Mitsuaki Ishioka

Toll-like Receptor 4 on Macrophage Promotes the Development of Steatohepatitis-related Hepatocellular Carcinoma in Mice

The role of Toll-like receptor (TLR) signaling has attracted much attention in the development of hepatic inflammation and hepatocellular carcinoma (HCC). We herein sought to determine the role of TLRs and responsible cells in steatohepatitis-related HCC. We used hepatocyte-specific Pten-deficient (PtenΔhep) mice, which exhibit steatohepatitis followed by liver tumor formation, including HCC. We then generated PtenΔhep/Tlr4−/− and PtenΔhep/Tlr2−/− double-mutant mice and investigated the role of macrophages using reconstitution of bone marrow (BM)-derived cells, chemical depletion of macrophages, and isolated macrophages. Tlr4 but not Tlr2 deficiency in the PtenΔhep mice suppressed tumor growth as well as hepatic inflammation. Gut sterilization by an antibiotic mixture reduced the portal LPS levels as well as tumor growth in the PtenΔhep mice. Tumor growth was also decreased by reconstitution of BM-derived cells to Tlr4−/− BM cells. In addition, chemical depletion of macrophages significantly reduced tumor size and numbers. Macrophages expressing Ly6C were increased in number, which was associated with inflammation and tumor progression in the PtenΔhep mice. Hepatic macrophages isolated from the PtenΔhep mice abundantly expressed the Ly6C gene and produced much more IL-6 and TNFα in response to LPS. These proinflammatory cytokines induced the proliferation of HCC cells as well as oval cells, putative cancer progenitor cells. Indeed, putative cancer progenitor cells emerged before the development of macroscopic liver tumors and then increased in number under sustained inflammation. TLR4 on macrophages contributes to the development of steatohepatitis-related HCC in mice.

The Roles of the Gut Microbiota and Toll-like Receptors in Obesity and Nonalcoholic Fatty Liver Disease

Obesity is characterized by low-grade chronic inflammation and is closely associated with the cardiovascular diseases, diabetes, and nonalcoholic fatty liver disease. Emerging data demonstrate that the gut microbiota contributes to the development of obesity by regulating the innate immune system, including the Toll-like receptors (TLRs): an altered gut microbiota composition and elevated TLR ligands are observed in obese mice and humans. The changes in the gut microbiota include an increased abundance of Firmicutes phylum and a decreased abundance of Bacteroidetes phylum. The population of beneficial bacteria that function as probiotics is decreased whereas harmful bacteria that can produce lipopolysaccharide, a TLR4 ligand, are increased in the obese state. In addition, the gut permeability is increased in obesity, which allows the delivery of larger amounts of bacterial components to the liver through the portal vein. Immune cells recognize these bacterial components through TLRs and produce diverse cytokines that kill invading pathogens. However, the sustained activation of TLR signaling induces host damage due to chronic exposure to harmful cytokines, which are produced from TLR expressing cells, including monocytes/macrophages. In the obese state, the expression of TLR is increased in several organs, including the adipose tissue and the liver. At the cell level, negative regulators of TLR signaling are suppressed, leading to activation of TLR signaling. These alterations promote inflammation in many organs. Thus, the gut microbiota and TLR signaling are therapeutic targets in patients with obesity and its related diseases.

True Primary Enterolith Treated by Balloon-assisted Enteroscopy

Primary enterolith is a rare condition that can induce ileus and intestinal perforation. We report the first case of a true primary enterolith treated by balloon-assisted enteroscopy. The patient presented with a small intestinal ileus. After its improvement following the insertion of an ileus tube, radiography with amidotrizoate sodium meglumine detected a round, movable defect in the ileum measuring 42 mm diameter. The patient was diagnosed with a primary enterolith based on her past history. The enterolith was fractured and removed using balloon-assisted enteroscopy. This case suggests that balloon-assisted enteroscopy may be an effective non-invasive treatment option for enteroliths.

Phlegmonous Gastritis: A Report of Three Cases with Clinical and Imaging Features

Phlegmonous gastritis is a rare but often fatal acute pyogenic infection of the stomach. We herein report three cases of phlegmonous gastritis with different causes: the long-term placement of a nasogastric feeding tube, bacteremia associated with cellulitis in a diabetic patient, and an adverse reaction to paclitaxel/carboplatin chemotherapy for cancer of unknown primary cause, which were classified as primary, secondary, and idiopathic types, respectively. Coping with the increasing morbidity rate associated with the diverse background of such patients requires a thorough understanding of the clinical features and image findings associated with this entity.

Successful treatment with infliximab for refractory para-ileostomal ulceration in a patient with Behҫet’s disease

Behҫet’s disease (BD) is a chronic disorder involving multiple organ systems including the small and large intestines. A 46-year-old female diagnosed with intestinal BD presented with ileocecal perforation and diffuse peritonitis and subsequently underwent ileocolic resection with ileostomy. After surgery, she suffered from refractory para-ileostomal ulceration associated with BD. Most importantly, however, treatment with infliximab was significantly effective in healing the ulceration. This is the first report of para-ileostomal ulceration associated with BD successfully treated with infliximab, suggesting the possible use of infliximab as a therapeutic option for para-stomal ulcers related to BD.

Homocysteine supplementation ameliorates steatohepatitis induced by a choline-deficient diet in mice: Homocysteine and choline in experimental NASH

High concentrations of homocysteine are believed to induce lipid synthesis and cell injury through endoplasmic reticulum (ER) stress in metabolic syndrome. However, homocysteine could be used to improve steatohepatitis induced by choline deficiency, in which methyl donors are decreased. The aim of the present study was to clarify the role of the physiological concentration of homocysteine in the development of steatohepatitis induced by choline deficiency.

A case of esophageal actinomycosis with a unique morphology presenting as a refractory ulcer

A 60-year-old man presented with odynophagia after bronchial artery infusion chemotherapy for pulmonary metastasis of hepatocellular carcinoma. Esophagogastroduodenoscopy (EGD) revealed an esophageal ulcer in the middle thoracic esophagus. An esophageal biopsy demonstrated no malignancy. However, the symptoms had not improved after a month. EGD was performed again and showed a white cord lump at the bottom of the same esophageal ulcer identified before, showing no improving tendency. A repeated biopsy of the lump revealed actinomycosis, and the symptoms were improved by the oral administration of ampicillin. We herein report a case in which esophageal actinomycosis with a unique morphology of refractory esophageal ulcer was rapidly improved by the administration of antibiotics.

456 TLR4 Signaling on Macrophages Promotes the Progression of Steatohepatitis and Liver Tumors in Hepatocyte-Specific PTEN Deficient Mice

A S L D A b st ra ct s BGJ398, a pan-FGFR inhibitor currently being employed in human trials, resulted in a significant increase in cellular apoptosis. Tumor tissue from mice sacrificed 10 weeks after biliary oncogene transduction of AKT and YAP also demonstrated increased expression of FGFR 1-4. BGJ398 treatment resulted in a significant reduction in tumor burden and increase in tumor cell apoptosis as assessed by the TUNEL assay in our mouse model of CCA. In Conclusion, YAP is a critical oncogene in CCA and promotes biliary carcinogenesis, in part, via upregulation of FGFR. In a murine genetic model of CCA, the FGFR specific inhibitor BGJ398 significantly reduces tumor burden by inducing apoptosis. Thus, inhibition of FGFR represents a promising therapeutic approach in YAP-driven human CCA.