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Yasuni Nakanuma

Publications and source records attributed to Yasuni Nakanuma.

At least 19 recordsLinked to original sources
PubMed2006

Naturally-occurring regulatory T cells are increased in inflamed portal tracts with cholangiopathy in primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC) is an autoimmune liver disease targeting the intrahepatic small bile ducts showing chronic non-suppurative destructive cholangitis (CNSDC). Recent studies suggest that naturally-occurring CD4+CD25high regulatory T cells (Tregs) expressing Forkhead box P3 (Foxp3) play an active role in immunological self-tolerance. AIMS: To investigate whether Foxp3+Tregs are involved in the pathogenesis of PBC. METHODS: Foxp3+Tregs was detected immunohistochemically in livers from patients with PBC (n = 27), chronic viral hepatitis (CVH) (n = 15), and normal subjects (n = 10). The distribution of Tregs in portal tracts was semi-quantitatively evaluated in each groups. Levels of Foxp3, IL-10, TGFbeta, IFNgamma and TNFalpha mRNA was evaluated in PBC (n = 15) and control livers (n = 21) using semi-quantitative reverse transcriptase-PCR. RESULTS: In PBC and CVH livers, the amounts of infiltrating Foxp3+Tregs in portal tracts were in parallel with the degree of portal inflammation irrespective of disease. The infiltration of Foxp3+Tregs into portal tracts with CNSDC in PBC was foremost in comparison with inflamed portal tracts in CVH or those without CNSDC in PBC (p<0.05). Focally, Tregs infiltrated into the biliary epithelial layer at the site of CNSDC. The level of Foxp3, IL-10 and TGFbeta mRNA expression was high in PBC compared with normal livers (p<0.05). IFNgamma and TNFalpha mRNA was high in early PBC and CVH livers. CONCLUSION: Results of this evaluation of Foxp3+Tregs do not suggest that the reduced regulatory function accounts for the development of CNSDC in PBC.

Autoimmune Diseases↗
PubMed2006

Augmented expression of hepatocytes growth factor activator inhibitor type 1 (HAI-1) in intrahepatic small bile ducts in primary biliary cirrhosis.

The repair system of damaged biliary mucosa was not fully clarified so far in primary biliary cirrhosis (PBC). Given that related factors of the hepatocyte growth factor (HGF) such as HGF activator (HGFA) and HGFA inhibitor type 1 (HAI-1) participate in the repair of injured gastrointestinal mucosa, we investigated the involvement of the HGF/HGFA/HAI-1 system in PBC and control livers. The expression of HGFA, HAI-1, and c-Met was examined in PBC livers (n=24), diseased livers (control, n=30), and normal livers (n=15) by immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction. We examined the expression of HGFA, HAI-1, and c-Met, and the effect of HGF administration on cell proliferation and wound healing, and HAI expression in cultured mouse biliary epithelial cells (BECs). HAI-1 expression was faint in control livers, whereas it was significantly augmented in damaged small bile ducts, bile ductules, and periportal hepatocytes in PBC (p<0.05). HGFA and c-Met were homogeneously expressed in BECs in PBC and control livers. HAI-1 expression was increased at the front of wound healing and the treatment with HGF-enhanced HAI-1 expression, cell proliferation, and wound healing in cultured BECs. HGF/HGFA/HAI-1 system may participate in biliary mucosal repair as reported in gastrointestinal mucosal repair.

Bile Ducts, Intrahepatic↗
PubMed2006

Biliary cystic tumors with bile duct communication: a cystic variant of intraductal papillary neoplasm of the bile duct.

