Kei Yonezawa

Suppression of tumor necrosis factor-α production and neutrophil infiltration during ischemia–reperfusion injury of the liver after heat shock preconditioning

BACKGROUND/AIMS Heat shock preconditioning provides the liver with ischemic tolerance. In this study we examined the effects of heat shock preconditioning on hepatic nonparenchymal cells in light of tumor necrosis factor-alpha (TNF-alpha) production and neutrophil infiltration. METHODS Rats were exposed to heat shock pretreatment at 42 degrees C in the heat shock group (group HS) and at 37 degrees C in the control group (group C). After a 48-h recovery, the left hepatic lobes were given a 90-min ischemia and reperfused. Plasma concentrations of TNF-alpha, cytokine-induced neutrophil chemoattractant (CINC) and alanine aminotransferase (ALT) were measured. Liver tissues were checked for the presence of TNF-alpha mRNA. Histological staining for CINC and polymorphonuclear leukocyte (PMN) was also evaluated. RESULTS In group HS, plasma TNF-alpha levels were significantly more suppressed than in group C (P<0.0001). Expressions of TNF-alpha mRNA in the liver was suppressed in group HS. Production of CINC 2 h after reperfusion was reduced in group HS (P<0.05). PMN infiltration was significantly reduced in group HS (P<0.01). In group HS, liver histology revealed less cellular damage and the plasma level of ALT was significantly reduced (P<0.0001). CONCLUSIONS Heat shock preconditioning suppressed the production of TNF-alpha and CINC in the liver during reperfusion and consequently reduced neutrophil infiltration.

In situ pedicle resection in left trisegmentectomy of the liver combined with reconstruction of the right hepatic vein to an inferior vena caval segment transpositioned from the infrahepatic portion.

A combination of an in situ pedicle resection of the liver and a hepatic vein reconstruction using a cranially transpositioned segment of the IVC after implantation of an ePTFE graft at the missing IVC was useful in treating a patient who suffered from a huge liver tumor involving all of the hepatic venous confluence and the IVC. Although early tumor recurrence remains an unresolved problem for such patients, a surgical approach is feasible. This technique can be justified as a therapeutic modality, not only because it improves quality of life, but also because it provides patients with an opportunity for additional treatment.

Impact of novel histone deacetylase inhibitors, CHAP31 and FR901228 (FK228), on adenovirus-mediated transgene expression

Histone deacetylase inhibitors (HDIs) are known to enhance adenovirus (Ad)‐mediated transgene expression. Recently, novel HDIs, including cyclic hydroxamic‐acid‐containing peptide 31 (CHAP31) and FR901228 (FK228), have been developed.

Effectiveness of an inferior vena caval filter as a preventive measure against pulmonary thromboembolism after abdominal surgery

In three patients with a previous history of pulmonary thromboembolism, inferior vena caval filters were inserted before elective laparotomies to prevent a recurrent pulmonary thromboembolism. Two patients had colon cancer and underwent colectomies, while the other had myoma uteri, which might have been the cause of deep vein thrombosis, and thus a hysterectomy was performed. In spite of their poor risks, their postoperative courses were fairly good owing to perioperative management including anticoagulant therapy, and no recurrence has been observed since the operation in every case. A pulmonary thromboembolism is a fatal complication which follows deep vein thromboses. In patients with such a previous history, the risk is much higher after a laparotomy because of long-term bed rest, hypercoagulability, and so on. The mortality rate after a recurrence of pulmonary thromboembolism is reported to reach 30% without adequate therapy, whereas it is reduced to 8% with anticoagulant therapy, and to 0.8% with additional inferior vena caval filter placement. Considering the feasibility of insertion and the low incidence of complications, preoperative inferior vena caval filter placement is thus recommended for patients having a previous history of either pulmonary thromboembolism or deep vein thrombosis.

Role of preferential cyclooxygenase-2 inhibition by meloxicam in ischemia/reperfusion injury of the rat liver.

