Ampullary Adenoma Treated by Endoscopic Double-Snare Retracting Papillectomy.

We report herein improved methods for the safe and successful completion of endoscopic papillectomy (EP). Between January 2008 and November 2011, 12 patients underwent double-snare retracting papillectomy for the treatment of lesions of the major duodenal papilla. The main outcomes were en bloc resection rates, pathological findings, and adverse events. All of the patients (mean age, 60.1 years; range, 38 to 80 years) were diagnosed with ampullary adenoma by endoscopic forceps biopsies prior to endoscopic snare papillectomy. En bloc resection by double-snare retracting papillectomy was successfully performed for all lesions (median size, 12.3 mm), comprising six tubular adenomas, one tubulovillous adenoma, three cases of epithelial atypia, one hamartomatous polyp, and one case of duodenitis with regenerative change. Significant hemorrhage and pancreatitis were observed in one case after EP. Adenoma recurrence occurred in three patients during follow-up (median, 28.5 months) at a mean interval of 2 months postoperatively (range, 1 to 3 months). No serious adverse events were observed. Double-snare retracting papillectomy is effective and feasible for treating lesions of the major duodenal papilla. Further treatment experience, including a single-arm phase II study, needs to be accumulated before conducting a randomized controlled study.

Prominent steatosis with hypermetabolism of the cell line permissive for years of infection with hepatitis C virus.

Most of experiments for HCV infection have been done using lytic infection systems, in which HCV-infected cells inevitably die. Here, to elucidate metabolic alteration in HCV-infected cells in a more stable condition, we established an HCV-persistently-infected cell line, designated as HPI cells. This cell line has displayed prominent steatosis and supported HCV infection for more than 2 years, which is the longest ever reported. It enabled us to analyze metabolism in the HCV-infected cells integrally combining metabolomics and expression arrays. It revealed that rate-limiting enzymes for biosynthesis of cholesterol and fatty acids were up-regulated with actual increase in cholesterol, desmosterol (cholesterol precursor) and pool of fatty acids. Notably, the pentose phosphate pathway was facilitated with marked up-regulation of glucose-6-phosphate dehydrogenase, a rete-limiting enzyme, with actual increase in NADPH. In its downstream, enzymes for purine synthesis were also up-regulated resulting in increase of purine. Contrary to common cancers, the TCA cycle was preferentially facilitated comparing to glycolysis pathway with a marked increase of most of amino acids. Interestingly, some genes controlled by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master regulator of antioxidation and metabolism, were constitutively up-regulated in HPI cells. Knockdown of Nrf2 markedly reduced steatosis and HCV infection, indicating that Nrf2 and its target genes play important roles in metabolic alteration and HCV infection. In conclusion, HPI cell is a bona fide HCV-persistently-infected cell line supporting HCV infection for years. This cell line sustained prominent steatosis in a hypermetabolic status producing various metabolites. Therefore, HPI cell is a potent research tool not only for persistent HCV infection but also for liver metabolism, overcoming drawbacks of the lytic infection systems.

Progressive liver failure induced by everolimus for renal cell carcinoma in a 58-year-old male hepatitis B virus carrier.

A 58-year-old man was diagnosed as a hepatitis B virus (HBV) carrier approximately 30 years ago. He was diagnosed with renal cell carcinoma when he was 57 years old. Radical nephrectomy was performed, and everolimus was administered to treat his lung metastasis. After beginning the everolimus, intermittent fever, general fatigue, and jaundice developed. He was admitted under a diagnosis of flare (acute exacerbation) of chronic B hepatitis due to HBV reactivation. Despite intensive care, he died of hepatic failure and fungus infection. The autopsy findings were compatible with hepatic failure due to HBV reactivation by everolimus. Antiviral prophylaxis must be taken into consideration before beginning immunosuppressive therapy such as everolimus in HBV carriers.

CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion.

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

MyD88-dependent interleukin-10 production from regulatory CD11b⁺Gr-1(high) cells suppresses development of acute cerulein pancreatitis in mice.