Biliary cystic tumors, which are also called biliary cystadenoma and cystadenocarcinoma, are thought to be a heterogeneous disease entity, and some of them are known to show a luminal communication to the bile duct. In this study, we examined the clinicopathological features of nine cases of biliary cystic tumors with bile duct communication. They were composed of five males and four females with an average age of 67 years (52-84 years). They were multilocular (eight cases) or unilocular (one case), and all cases contained mucinous fluid. A direct luminal communication with the bile ducts was identified in five cases on preoperative or intraoperative cholangiographies. Biliary cystic tumors examined in this study were histologically adenoma (one case), adenocarcinoma in situ (six cases), and adenocarcinoma associated with microinvasive mucinous carcinoma (two cases). One case of adenocarcinoma in situ also had the adenoma component (adenocarcinoma in adenoma). Dysplastic mucinous epithelium proliferated in flat, micropapillary and papillary fashions within the intracystic spaces. Intraepithelial neoplasm was observed within non-dilated adjacent bile ducts, suggesting a direct luminal communication between the cystic tumors and the bile duct. Ovarian-like stroma was not observed in their walls in any cases. Immunohistochemically, seven cases expressed MUC1 or MUC2 in the neoplastic biliary epithelium. All cases except one were alive without any evidences of tumor recurrence after total excision (3-156 months after surgery). These clinicopathological features resembled those of intraductal papillary neoplasm of the bile duct, which had been reported as a biliary counterpart of pancreatic intraductal papillary mucinous neoplasm. In conclusion, biliary cystic tumors with bile duct communication could be regarded as intraductal papillary neoplasm with a prominent cystic dilatation of the bile duct and mucin retention, rather than true biliary cystic neoplasms.

Adenocarcinoma, Papillary↗
PubMed2006

Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas.

Recently, attention has been drawn to papillary neoplasm of the pancreatobiliary systems. In the pancreas, the disease entity of intraductal papillary mucinous neoplasm (IPMN-P) is widely recognized. In contrast, the pathological characteristics of biliary papillary tumors, such as biliary papilloma(tosis) and papillary cholangiocarcinoma, have not yet been well documented. In this study, we compared the pathological features and post-operative prognosis among biliary papillary tumors (10 cases of biliary papilloma(tosis) and 22 cases of papillary cholangiocarcinoma), conventional non-papillary cholangiocarcinoma (15 cases), and IPMN-P (31 cases). Macroscopically, all biliary papillary tumors were characterized by the prominent intraductal papillary proliferation, and macroscopic mucin-hypersecretion was seen in 9 of 32 cases (28%). Histologically, biliary papillary tumors consisted of three types of tumor cells (pancreaticobiliary, intestinal and gastric types), whereas only the pancreaticobiliary type was observed in non-papillary cholangiocarcinoma. Immunohistochemically, biliary papillary tumors were characterized by the common expression of MUC2, CDX2 and cytokeratin 20. In addition, biliary papillary tumors could be associated with two types of invasive lesions: tubular adenocarcinoma (9 cases) and mucinous carcinoma (5 cases). Patients with tubular adenocarcinoma had a poor prognosis compared to non-invasive papillary tumor or papillary tumor with mucinous carcinoma. These pathological characteristics and the survival status of biliary papillary tumors were different from those of non-papillary cholangiocarcinoma, and rather closely resembled those of IPMN-P. In conclusion, biliary papillary tumors may be the biliary counterpart (intraductal papillary neoplasm of the bile duct) of IPMN-P.

Adenocarcinoma↗
PubMed2006

Intraductal papillary neoplasm of the bile duct extending superficially from the intrahepatic to extrahepatic bile duct.

