Akifumi Kimura

Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells

BACKGROUND & AIMS Acyl-coenzyme A: cholesterol acyltransferase (ACAT) catalyzes the conversion of free cholesterol (FC) to cholesterol ester, which prevents excess accumulation of FC. We recently found that FC accumulation in hepatic stellate cells (HSCs) plays a role in progression of liver fibrosis, but the effect of ACAT1 on liver fibrosis has not been clarified. In this study, we aimed to define the role of ACAT1 in the pathogenesis of liver fibrosis. METHODS ACAT1-deficient and wild-type mice, or Toll-like receptor 4 (TLR4)(-/-)ACAT1(+/+) and TLR4(-/-)ACAT1(-/-) mice were subjected to bile duct ligation (BDL) for 3 weeks or were given carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis. RESULTS ACAT1 was the major isozyme in mice and human primary HSCs, and ACAT2 was the major isozyme in mouse primary hepatocytes and Kupffer cells. ACAT1 deficiency significantly exaggerated liver fibrosis in the mouse models of liver fibrosis, without affecting the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation. ACAT1 deficiency significantly increased FC levels in HSCs, augmenting TLR4 protein and downregulating expression of transforming growth factor-β (TGFβ) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of HSCs to TGFβ activation. Exacerbation of liver fibrosis by ACAT1 deficiency was dependent on FC accumulation-induced enhancement of TLR4 signaling. CONCLUSIONS ACAT1 deficiency exaggerates liver fibrosis mainly through enhanced FC accumulation in HSCs. Regulation of ACAT1 activities in HSCs could be a target for treatment of liver fibrosis.

Removal of increased circulating CD4+CD25+Foxp3+ regulatory T cells in patients with septic shock using hemoperfusion with polymyxin B-immobilized fibers.

BACKGROUND Although sepsis-induced immunosuppression has long been considered to be a factor in the late mortality of patients with sepsis, little is known about regulatory T cell (Treg)-mediated immunosuppression and the effect of polymyxin B-immobilized fiber (PMX-F) on sepsis-induced immunosuppression. We sought to investigate the role of CD4(+)CD25(+)Foxp3(+) Tregs in septic patients, and to evaluate the effect of hemoperfusion with PMX-F on the recovery from immunosuppression owing to septic shock. METHODS Thirty-two septic patients who had an identified focus of infection in the abdominal cavity were enrolled in this study. Peripheral blood mononuclear cells in the septic patients were examined to evaluate the roles of Tregs and the serum cytokine levels. We also examined the effects of PMX-F therapy on CD4(+) T cells, especially Tregs and serum cytokine levels in patients with septic shock. RESULTS The percentage of Tregs in the CD4(+) T-cell population, and the serum IL-6 and IL-10 levels, were significantly higher among patients with septic shock compared with those without septic shock, and PMX-F therapy significantly decreased the number of Tregs, as well as the serum IL-6 and IL-10 levels. Furthermore, a significant increase in the number of CD4(+) T cells, a significant decrease in the percentage of Tregs in the CD4(+) T-cell population, and a significant decrease in the serum IL-6 and IL-10 levels 24 hours after PMX-F therapy were observed in septic shock survivors compared with nonsurvivors. CONCLUSION We found a major increase in the percentage of Tregs in peripheral blood circulating CD4(+) T cells from patients with septic shock, and observed that the removal of Tregs by hemoperfusion with PMX-F might represent a novel strategy for inducing recovery from the immunosuppression associated with sepsis.

Postoperative serum concentrations of high mobility group box chromosomal protein-1 correlates to the duration of SIRS and pulmonary dysfunction following gastrointestinal surgery.

OBJECTIVE To clarify the time course of changes in the serum HMGB-1 concentrations in patients undergoing major gastrointestinal surgery, and to investigate whether the serum HMGB-1 levels correlate with the postoperative clinical course of the patients. METHODS Twenty-eight patients with alimentary tract carcinoma who underwent elective gastrointestinal surgery were enrolled in this study. The correlation between the serum HMGB-1 levels and the postoperative clinical course were evaluated. RESULTS Serum HMGB-1 concentrations in patients who underwent surgery for gastrointestinal cancer increased gradually during postoperative days, and reached peak concentrations on postoperative day 3 (POD3). There was a statistically significant positive correlation between the serum HMGB-1 levels on POD3 or POD5 and the duration of SIRS (r = 0.68, P < 0.001, r = 0.45, P < 0.05, respectively). A significantly positive correlation was found between the serum HMGB-1 levels on POD3 or POD5 and the heart rates on POD3 or POD5. Furthermore, there was a negative correlation between the serum HMGB-1 levels and PaO2/FiO2 ratio on POD3. CONCLUSIONS Serum HMGB-1 levels increase after major gastrointestinal surgery, and the serum peak HMGB-1 levels correlate with the duration of SIRS and postoperative pulmonary dysfunction.

Intrahepatic Cholangiocarcinoma With Lymphoepithelioma-like Carcinoma Components Not Associated With Epstein-Barr Virus: Report of a Case

A carcinoma displaying undifferentiated features with dense lymphoplasmacytic infiltration is defined as lymphoepithelioma-like carcinoma (LELC). Intrahepatic cholangiocarcinoma (ICC) with LELC components is rare, and most LELCs are associated with Epstein-Barr virus (EBV). We report here on a case of ICC with LELC components not associated with EBV. A 65-year-old woman was incidentally found to have a hepatic tumor in the caudate lobe. An extended right hepatectomy with lymphadenectomy was performed. Histologically, the tumor was mainly composed of large undifferentiated epithelial cells with vesicular nuclei, prominent nucleoli, indistinct cell borders, and heavy small lymphocytic infiltration, which are the characteristic features of LELC. Immunohistochemical studies revealed that the tumor cells were positive for cytokeratin 19 but were negative for glypican 3. In situ hybridization using EBV-encoded RNA was negative. Therefore, a diagnosis of ICC with LELC components not associated with EBV was made. Because there is limited information available regarding the prognosis and treatment of ICC with LELC components because of the limited number of reported cases, additional studies will be needed to clarify the clinicopathologic features of this disease.