We explored the role of the MyD88 signaling pathway. This pathway mediates the recognition of pathogen-associated molecular patterns and damage-associated molecular patterns via Toll-like receptors (TLRs) and/or IL-1/IL-18 via each cytokine receptor in a murine model of acute pancreatitis induced by cerulein administration. Our analysis revealed that: various TLRs and MyD88 molecules were constitutively expressed in the pancreas of cerulein-treated and untreated wild-type (WT) mice. MyD88⁻/⁻ mice administered cerulein developed severe pancreatitis as compared with MyD88⁺/⁺ WT mice. The number of IL-10-expressing CD11b⁺Gr-1(high) cells in cerulein-administered MyD88⁻/⁻ mice was significantly decreased. This was in accordance with a reciprocal increase in the infiltration of CD4⁺ T cells as compared with that in control MyD88⁺/⁺ mice. WT mice pretreated with antibiotics and administered cerulein developed milder pancreatitis as compared with control cerulein-administered mice without antibiotic treatment. The MyD88 signaling pathway contributes to the induction of regulatory IL-10-producing macrophages/myeloid-derived suppressor cells, possibly in response to non-bacterial components in the damaged pancreas. These results provide a new concept for therapeutic strategies against acute pancreatitis.

CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice.

BACKGROUND & AIMS: Acute pancreatitis is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes. We investigated the pathologic roles of innate immune cells, especially macrophages, in cerulein- and L-arginine-induced acute pancreatitis in mice. METHODS: Acute pancreatitis was induced by sequential peritoneal administration of cerulein to mice. We determined serum concentrations of amylase and lipase, pancreatic pathology, and features of infiltrating mononuclear cells. We performed parabiosis surgery to assess the hemodynamics of pancreatic macrophages. RESULTS: Almost all types of immune cells, except for CD11b(high)CD11c(-) cells, were detected in the pancreas of healthy mice. However, activated CD11b(high)CD11c(-) cells, including Gr-1(low) macrophages and Gr-1(high) cells (granulocytes and myeloid-derived suppressor cells), were detected in damaged pancreas after cerulein administration. CCL2(-/-) mice given cerulein injections developed significantly less severe pancreatitis, with less infiltration of CD11b(high)CD11c(-)Gr-1(low) macrophages, but comparable infiltration of myeloid-derived suppressor cells, compared with cerulein-injected wild-type mice. Parabiosis and bone marrow analyses of these mice revealed that the CD11b(high)CD11c(-)Gr-1(low) macrophages had moved out of the bone marrow. Furthermore, mice with macrophage-specific deletion of suppressor of cytokine signaling 3 given injections of cerulein developed less severe pancreatitis and Gr-1(low) macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11b(high)CD11c(-)Gr-1(low) macrophages was comparable between strains. Induction of acute pancreatitis by L-arginine required induction of macrophage migration by CCL2, via the receptor CCR2. CONCLUSIONS: Cerulein induction of pancreatitis in mice involves migration of CD11b(high)CD11c(-)Gr-1(low) macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3-dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis.

Anticoagulation therapy dramatically improved severe sigmoiditis with findings resembling inflammatory bowel disease, which was caused by mesenteric venous thrombosis.

Mesenteric venous thrombosis is an insidious disease, with a high mortality rate typically attributed to the long delay in diagnosis. Rapid diagnosis and treatment are important. Here, we present a patient with idiopathic inferior mesenteric venous (IMV) thrombosis. A 65-year-old man presented with constant abdominal pain associated with fever and bloody diarrhea. He was diagnosed with severe ulcerative colitis and was treated with mesalazine and prednisolone. The prednisolone was tapered because of liver dysfunction, and he received total parenteral nutrition for a month. His abdominal pain and bloody diarrhea worsened, and he lost 5 kg of weight. He was then transferred to our institute. Computed tomography showed thickening of the left colon. Colonoscopy showed diffuse colitis with multiple ulcers, large edematous folds, congested mucosa, and stenosis of the sigmoid colon, with sparing of the rectum, raising the possibility of IMV thrombosis. Angiography confirmed IMV thrombosis. Anticoagulation therapy was initiated with intravenous heparin followed by oral warfarin. His abdominal pain and diarrhea resolved, and he was discharged from hospital. Six months later, he remained asymptomatic with normal colonoscopic findings.

Hemobilia due to biliary intraepithelial neoplasia associated with Zollinger-Ellison syndrome.