Intraductal papillary neoplasm of the bile duct (IPNB) or liver is a recently noted rare disease, and its pathogenesis remains unclear. Here we present a case of IPNB with an interesting morphology, which was treated by resection of the right hemiliver and extrahepatic bile duct. A 79-year-old woman was found to have a high alkaline phosphatase level and slight dilatation of the right intrahepatic bile duct on imaging studies. The right intrahepatic bile duct became dilated over a 2-year period; however, no solid mass could be detected, and tumor markers were not elevated. Hepatic resection was scheduled because a mucin-producing bile duct carcinoma of the liver was suspected. A right hemihepatectomy was conducted, and the extrahepatic bile duct was also resected after malignant cells were found in the surgical stump of the right bile duct and in the bile itself. Macroscopically, diffuse dilatation of the intrahepatic bile duct was noted, but no solid component or mucin within the duct was found. Histopathological findings revealed carcinoma in situ, IPNB, in the majority of intrahepatic bile ducts, with no lymph node metastasis, and it extended continuously to the epithelium of the common bile duct. No tumor recurrence or biliary dilatation was observed at follow-up 2 years after surgery. It is important to consider malignancy in the presence of a dilated bile duct and in the absence of any cause of occlusion. Complete resection of IPNB results in a good prognosis and no recurrence.

Aged↗
PubMed2006

A modified Japan Integrated Stage score for prognostic assessment in patients with hepatocellular carcinoma.

BACKGROUND: For patients with hepatocellular carcinoma (HCC), the selection of effective therapeutic options depends on a reliable prognostic assessment of both the tumor characteristics and liver impairment. This study sought to provide a modified Japan Integrated Stage (m-JIS) score to predict more accurately the survival of patients with HCC. METHODS: We analyzed the records of 42,269 patients diagnosed with HCC that were registered between 1992 and 1999 in a nationwide Japanese database. The m-JIS score was calculated from the tumor-node-metastasis stage and the grade of liver damage as defined by the Liver Cancer Study Group of Japan. The predictive accuracy for patient survival based on the m-JIS score was compared with that determined by the modified Cancer of the Liver Italian Program (m-CLIP) score using the cross-validation method. RESULTS: Patients were divided randomly into two groups, a training sample for construction of prediction models (n = 21,127 patients with 8,458 deaths) and a validation sample for assessment of those prediction models (n = 21,142 patients with 8,434 deaths). Both the m-JIS score and the m-CLIP score showed good discriminatory ability in the training sample. In the validation sample, the residuals of prediction based on the m-JIS score were smaller than those of the m-CLIP score (P < 0.0001). CONCLUSIONS: The m-JIS scoring system had better predictive accuracy than the m-CLIP score system for survival of Japanese patients with HCC.

Carcinoma, Hepatocellular↗
PubMed2006

Molecular mechanisms of cholangiopathy in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is histologically characterized by chronic nonsuppurative destructive cholangitis (CNSDC) and the progressive loss of intrahepatic small bile ducts. Cellular immune mechanisms involving T-cell reaction are thought to be significantly involved in the formation of CNSDC and bile duct loss. In inflamed portal tracts of PBC, CD4+ T cells of Th1 type expressing IFN-gamma or CXCR3 are aggregated and more commonly detected around injured bile ducts than Th2-type CD4+ T cells expressing IL-4 or CCR4, indicating that Th1-dominant cellular immunity plays a more-prominent role in recruitment of memory T-cell subsets in PBC and may be responsible for the progressive bile duct damage. Biliary epithelial apoptosis is demonstrated to be a major pathogenic process of bile duct loss in PBC. In CNSDC, several biliary apoptotic cells, an aberrant expression of Fas antigen (proapoptotic molecule) and decreased expression of bcl-2 and mcl-1 (antiapoptotic molecules) are found, although interlobular bile ducts express bcl-2 and mcl-2 but lack Fas. In addition, the upregulation of WAF1 and p53 related to biliary apoptosis is found in biliary epithelial cells of PBC, which may be due to cell senescence in response to genotoxic damage such as oxidative stress. Several steps and mechanisms during induction and progression of cholangitis and biliary apoptosis followed by bile duct loss are now being proposed in PBC, but future analysis of an etiopathogenesis to explain the characteristic histopathogenesis of PBC is required.

Apoptosis↗
PubMed2006

Multicystic biliary hamartoma: a hitherto undescribed lesion.

