel DDS. Protecting the sinusoidal structure by suppressing LSEC damage will be an effective treatment for acute liver failure.

Novel functions of platelets in the liver.

Platelets contain not only proteins needed for hemostasis but also many growth factors that are required for organ development, tissue regeneration, and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, is due to various causes, such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in CLD are poorly understood. Thus, in this paper, the experimental evidence for platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. Platelets improve liver fibrosis by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cAMP is increased by adenosine through its receptors on hepatic stellate cells, thereby resulting in inactivation of these cells. Adenosine is produced by degradation of adenine nucleotides, which are stored in abundance within the dense granules of platelets. The regenerative effect of platelets in the liver consists of three mechanisms: a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these experiments, a clinical trial suggested that the increase in platelets induced by platelet transfusion improved liver function in patients with CLD in a clinical setting.We highlight the current knowledge concerning the role of platelets in CLD and expect to open a novel avenue for application of these clinical therapies to treat liver disease.