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High-mobility group box 1 (HMGB1) is a monocyte-derived inflammatory mediator that is released in some conditions including shock, tissue injury, and endotoxin-induced lethality. In this study, we determined the plasma and hepatic tissue levels of HMGB1 in a drug-induced rat acute liver failure (ALF) model and investigated the effect of HMGB1 blockade on ALF. Adult male Sprague-Dawley rats, weighing 250 to 300 g, were used for this study. d-galactosamine was injected into the penile vein to induce ALF. To determine HMGB1 levels, plasma and hepatic tissue samples were serially collected after the d-galactosamine injection. To test the effect of HMGB1 blockade, anti-HMGB1 polyclonal antibodies or control antibodies were injected into the penile vein right after injection of d-galactosamine. Levels of HMGB1 were increased in plasma and decreased in hepatic tissue after induction of ALF. Immunohistochemical examination for HMGB1 showed that liver from animals with ALF had little staining, whereas normal liver had strong staining in the nuclei. Injection of anti-HMGB1 antibodies resulted in significant suppression of plasma HMGB1 and hepatic enzymes, marked suppression of plasma inflammatory cytokines, marked improvement of histological findings, and significant improvement of survival. The decrease of hepatic HMGB1 was also significantly suppressed in the group injected with anti-HMGB1 antibodies. The present study suggests that in ALF, the liver may release HMGB1 into the plasma, and that neutralizing the released HMGB1 has a protective effect against injury.

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1beta (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.

Objectives Transforming growth factor beta (TGF-beta) is a dominant mediator of pancreatic fibrosis. The objective of this study was to identify cellular sources of TGF-beta mRNA and compare the results with previous immunohistochemical/in situ hybridization studies. Methods In situ hybridization of TGF-beta was conducted for 9 human tissues of chronic obstructive pancreatitis (COP) and 2 control specimens. By classifying these 9 COP tissues into 3 fibrosis phases by the amount of fibrotic space, histopathologic changes were examined for each fibrosis phase. Whether or not TGF-beta-positive cells were closely distributed to fibrosis was also investigated in control and COP cases. Results Three cases were categorized in early, intermediate, and advanced stages of fibrosis. Transforming growth factor beta mRNA was identified for a part of small duct epithelia, that is, intercalated ductule cells, centroacinar cells, and/or metaplastic ductal structures adjacent to acinar cells. The number of TGF-beta-positive cells was greater in COP cases than in controls. In controls and in the early stage of fibrosis, no fibrosis was seen near TGF-beta-positive cells. Conclusions Small duct epithelia are the main cellular sources of TGF-beta in COP, and many of them may be working for COP fibrosis either directly or indirectly.

Objectives There are many experimental models for chronic pancreatitis. However, it remains unclear which animal models of pancreatic fibrosis can be categorized as chronic pancreatitis models. We compared the histologic features of some animal models of pancreatic fibrosis/chronic pancreatitis and chronic pancreatitis in humans. Methods and results Human chronic pancreatitis due to chronic alcohol abuse and unknown etiology showed interlobular fibrosis and a cirrhosis-like appearance. Histopathologically, spontaneous pancreatitis models, WBN/Kob rats and OLETF rats, showed localized/nodular fibrotic lesions, which consisted of swollen, aggregated, atrophic islets of Langerhans; loss of the exocrine parenchyma and hemosiderin deposition that was seldom distributed in the interlobular area. On the other hand, fibrosis in the canine model, which was produced by combining alcohol administration with incomplete pancreatic duct obstruction, was characterized by interlobular fibrosis admixed with a cirrhosis-like appearance very similar to that in human chronic pancreatitis. Conclusion Most experimental models for chronic pancreatitis, except alcohol administration combined with other procedures such as incomplete pancreatic duct obstruction, are different from human chronic pancreatitis.

The distribution and clinicopathologic features of pancreatic fibrosis were studied histopathologically in 137 autopsy cases of chronic alcohol abuse. Fibrosis was observed in 90 of the cases and was classified as perilobular sclerosis (PS) and intralobular sclerosis (IS). Fibrosis of the PS type was irregular and sometimes patchy and extended into the intralobular area in advanced cases. In some advanced cases, complete replacement of the pancreatic tissue by extensive fibrosis was seen. Fibrosis of the IS type was uniformly distributed. The tissues in some cases showed prominently periacinar fibrosis. In these cases, the pancreatic parenchyma had not been completely replaced by extensive fibrosis. Clinicopathologic comparisons revealed the following results : accompanying liver cirrhosis was greater in the IS than in the PS of fibrosis. However, a higher frequency of protein plugs, pancreatic stones, extensive fibrosis replacement, peripancreatic fibrosis, splenic vein involvement, choledochus involvement, pseudocyst, and ductal hyperplasia was found in the PS type compared to the IS type. In conclusion, the findings on the perilobular and intralobular distribution of fibrosis and differences in various components or accompanying diseases in pancreatic fibrosis suggest that this entity shows two distinct pathologic patterns with differing mechanisms.

「自己免疫性膵炎autoimmune pancreatitis（AIP）臨床診断基準2006」の特徴は「小さな材料·生検」での診断，routine以外の特殊染色を用いないことである．本邦のAIPの組織像はlymphoplasmacytic sclerosing pancreatitisに一致し，その特徴は膵管周囲のリンパ球·IgG4陽性形質細胞の浸潤，小葉間/内の線維化（storiform fibrosis），閉塞性静脈炎である． Mayo clinicの診断基準では「小さな材料·生検」が前提とは思えず，またIgG4陽性形質細胞が必須で，本邦の基準と異なる．韓国と本邦の診断基準は類似するが，生検方法が異なる．生検上の課題は，全体を反映しdiagnosticに足る検体の採取である．IgG4陽性形質細胞は，「storiform fibrosis内に認める」ことがdiagnosticであり，生検でも病変部が的確に採取されていれば診断可能である．