In this report, we presented 3 cases of unusual hamartomatous nodules of the liver. These nodules were located around hepatic capsule of the left hepatic lobe and characteristically protruded from the liver. Histologically, these nodular lesions consisted of ductal structures, periductal glands, and fibrous connective tissues containing blood vessels. Smooth muscle bundles focally surrounded ductal structures. Bile-like materials were observed within some ducts. Two cases were associated with xanthogranulomatous inflammation around bile-like materials, and this inflammatory process extended from ductal lumens to periductal connective tissues. In contrast, the remaining case, which was not associated with inflammation, showed a honeycomb appearance. Ductal epithelium and periductal glands resembled biliary epithelium and peribiliary glands, respectively, and they also expressed biliary-type cytokeratins such as cytokeratins 7 and 19. These nodules shared pathologic characteristics of ciliated hepatic foregut cysts, such as their location (around the falciform ligament) and periductal smooth muscle bundles, but did not fulfill the diagnostic criteria (no ciliated cells and multilocular lesions). These hamartomatous nodules of the liver did not fit into any of the described categories of hepatic nodular lesions. At present, we speculate that these lesions might be related to developmental abnormalities of the biliary tract or embryonal foregut.

Aged↗
PubMed2006

Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients.

BACKGROUND & AIMS: To elucidate the survival of the patients with unresectable hepatocellular carcinoma (HCC) who underwent transcatheter arterial lipiodol chemoembolization (TACE) and to analyze the factors affecting the survivals. METHODS: During the last 8 years, a nationwide prospective cohort study was performed in 8510 patients with unresectable HCC who underwent TACE using emulsion of lipiodol and anticancer agents followed by gelatin sponge particles as an initial treatment. Exclusion criteria were extrahepatic metastases and/or any previous treatment prior to the present TACE. The primary end point was survival. The survival rates were calculated by the Kaplan-Meier method. The multivariate analyses for the factors affecting survival were evaluated by the Cox proportional hazard model. The mean follow-up period was 1.77 years. RESULTS: For overall survival rates by TACE, median and 1-, 3-, 5-, and 7-year survivals were 34 months, 82%, 47%, 26%, and 16%, respectively. Both the degree of liver damage and the tumor-node-metastasis (TNM) system proposed by the Liver Cancer Study Group of Japan demonstrated good stratification of survivals (P = .0001). The multivariate analyses showed significant difference in degree of liver damage (P = .0001), alpha-fetoprotein value (P = .0001), maximum tumor size (P = .0001), number of lesions (P = .0001), and portal vein invasion (P = .0001). The last 3 factors could be replaced by TNM stage. The TACE-related mortality rate after the initial therapy was .5%. CONCLUSIONS: TACE showed safe therapeutic modality with a 5-year survival of 26% for unresectable HCC patients. The degrees of liver damage, TNM stage, and alpha-fetoprotein values were independent risk factors for patient survival.

Aged↗
PubMed2006

Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory.

BACKGROUND & AIMS: Autoreactive T cells that proliferate in response to autoantigens are found in both autoimmune disease and controls but have important qualitative differences in relative activation states, costimulation signal requirements, and pathogenetic significance. Understanding the mechanism for activation of autoreactive T cells will be critical in the treatment of autoimmune diseases. METHODS: To understand the differences between autoreactive T cells in primary biliary cirrhosis (PBC) versus controls, we have developed autoreactive T-cell clones (TCCs) from patients with PBC and healthy controls and have used a peptide corresponding to the CD4 major autoepitope to define the relative proliferative and cytokine response. RESULTS: Using an enzyme-linked immunosorbent spot assay, peripheral blood mononuclear cells (PBMCs) from PBC, but not from controls, produce interferon (IFN)-gamma regardless of whether costimulation-competent or -incompetent antigen-presenting cells (APC) were used. In contrast, a significant number of IFN-gamma-producing cells were found in PBMCs from controls but only if costimulation-competent PBMCs presented an autoantigenic peptide. In addition, costimulation-dependent autoreactive TCCs became anergic after a single round of stimulation in the presence of APC that did not provide a costimulatory signal, whereas some costimulation-independent autoreactive TCCs required repeated stimulation to become anergic and the others did not become anergic. Finally, anergic TCCs produced interleukin-10, but no IFN-gamma, and exhibited regulatory functions in an antigen-dependent, cell contact-independent, and partially interleukin-10-mediated manner. CONCLUSIONS: These data relate specifically to the functional characteristics of autoreactive T cells in PBC but are also generically important for understanding the mechanisms for generating pathogenetic autoreactive T cells.