A 58-year-old man was transferred to us from his local hospital because of failure to control his gastrointestinal bleeding by endoscopic hemostasis. Abdominal imaging suggested a hypervascular tumor of the pancreatic head (36 mm diameter), and laboratory testing showed an elevated serum gastrin level (17,800 pg/mL). Gastroduodenal endoscopy revealed multiple duodenal ulcers and active bleeding from the ampulla of Vater. The selective arterial secretagogue injection test suggested a gastrinoma in the pancreatic head, but no gastrinoma in the pancreatic tail. The patient was diagnosed with solitary pancreatic head gastrinoma complicated by hemosuccus pancreaticus, and pancreaticoduodenectomy was performed. Intraoperatively, the diagnosis was changed to primary peripancreatic lymph node gastrinoma without pancreatic involvement. The gastrointestinal bleeding stopped postoperatively and serum gastrin levels returned to normal. Histological examination of the surgical specimens revealed a small submucosal gastrinoma in the duodenum (7 mm diameter). The final diagnosis was microgastrinoma of the duodenum with peripancreatic lymph node metastasis. The cause of bleeding from the ampulla of Vater was initially obscure, but eventually a hemorrhagic erosion with moderate atypia was found in the common bile duct, indicating biliary intraepithelial neoplasia (BilIN). This is the first report of hemobilia due to BilIN with gastrinoma.

[A case of metastatic esophageal cancer - endoscopic resection of the primary site following systemic chemotherapies].

A 64-year-old male presented with discomfort in the chest. His endoscopic examination and CT scan showed esophageal cancer with multiple liver metastases. A total of ten courses of systemic chemotherapy by 5-fluorouracil (5-FU) (800 mg for five days) and cisplatin (CDDP) (80 mg/day on the first day of the week for four weeks) were performed, and liver and lymph node metastases disappeared. The primary lesion was the only site detected positive by PET scan. After a concurrent chemoradiation therapy, salvage endoscopic mucosal resection (EMR) was performed on the remainder of the primary site and the patient gained a complete response (CR). We report this case because, although the mean survival time of advanced esophageal cancer is less than one year, this patient responded to chemotherapy and gained complete response by salvage EMR. This patient has had no recurrence for four years since his initial diagnosis.

Evaluation of liver fibrosis by transient elastography using acoustic radiation force impulse: comparison with Fibroscan(®).

BACKGROUND: Accurate evaluation of liver fibrosis in patients with chronic liver damage is required to determine the appropriate treatment. Various approaches, including laboratory tests and transient elastography, have been used to evaluate liver fibrosis. Recently, transient elastography with acoustic radiation force impulse (ARFI) has been developed and applied with conventional ultrasonography. The aim of this study was to evaluate the clinical utility of transient elastography with ARFI and to compare the results with this method and those of the Fibroscan(®) procedure. METHODS: One hundred and thirty-one patients with liver damage, who underwent liver biopsy at our department, were enrolled prospectively in this study. Elastography with ARFI (applied with ACUSON S2000(®)), and Fibroscan(®) was performed at the same time as liver biopsy. These measurements were compared with histological findings in liver biopsy specimens, and measurement accuracy was evaluated by receiver-operating characteristic analysis. RESULTS: Elastography values with both procedures were significantly correlated with the stages of liver fibrosis and there was little difference in the results obtained using the 2 procedures. The accuracy of differential diagnosis between no fibrosis at F0 and more than F1 stage was insufficient with ARFI, but this procedure was sufficient for diagnosing advanced fibrosis. The accuracy of ARFI was almost equivalent to that of the Fibroscan(®) method. Moreover, both ARFI and Fibroscan(®) values increased in proportion to the severity of hepatic inflammation when fibrosis stage is low, but not in proportion to the severity of steatosis. CONCLUSIONS: Transient elastography with ARFI is simple, non-invasive and useful for diagnosing the stage of fibrosis in chronic liver disease. The utility of ARFI was almost equivalent to that of the Fibroscan(®) method.

MyD88-dependent pathway accelerates the liver damage of Concanavalin A-induced hepatitis.

