Yutaka Umehara

Warm ischemia and reperfusion injury in diet-induced canine fatty livers.

BACKGROUND Fatty liver is associated with primary nonfunction after liver transplantation, contributing a shortage of suitable liver grafts. Because extensive investigation of mechanisms underlying such nonfunction has been limited largely to rodents, we made a new fatty liver model in dogs and studied primary nonfunction after warm ischemia. METHODS We developed a diet rich in fat but deficient in choline to induce fatty change in canine liver and investigated effects of 60 min of warm ischemia and reperfusion in dogs with such fatty livers. RESULTS Microscopically evident steatosis increased with duration of dietary manipulation (up to 12 weeks), as did hepatic total lipid and triglyceride levels. No dog with >30% of steatotic hepatocytes, >445 mg/g hepatic total lipid or >145 mg/g hepatic triglyceride survived after 60 min of warm ischemia. Arterial ketone body ratios decreased and blood endotoxin increased after reperfusion in nonsurvivors. The main histologic finding in livers of nonsurvivors was marked sinusoidal congestion. CONCLUSIONS Damage to hepatocytes and nonparenchymal cells after warm ischemia and reperfusion was thought to be closely related to sinusoidal microcirculatory disturbances in fatty livers. The canine fatty liver model reported here may be useful in studying the pathology of primary nonfunction and in establishing criteria for allowable degrees of fatty change in potential liver grafts.

Plasma Exchange-based Plasma Recycling Dialysis System as an Artificial Liver Support

Abstract:  We developed a plasma recycling dialysis (PRD) system based on plasma exchange (PE). In this system, rapid reduction of toxic substances and restitution of deficient essential substances are performed by PE and subsequent blood purification is performed by dialysis between separated plasma recycled over a purification device and the patients blood across the membrane of a plasma separator. To demonstrate the safety and efficacy of this system, we used a pig model of fulminant hepatic failure (FHF) and anion exchange resin, activated charcoal and hemodialysis for the purification device. FHF was induced by intraportal administration of α‐amanitine (0.1 mg/kg) and lipopolysaccharides (1 µg/kg) in pigs. Three groups of animals were studied: group 1, diseased controls (N = 4); group 2, PE group (N = 4), 16 h after drug infusion the pigs underwent PE of approximately 1.2 L for 2 h; and group 3, PE + PRD group (N = 4), the pigs underwent PE followed by PRD for 6 h. The hemodynamic status of all animals was stable during the procedure. In group 3, the values of ammonia, total bile acid and total bilirubin continuously decreased and were significantly lower than those of the animals in group 2 24 h after the induction of FHF. The Fischer ratio was significantly higher than in group 2 after 24 h. Group 3 pigs maintained a higher level of consciousness and survived longer than group 2 pigs. Safety of this PE‐based PRD system was demonstrated and the removal of toxic substances was significant. This study confirmed the clinical utility of this system as an artificial liver support.

Gene expression of ATP-binding cassette transporters during liver regeneration after 90% hepatectomy in rats

Liver damage with hyperbilirubinemia during regeneration of the small liver is the major hurdle to expand the indications of adult living donor liver transplantation. We performed a large-scale gene expression analysis of the regenerating liver after a 90% hepatectomy in rats, and analyzed the changes in the gene expression patterns related to the ATP-binding cassette (ABC) transporters. RNAs were prepared from 3 rat livers at 0, 24, 72 and 168 h after a 90% hepatectomy. The gene expression profile was analyzed by the Rat Genome 230 2.0 array with special references to the ABC transporters. Among 31,042 probes, 1,587 reported genes were identified as either upregulated or downregulated more than 2-fold. Among 20 ABC transporter genes, multidrug resistance protein (MRP) 2 and organic anion transporting polypeptide (OATP) 1 were significantly downregulated, while MRP1 and MRP3 tended to be expressed. These genetic changes were confirmed by real-time PCR. A microarray analysis demonstrated not only an extensive gene expression profile in the regenerating liver but more specific molecular events related to bilirubin transport at the same time. Changes in the expression pattern of the ABC transporters, therefore, seem to be the key event in liver failure during liver regeneration.

Three-stage total hepatectomy using a portocaval shunt tube in rats.

Male Wistar rats (CLEA Japan, Inc., Tokyo, Japan) weighing 230 to 300 g were housed in metal cages with controlled light and dark cycles. They were fed standard rat chow until 24 hours before each operation, at which time they were given free access only to water. Total hepatectomy was performed as a three-stage procedure under clean conditions. The study protocols complied with the Guidelines for Animal Experimentation, Hirosaki University, for human care of experimental animals.

Two Cases of Ulcerative Colitis With Gastric Ulcer and Duodenal Ulcer or Gastric Ulcer Alone

There are many reports of ulcerative colitis in Europe and the United States, but they have been hardly met with in Japan except those of F. MATSUNAGA clinically studied. However, this problem seems not to have been well dissolved pathologically and therapeutically. As the authors happened to observe two autopsy cases of ulcerative colitis with peptic ulcers, they will report their clinical data and autopsy findings.