Toshiro Ogata

Role of cyclic nucleotides in ischemia and reperfusion injury of canine livers

BACKGROUNDnIn a series of canine liver ischemia experiments, we have shown that amelioration of hepatic injury is achievable by the inhibition of vasoconstriction, cytokine production, platelet aggregation, and neutrophil infiltration. Cyclic adenosine diphosphate (cAMP) was considered to be involved in most of these events. In our study, we tested our hypothesis that augmentation of endogenous cAMP by phosphodiesterase (PDE) 3 inhibitor, amrinone (AM), or adenylate cyclase stimulator, NKH477 (NKH), could attenuate ischemia and reperfusion injury of the liver.nnnMETHODSnThirty-six beagle dogs were used. They were divided into group CT (untreated control), group AM, group NKH, and group CB (treated by both agents). AM or NKH were administered i.v. 1 hr before ischemia (group preAM and group preNKH) or 15 min before reperfusion (pos-AM and postNKH). Combination group animals were treated only before ischemia. Animal survival, hepatic tissue blood flow, liver enzymes, platelet counts, energy metabolism, hepatic cAMP and cyclic guanosine 3,5-cyclic monophosphate levels, and histopathology were analyzed.nnnRESULTSnTwo-week animal survival was significantly improved by pre- or posttreatment with either agent. After reperfusion, hepatic tissue blood flow, liver enzyme release, platelet counts, energy metabolism, tissue cAMP levels, and histological architecture were also ameliorated markedly. Combination of both agents induced severe liver damage and lethal hypotension. AM treatment exhibited more protective effects than NKH, particularly when it was given before ischemia. Interestingly, not only cyclic guanosine 3,5-cyclic monophosphate, were also restored at higher levels after reperfusion by preischemia treatment.nnnCONCLUSIONSnAdministration of amrinone or NKH477 maintained hepatic tissue concentrations of cyclic nucleotides, and attenuated ischemia and reperfusion injury of the liver. Thus, regulation of hepatic tissue cyclic nucleotides is an important alternative for prevention of hepatic damage in liver preservation and surgery.

Inducible expression of basic transcription factor-binding protein 2 (BTEB2), a member of zinc finger family of transcription factors, in cardiac allograft vascular disease.

Background. We have recently identified basic transcription factor-binding protein 2 (BTEB2), which is involved in phenotypic modulation of vascular vascular smooth muscle cells. The aim of this study was to investigate the expression of BTEB2 in cardiac allograft vascular disease. Methods. Heterotopic cardiac transplantation was performed in rats. All grafts were stained with antibodies against for BTEB2 and cyclin-dependent kinase 4 for immunohistochemical study. The intensity of BTEB2 expression was also calculated. Results. In the allografts at 4 and 8 weeks after transplantation, smooth muscle cells were positive for BTEB2 in the diffusely thickened coronary arteries and the perivascular space. BTEB2 expression was closely associated with cyclin-dependent kinase 4 expression. The BTEB2 expression score was significantly higher in the allografts compared with the isografts. Conclusions. The induced expression of BTEB2 may play a potential role in the development of the cardiac allograft vascular disease.

Angiogenesis inhibitor TNP-470 (AGM-1470) suppresses vascular smooth muscle cell proliferation after balloon injury in rats

BACKGROUNDnAlthough TNP-470, a synthetic analog of fumagillin, may inhibit vascular intimal hyperplasia, the effects of TNP-470 on smooth muscle cell (SMC) proliferation have not been demonstrated in vivo. The aim of this study was to confirm the effect of TNP-470 on vascular SMC proliferation using a rat carotid artery balloon injury model.nnnMATERIALS AND METHODSnRats were treated with vehicle or with TNP-470 at low dosage (10 mg/kg), medium dosage (20 mg/kg), or high dosage (40 mg/kg). The animals received subcutaneous injections of materials three times a week from the day following balloon injury. All rats were sacrificed at 2 weeks after injury. The ratio of intimal-to-medial cross-sectional areas (I/M ratio) and the PCNA labeling index was calculated for each group. The DNA synthesis of cultured SMCs was also evaluated using [3H]thymidine incorporation assays. Smooth muscle cells were stimulated with basic fibroblast growth factor and TNP-470 (0.01-100 ng/ml) were added.nnnRESULTSnThe inhibition of intimal hyperplasia increased in a dose-dependent manner. TNP-470 also decreased PCNA expression in the neointima and inhibited DNA synthesis of cultured SMCs.nnnCONCLUSIONSnTNP-470 may be useful in the prevention of vascular intimal hyperplasia.

Perioperative Challenges and Surgical Treatment of Large Simple, and Infectious Liver Cyst - A 12-Year Experience

Background Cystic lesions of the liver consist of a heterogeneous group of disorders that can present diagnostic and therapeutic challenges. Methods A retrospective review of all medical records of adult patients diagnosed with large (>7 cm) cystic lesions of the liver between January 2000 and December 2011, at Kurume University Hospital. Cases with polycystic disease were excluded. Results Twenty three patients were identified. The mean size was 13.9 cm (range, 7-22cm). The majority of simple cysts were found in women (females: males, 2: 21). In 19 patients, the cyst was removed surgically by wide deroofing (laparoscopically in 16 cases, combined with ethanol sclerotherapy in 13 cases). Infection of the liver cyst occurred in one patient, who later underwent central bi-segmentectomy. Conclusion Simple large cysts of the liver can be successfully treated by laparoscopic deroofing and alcohol sclerotherapy. Large hepatic cyst considered to need drainage should be removed surgically to avoid possible infection.