We have explored the pathological role of the MyD88 signaling pathway via Toll-like receptors (TLRs) that mediate the recognition of pathogen-associated molecular patterns (PAMPs) in a murine model of autoimmune hepatitis induced by administering Concanavalin A (ConA). We first found that various TLRs and MyD88 molecules were expressed in liver of Con A-treated and untreated wild-type (WT) mice including liver macrophages. Flowcytometric analysis revealed that liver CD11b(+)CD11c(-) and CD11b(+)CD11c(+) antigen-presenting cells express TLR2, although NK and NKT cells did not. When WT and MyD88(-/-) mice were intravenously administered with Con A, the severity of hepatitis was significantly lower in Con A-injected MyD88(-/-) mice than in WT mice in terms of the histopathology, the levels of serum transaminase and pro-inflammatory cytokines (TNF-alpha, IFN-gamma, and IL-6), and upregulation of CD80/CD86 and TNF-alpha on/in liver macrophages. The results provide evidence of a possible contribution of the TLRs-MyD88 signaling pathway in activating TLR-expressing liver macrophages in the autoimmune hepatitis model, and thus indicate that the strategy of blockade of pathological pathogens via the intestinal lumen may be feasible for the treatment of the disease.

Gemcitabine as first-line chemotherapy in elderly patients with unresectable pancreatic carcinoma.

BACKGROUND: Gemcitabine (GEM) is the key drug for the chemotherapy of unresectable pancreatic cancer. However, the efficacy and safety of GEM has not been established in elderly patients. We retrospectively examined the prognosis of elderly pancreatic cancer patients treated with GEM. METHODS: Sixty-six patients with unresectable pancreatic cancer (pathologically identified) and no prior chemotherapy were divided into three groups. Group A: patients aged 70 years or more who received standard GEM (1000 mg/m(2)) on days 1, 8, and 15 and rest on day 21; Group B: patients less than 70 years old who received standard GEM therapy; and Group C: patients under best supportive care. RESULTS: Median survival times (MSTs) (days) were 311 in group A (p < 0.05 vs. group C), 292 in group B (p < 0.05 vs. group C), and 127 in group C. Among the patients who received GEM, 23% patients in group A and 16% patients in group B obtained partial responses. The response rates and MSTs were similar in groups A and B, as well as in more aged (≥75 years) patients. Bone marrow suppression was more frequently seen in elderly patients. Cox's hazard model in patients aged 70 years or more revealed that GEM therapy reduced the hazard ratio for death (hazard ratio: 0.683, p = 0.041). CONCLUSIONS: Chemotherapy with GEM appears to be effective and safe in elderly patients as well as in younger patients. Patients with unresectable pancreatic carcinoma should receive GEM therapy even if they are aged 70 or more, even if they are aged 75 or more.

Bouveret's syndrome with a concomitant incidental T1 gallbladder cancer.

Bouveret's syndrome, which is a gastric outlet obstruction caused by a gallstone in the duodenum, is a rare complication of gallstone disease. We report a case of Bouveret's syndrome in an 81-year-old woman who also exhibited incidental gallbladder cancer. She was admitted to our hospital complaining of upper abdominal pain and vomiting. A computed tomography examination showed a cholecystoduodenal fistula, a large impacted stone at the gastric outlet, and a dilated stomach. She was diagnosed as having Bouveret's syndrome. The patient underwent an upper gastrointestinal endoscopy and a mechanical lithotripsy was successfully performed for the stone. She then underwent a cholecystectomy with primary closure of the duodenal fistula. An intra-operative histopathology examination revealed severe cholecystitis with an adenocarcinoma in part of the gallbladder. Gallbladder bed resection and regional lymph node dissection were also performed. To the best of our knowledge, this is the first published report of a case in which Bouveret's syndrome and gallbladder cancer co-existed.

Hepatocellular carcinoma in Keio affiliated hospitals--diagnosis, treatment, and prognosis of this disease.