Autoantigens↗
PubMed2006

Characterization of biliary intra-epithelial lymphocytes at different anatomical levels of intrahepatic bile ducts under normal and pathological conditions: numbers of CD4+CD28- intra-epithelial lymphocytes are increased in primary biliary cirrhosis.

Distribution of intra-epithelial lymphocytes along intrahepatic biliary tree (bIEL), and their density and phenotype were examined in normal and diseased livers, particularly in primary biliary cirrhosis (PBC). Immunohistochemically, bIEL were examined in 28 normal livers, 13 cases of chronic viral hepatitis (CVH), 13 cases of PBC, five cases of primary sclerosing cholangitis (PSC), seven cases of extrahepatic biliary obstruction (EBO), and 16 hepatolithiatic livers. In normal livers, bIEL were relatively dense at large and septal bile ducts compared to interlobular ducts. Most of them were positive for CD3 and CD8, while a few were positive for CD4, CD20 and CD57. In CVH, PSC and EBO, neither distribution, phenotype nor density of bIEL differed from normal liver. In hepatolithiasis, numbers of CD8(+)bIEL were increased in stone-containing ducts. In PBC, numbers of CD4(+)CD28(-)bIEL, which are reportedly responsible for target tissue destruction in autoimmune diseases, were markedly increased in damaged interlobular ducts. In conclusion, CD3(+)CD8(+)bIEL may be involved in immune homeostasis of intrahepatic bile ducts in normal livers and in CVH, PSC and EBO. Altered distribution and phenotypes of bIEL in PBC and hepatolithiasis may reflect their participation in biliary lesions. Increased CD4(+)CD28(-)bIEL in damaged bile ducts of PBC may be related to immune-mediated biliary damage.

Bile Ducts, Intrahepatic↗
PubMed2006

Ciliated hepatic cyst without smooth muscle layer: a variant of ciliated hepatic foregut cyst?

The ciliated hepatic foregut cyst (CHFC) is a rare lesion that may arise from remnants of the embryonic foregut. Its wall is lined by pseudostratified ciliated columnar epithelium, and is characterized by the presence of bundles of smooth muscle. Herein is presented two cases of ciliated hepatic cyst without smooth muscle layer. One case was an incidental autopsy finding, and the other was a surgically resected cystic lesion of the liver. Both cysts were <2.0 cm in diameter, and were located subcapusularly in the medial segment (S4) of the liver. The histological appearance of the two cases was identical. They had an epithelial lining of ciliated pseudostratified cells with occasional goblet cells, and lacked a smooth muscle layer, as shown by the actin immunostaining. The lining epithelium contained cells positive for immunohistochemical staining of surfactant apoprotein A, suggesting the embryonic foregut origin of the cysts and differentiation toward bronchiolar structures, rather than ciliated metaplasia of the epithelium of the simple (cholangiogenic) cyst. It is considered that ciliated hepatic cysts of the present case are a rare histological variant of CHFC where the smooth muscle layer is inconspicuous or absent.

Aged↗
PubMed2006

Local balance of transforming growth factor-beta1 secreted from cholangiocarcinoma cells and stromal-derived factor-1 secreted from stromal fibroblasts is a factor involved in invasion of cholangiocarcinoma.