The Postoperative Serum Interleukin-15 Concentration Correlates with Organ Dysfunction and the Prognosis of Septic Patients Following Emergency Gastrointestinal Surgery

OBJECTIVE To clarify the time course of changes in the serum interleukin-15 (IL-15) concentrations in septic patients undergoing emergency surgery for abdominal infection and to investigate whether the serum IL-15 levels correlate with the postoperative clinical course of septic patients. METHODS Twenty-four septic patients who had intra-abdominal infection and who underwent an emergency operation were enrolled in this study. The serum IL-15 levels were measured before surgery, and on postoperative d 1 (POD1), POD3, and POD5, and the relationship between the serum IL-15 levels and the postoperative clinical course estimated by the Systemic Inflammatory Response Syndrome (SIRS) criteria, Acute Physiology and Chronic Health Evaluation (APACHE-II) score, the parameters of organ function, and the 30-d mortality were evaluated. RESULTS The time course of changes of the serum IL-15 levels were significantly different between survivors and non-survivors (P < 0.05, by repeated measures analysis of variance [ANOVA]). There was a statistically significant relationship between the serum IL-15 levels on POD1 or POD3 and the duration of SIRS (R = 0.50, P < 0.05, R = 0.65, P < 0.01, respectively). Furthermore, a significant positive correlation was observed between the serum IL-15 levels on POD1 and the creatinine levels on POD1 or POD3 (R = 0.48, P < 0.05, R = 0.50, P < 0.05, respectively), and a significant negative correlation between the serum IL-15 levels on POD1 or POD 3 and the PaO(2)/FiO(2) on POD3 (R = -0.51, P < 0.05, R = -0.69, P < 0.01, respectively). CONCLUSIONS The measurement of postoperative serum level of IL-15 might be useful for predicting the severity of SIRS and organ dysfunction, especially renal and pulmonary dysfunction.

Multifocal lesions with pancreatic atrophy in IgG4-related autoimmune pancreatitis: report of a case

We herein report a case of IgG4-related autoimmune pancreatitis (AIP). A 72-year-old male with jaundice visited our hospital complaining of epigastralgia. A blood chemistry analysis revealed elevated serum levels of total bilirubin and DUPAN-II. Computed tomography (CT) revealed irregularly shaped pancreatic masses with a stricture of the main pancreatic duct (MPD) in the head and tail that were interposed by marked atrophy with MPD dilation in the body. F-18 fluorodeoxyglucose (FDG)-positron emission tomography/CT revealed abnormally intense FDG uptake only at the masses. During surgery, another small tumor was also found in the atrophied body; therefore, a total pancreatectomy was performed under the diagnosis of multiple pancreatic cancers. The histological analysis revealed fibrosis with dense and diffuse infiltrations of lymphocytes and IgG4-positive plasma cells. The pancreatic parenchyma of the body was firmly replaced by fibrosis. AIP can lead to the formation of multiple pancreatic lesions, and thus the correct diagnosis is occasionally difficult to establish in atypical cases.

Pancreatic metastasis of uterine cervix cancer mimicking a primary cancer

The majority of cancers occurring in the pancreas are of primary ductal origin, and secondary tumors of the pancreas are rare [1-3]. In the past, secondary tumors of the pancreas were usually found in the autopsy. The most common origins include lung, breast, skin (melanoma), stomach, colorectum, kidney, and ovary or, in surgical series, lung, kidney, breast, colorectum, and skin (melanoma) [1]. However, a pancreatic metastasis of uterine cancer is very rare [2, 3]. Indeed, there were none among 103 (reported from Japan [3]) or 81 (reported from the Unites States [2]) cases in autopsy series with secondary tumors of the pancreas. In surgical series, only five cases of a pancreatic secondary tumor arising from cervical cancer have been reported [2,4-7]. Here, we present a Japanese case with a pancreatic metastasis of an invasive cervical cancer that was manifested by obstructive jaundice. A pancreas head tumor was clinically diagnosed from laboratory data and from imaging studies. However, the pancreatic tumor was concluded to be metastatic from her uterine invasive cervix cancer. We describe the lesions’ features and discuss the route of metastasis. Further, we emphasize that in such cases the tumor should be ruled out or ruled in as a secondary, although unfortunately few surgeons have so far had the opportunity for such diagnosis.

Long great saphenous vein grafting as temporary coronary bypass for extended left hepatectomy: report of a case.

The right gastroepiploic artery (RGEA) has been used in coronary artery bypass grafting (CABG) as an alternative graft. In particular abdominal surgeries, surgery is required to rescue the graft flow into the coronary artery. A 77-year-old male with a history of CABG using RGEA was admitted with a diagnosis of a large hepatocellular carcinoma (HCC) occupying the whole caudate lobe. Preoperative coronary angiography indicated that the graft from the right internal mammary artery to the proximal left circumflex artery was obliterated among three branch bypasses. Following laparotomy, a great saphenous vein was harvested and delivered from the right axial artery to the RGEA graft over the thoracic wall, and the RGEA graft was ligated and divided. Subsequently, extended left hepatectomy was safely performed. Following hepatectomy, the RGEA graft was restored to the former condition, and the temporary graft was removed. After overcoming hyperbilirubinemia, the patient was discharged on postoperative day 28. This experience indicates that temporary bypass using the long great saphenous vein is effective and safe during long and invasive surgeries.