We have retrospectively investigated patients with hepatocellular carcinoma (HCC) (912 cases) treated in the Affiliated Hospitals of Keio University (the Keio Association for the Study of Liver Diseases: KASLD) and here we review the recent diagnosis and treatment of HCC. HCC is a major cause of death in Japan and a major etiology of this disease is chronic viral infection such as hepatitis C virus (HCV) and hepatitis B virus (HBV). Screening of HCC by imaging studies and measurement of serum tumor markers successfully prolonged survival of the patients in Japan. The prognosis of this disease has been determined by both tumor factors and degree of liver function, and its staging is usually established with a recent system such as Japan Integrated Staging Score (JIS). The 5-year survival rate of JIS stage 0, 1, 2 and 3 were 68.3%, 51.9%, 25.8% and 16.6%, respectively in our cohort. Multivariate analysis using Cox proportional hazard models showed that age (>65) , HCV infection, tumor number, TB (>1.0), AFP (>20) and PIVKA-II (>40) were significant factors affecting survival among the entire patients. Major treatment strategies are hepatic resection, radio frequency ablation and transarterial chemo-embolization, but alternative treatments such as radiation, chemotherapy, and their combination have been used to reduce tumor sizes resulting prolongation of the survival or maintenance of patients' quality of life, while liver transplantation has not been popular in Japan. However, the overall survival continues to decrease from year to year, and does not show a plateau phase in Kaplan-Mayer curve. These results suggest that the best way to improve survival can be achieved by prevention of the disease. Antiviral therapies have decreased the incidence of HCC, indicating that treatment for chronic hepatitis is the best way to prevent HCC development at present.

Performance evaluation of a high-sensitivity large-aperture small-animal PET scanner: ClairvivoPET.

OBJECTIVE: In this study, we evaluated the performance of a newly commercialized small-animal positron emission tomography (PET) scanner, ClairvivoPET, which provides significant advantages in spatial resolution, sensitivity, and quantitative accuracy. METHODS: This scanner consists of depth of interaction detector modules with a large axial extent of 151 mm and an external (137)Cs source for attenuation correction. Physical performances, resolution, sensitivity, scatter fraction (SF), counting rate including noise equivalent count (NEC) rate, quantitative accuracy versus activity strength, and transmission accuracy, were measured and evaluated. Animal studies were also performed. RESULTS: Transaxial spatial resolution, measured with a capillary tube, was 1.54 mm at the center and 2.93 mm at a radial offset of 40 mm. The absolute sensitivity was 8.2% at the center, and SFs for mouse-and rat-sized phantoms were 10.7% and 24.2%, respectively. Peak NEC rates for mouse-and rat-sized uniform cylindrical phantoms were 328 kcps at 173 kBq/ml and 119 kcps at 49 kBq/ml, respectively. The quantitative stability of emission counts against activity strength was within 2% over 5 half-lives, ranging from 0.6 MBq to 30 MBq. Transmission measurement based on segmented attenuation correction allowed 6-min and 10-min scans for mouse-and rat-sized cylindrical phantoms, respectively. Rat imaging injected with (18)F-NaF resulted in visibility of fine bone structures, and mouse imaging injected with (18)F-D-fluoromethyl tyrosine demonstrated the feasibility of using this system to obtain simultaneous time activity curves from separate regions, such as for the heart and tumors. CONCLUSIONS: ClairvivoPET is well suited to quantitative imaging even with short scan times, and will provide a number of advantages in new drug development and for kinetic measurement in molecular imaging.

[Alcoholic liver diseases and hepatitis virus C in Japan].

Recently incidence of alcoholic liver disease (ALD) has been increasing in Japan associated with an increase in alcoholic beverage consumption. There have been a large number of reports about the relationship between alcohol and hepatocarcinogenesis, but it remains controversial. In the present study, we addressed the recent trend in incidence of ALD including liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in heavy drinkers in Japan. We carried out nation-wide survey by asking for the hospitals that are approved by the Japanese Society of Gastroenterology for recent aspects of in-patients with ALD. Except for HCC, percentage of ALD without viral hepatitis is more than 70%, which is increased when compared to the national survey carried out in 1992. In alcoholic LC patients, those who did not have viral hepatitis were 81%. However, the percentage of HCC without viral hepatitis was 34% of all of the heavy drinkers with HCC. Regarding the case in our university hospital, 138 cases (32%) of 432 patients with HCC were heavy drinkers. However, regarding in our general hospital, 15 cases of 23 patients with HCC (61%) were heavy drinkers. In conclusion, since the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers.

[A case of intrahepatic cholangiocarcinoma effectively treated by hepatic arterial infusion chemotherapy].