Tumor-stromal interactions are important for the progression of malignant tumors. The purpose of the present study was to examine interactions of cholangiocarcinoma (CC) cells and stromal fibroblasts with respect to stromal-derived factor-1 (SDF-1) and transforming growth factor (TGF)-beta1. Two cell lines of CC (HuCCT-1 and CCKS-1) and WI-38 fibroblast cell line were used for cell culture, and 12 CC tissue specimens for immunohistochemical studies. Invasion of CC cells was increased significantly by the supernatant from fibroblast cultures, but not by the supernatant from fibroblasts cocultured with CC cells. Expression of SDF-1 in cultured fibroblasts was downregulated by TGF-beta1 treatment, and coculture with CC cells and anti-TGF-beta1 neutralizing antibody restored the decreased SDF-1 expression, suggesting that TGF-beta1 secreted from CC cells might have reduced the expression of SDF-1 by fibroblasts and might have reduced the increased invasion of CC cells induced by the supernatant from fibroblasts. Immunohistochemical expression of TGF-beta1 in CC cells was focal or negative and that of SDF-1 was evident in stromal fibroblasts at the invasive front of CC. In conclusion, local mutual influence of TGF-beta1 secreted from carcinoma cells and SDF-1 expressed by stromal fibroblasts may be involved in invasion of CC cells.

Aged↗
PubMed2006

Endotoxin tolerance in human intrahepatic biliary epithelial cells is induced by upregulation of IRAK-M.

BACKGROUND/AIM: Biliary epithelial cells possess an innate immune system consisting of Toll-like receptors (TLRs). Although the human bile contains lipopolysaccharide (LPS) in normal as well as diseased livers, LPS physiologically does not elicit an inflammatory response in the biliary tree. This absence of a response to LPS could be due to the 'endotoxin tolerance' speculated to maintain innate immune homeostasis in organs. Our aim here is to clarify the presence and molecular mechanisms of endotoxin tolerance of biliary epithelium. METHODS AND RESULTS: In nuclear factor-kappaB (NF-kappaB)-DNA binding assays using three-cultured human intrahepatic biliary epithelial cell (HIBEC) lines, all the cells responded to LPS (TLR4 ligand) by activating NF-kappaB, but pretreatment with LPS for 24 h effectively induced tolerance against any subsequent stimulation with LPS (endotoxin tolerance). This tolerance was also induced by pretreatment with Pam(3)Cys-Ser-(Lys)(4) trihydrochloride (Pam(3)CKS(4), TLR1/2 ligand). Then, real-time polymerase chain treaction and Western blotting revealed that LPS treatment upregulated the expression of IRAK-M (a negative regulator of TLR signaling), but did not affect interleukin-1 receptor-associated kinase-1 (IRAK-1, an essential molecule of TLR signaling), in HIBECs. Moreover, immunohistochemistry revealed that IRAK-M was diffusely expressed in intrahepatic bile ducts. CONCLUSIONS: This study showed that the mechanism of endotoxin tolerance exists in the intrahepatic biliary tree and is possibly induced by the expression of IRAK-M in the intrahepatic biliary epithelium, suggesting that the endotoxin tolerance is important in maintaining innate immune biliary homeostasis.

Bile Ducts, Intrahepatic↗
PubMed2006

Possible regulation of migration of intrahepatic cholangiocarcinoma cells by interaction of CXCR4 expressed in carcinoma cells with tumor necrosis factor-alpha and stromal-derived factor-1 released in stroma.