The patient was a 50-year-old woman who suffered from gastric discomfort. She was first diagnosed as intrahepatic cholangiocarcinoma with hepatic, paraaortic lymphnodal and bone metastasis. Initial systemic chemotherapy using gemcitabine (GEM) and 5-FU failed to control the disease activity. Then she was given GEM and cisplatin (CDDP) combination chemotherapy. The response was assessed as stable disease (SD), but grade 4 leukopenia was seen. Then systemic therapy using GEM, and hepatic arterial infusion therapy with CDDP, l-leucovorin and 5-FU were continued biweekly. Partial response (PR) was achieved six months later, and her disease status was maintained as SD. This hepatic arterial infusion chemotherapy would be safe and feasible as therapy for inoperable intrahepatic cholangiocarcinoma.

[A case of advanced gastric cancer with lymphangitis carcinomatosa after operation of Krukenberg tumor treated by TS-1 plus CPT-11 as third-line chemotherapy].

Chemotherapies for recurrent gastric cancer have not yet been established. Here we report a case of type 4 gastric cancer associated with lymphangitis carcinomatosis which became refractory to the previous chemotherapies. The case was a 40-year-old woman. She had been diagnosed with gastric cancer after a Krukenberg tumor operation. Chemotherapies (TS-1 plus CDDP as first-line, and TS-1 plus taxanes as second-line) were performed, and a partial response was achieved. Disease activity has been well controlled until this time. Since recurrence of left pleural effusion and lymphangitis carcinomatosis was recognized, we changed the chemotherapy TS-1 plus CPT-11. Pleural effusion decreased and lymphangitis carcinomatosis improved. The serum CA 19-9 level rose transiently after CPT-11 administration, and tended to fall at the second week of chemotherapy. However, the patient died 2 years 4 months after the onset. TS-1 plus CPT-11 combination chemotherapy would be effective for lymphangitis carcinomatosis and also useful as third-line chemotherapy for recurrent gastric cancer.

Herbal cardiotonic pills prevent gut ischemia/reperfusion-induced hepatic microvascular dysfunction in rats fed ethanol chronically.

AIM: Cardiotonic Pill (CP), an oral herbal medicine that includes Danshen (Salviae Miltiorrhizae), Panax notoginseny and Dyroblanops aromatica gaertn, has been clinically used for vascular diseases such as occlusive vasculitis, coronary diseases, atherosclerosis, and cerebral infarction. The main component, Salviae Miltiorrhizae, has been reported to prevent cerebral and intestinal reperfusion injury. However, little is known about the effect of CP on hepatic microcirculation. Thus, this study aimed to determine whether CP could affect hepatic microvascular dysfunction elicited by gut ischemia/reperfusion (I/R) in rats fed ethanol chronically. METHODS: Male Wistar rats were pair-fed with a liquid diet containing ethanol or isocaloric control diet for 6 wk. After laparotomy, one lobe of the liver was examined through an inverted intravital microscope. The rats were exposed to 30 min of gut ischemia followed by 60 min of reperfusion. Rhodamine-6G-labeled leukocytes in the sinusoids were observed 90 min after the onset of superior mesenteric artery occlusion. Plasma tumor necrosis factor (TNF)-alpha and endotoxin levels were measured 1 h after the onset of reperfusion. Plasma alanine aminotransferase (ALT) activities were measured 6 h after the onset of reperfusion. In another set of experiments, CP (0.8 g/kg, intragastrically) was administered 1 and 24 h before the onset of ischemia. RESULTS: In control rats, gut I/R elicited increases in the number of stationary leukocytes, and plasma TNF-alpha and endotoxin levels and plasma ALT activities. These changes were mitigated by pretreatment with CP. In ethanol-fed rats, the gut I/R-induced increases in the number of stationary leukocytes, plasma endotoxin levels and ALT activities were enhanced. Pretreatment with CP attenuated the enhancement of gut I/R-induced responses by chronic ethanol consumption. CONCLUSION: These results suggest that CP prevents the gut I/R-induced hepatic microvascular dysfunction and hepatocellular injury. A reduction of inflammatory responses such as TNF-alpha production via reduction of blood endotoxin levels appears to be involved in the mechanisms. Chronic ethanol consumption enhances gut I/R-induced hepatic microvascular and hepatocellular injury. CP also attenuates an enhancement of gut I/R-induced responses by chronic ethanol consumption via the reduction of blood endotoxin levels.