Intrahepatic cholangiocarcinoma (ICC) is highly fatal because of early invasion, widespread metastasis, and lack of an effective therapy. We examined roles of CXCR4 and its ligand, stromal cell-derived factor (SDF)-1, in migration of ICC with respect to tumor-stromal interaction by using two ICC cell lines, a fibroblast cell line (WI-38), and 28 human ICC tissues. The two ICC cell lines expressed CXCR4 mRNA and protein, and WI-38 fibroblasts expressed SDF-1 mRNA and protein. Migration of cultured ICC cells in Matrigel was induced by co-culture with WI-38 fibroblasts and by incubation with SDF-1. Anti-SDF-1 antibody suppressed migration, demonstrating that SDF-1 released from WI-38 fibroblasts was responsible for this migration. Tumor necrosis factor (TNF)-alpha pretreatment of ICC cells up-regulated CXCR4 mRNA and protein expression in a concentration-dependent manner. Administration of SDF-1 and TNF-alpha increased synergistically ICC cell migration, which was suppressed by the CXCR4 antagonist AMD3100. In ICC tissue, TNF-alpha was mainly expressed in infiltrated macrophages, CXCR4 in ICC cells, and SDF-1 in stromal fibroblasts. In conclusion, the interaction of SDF-1 released from fibroblasts and CXCR4 expressed on ICC cells may be actively involved in ICC migration, and TNF-alpha may enhance ICC cell migration by increasing CXCR4 expression. CXCR4 could be a therapeutic target to prevent ICC invasion.

Aged↗
PubMed2006

Inhibition of intrahepatic bile duct dilation of the polycystic kidney rat with a novel tyrosine kinase inhibitor gefitinib.

The polycystic kidney (PCK) rat represents a liver and kidney cyst pathology corresponding to Caroli's disease with congenital hepatic fibrosis and autosomal recessive polycystic kidney disease. We previously reported that an epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), significantly inhibited the abnormal growth of biliary epithelial cells of PCK rats in vitro. This study investigated the effects of gefitinib on cyst pathogenesis of the PCK rat both in vitro and in vivo. A three-dimensional culture model of biliary epithelial cells in the collagen gel matrix was used for in vitro analysis. For in vivo experiments, PCK and control rats were treated with gefitinib between 3 and 10 weeks of age. In vitro, gefitinib had strong inhibitory effects on biliary cyst formation of PCK rats. In vivo, treatment with gefitinib significantly inhibited the cystic dilatation of the intrahepatic bile ducts of PCK rats, which was accompanied by improvement of liver fibrosis. By contrast, no beneficial effects were observed on renal cyst development because of the treatment. These results suggest that signaling pathways mediated by epidermal growth factor receptor are involved in biliary dysgenesis of the PCK rat, with the mechanisms of cyst progression being different between the liver and kidney.

Animals↗
PubMed2006

Decreased expression of Bmi1 is closely associated with cellular senescence in small bile ducts in primary biliary cirrhosis.

Cellular senescence of biliary epithelial cells with p16INK4a and p21WAF1/Cip expression in damaged small bile ducts may be critical for progressive bile duct loss in primary biliary cirrhosis. We investigated the involvement of bmi1, a polycomb group gene repressing p16INK4a expression, in the pathogenesis of biliary cellular senescence. Bmi1 expression was examined immunohistochemically in livers taken from the patients with primary biliary cirrhosis (n=18) and other diseased (n=19) and normal livers (n=16). We examined the effect of oxidative stress and a short interference RNA (siRNA) targeting bmi1 on cellular senescence in cultured mouse biliary epithelial cells. Bmi1 was widely expressed in the nuclei of biliary epithelial cells in the control livers. In contrast, bmi1 expression was significantly decreased in damaged small bile ducts in 43% of livers with primary biliary cirrhosis of stage 1/2, coordinating with the increased p16INK4a expression. In cultured biliary epithelial cells, oxidative stress by H2O2 treatment significantly decreased bmi1 expression, followed by increased P16INK4a expression. A knockdown of bmi1 induced increased p16INK4a expression, decreased cell proliferation, and increased cellular senescence. In conclusion, the decreased bmi1 expression caused by oxidative stress may be involved in the pathogenesis of cellular senescence of biliary epithelial cells in primary biliary cirrhosis.

Animals↗