Background: Ischemia/reperfusion injury (IRI) is one of the major clinical problems in liver and transplant surgery. Livers subjected to warm ischemia in vivo often show a severe dysfunction and the release of numerous inflammatory cytokines and arachidonic acid metabolites. Cyclooxygenase (COX)-2 is the inducible isoform of an intracellular enzyme that converts arachidonic acid into prostaglandins. The aim of the study was to evaluate the effect of COX-2 inhibition and the role of Kupffer cells in IRI of the liver. Methods: Male Wistar rats [250- 280 g body weight (BW)] were anesthetized and subjected to 30-min warm ischemia of the liver (Pringles maneuver) and 60-min reperfusion after median laparotomy. The I/R group received no additional treatment. In the COX-2 inhibitor (COX-2I) group, the animals received 1 mg/kg BW meloxicam prior to operation. Gadolinium chloride (GdCl3) (10 mg/kg BW) was given 24 h prior to operation in the GdCl3 and GdCl3 + COX-2I groups for the selective depletion of Kupffer cells. The GdCl3 + COX-2I group received both GdCl3 and meloxicam treatment prior to operation. Blood and liver samples were obtained at the end of the experiments for further investigations. Results: After 30 min of warm ischemia in vivo, severe hepatocellular damage was observed in the I/R group. These impairments could be significantly prevented by the selective COX-2 inhibition and the depletion of Kupffer cells. Alanine aminotransferase was significantly reduced upon meloxicam and GdCl3 treatment compared to the I/R group: I/R, 3,240 ± 1,262 U/l versus COX-2I, 973 ± 649 U/l, p < 0.001; I/R versus GdCl3, 1,611 ± 600 U/l, p < 0.05, and I/R versus GdCl3 + COX-2I, 1,511 ± 575 U/l, p < 0.01. Plasma levels of tumor necrosis factor alpha (TNF-α) were significantly reduced in the COX-2I treatment group compared to I/R (3.5 ± 1.5 vs. 16.3 ± 11.7 pg/ml, respectively; p < 0.05). Similarly, the amount of TxB2, a marker for COX-2 metabolism, was significantly reduced in the meloxicam treatment groups compared to the I/R group: I/R, 22,500 ± 5,210 pg/ml versus COX-2I, 1,822 ± 938 pg/ml, p < 0.001, and I/R versus GdCl3 + COX-2I, 1,530 ± 907 pg/ml, p < 0.001. All values are given as mean ± SD (n = 6). Conclusion: These results suggest that the inhibition of COX-2 suppressed the initiation of an inflammatory cascade by attenuating the release of TNF-α, which is an initiator of the inflammatory reaction in hepatic IRI. Therefore, we conclude that preferential inhibition of COX-2 is a possible therapeutic approach against warm IRI of the liver.

Exogenous Superoxide Dismutase Prevents Peroxynitrite-Induced Apoptosis in Non-Heart-Beating Donor Livers

Objective: To investigate the role of oxygen free radicals in the induction of apoptosis in non-heart-beating donor (NHBD) livers, and if superoxide dismutase (SOD) ameliorates these alterations. Methods: Rat livers were perfused via the portal vein with histidine/tryptophan/α-ketoglutarate solution from heart-beating donors (HBD) or 60-min warm ischemia from NHBD, with or without the addition of SOD. After 24 h, cold storage livers were evaluated by isolated reperfusion. Results: NHBD showed significantly higher enzyme leakage and elevated portal venous pressure (PVP) versus HBD. Bile and total adenine nucleotides (TAN) were significantly decreased. Apoptosis was prominent in sinusoidal lining cells, coupled with strong nitrotyrosine staining (NTR). The concentrations of nitric oxide and lipoperoxides were largely increased. SOD medication reduced hepatic enzyme release by 30% and lipoperoxides by nearly 50%. Apoptosis and NTR were significantly decreased, and PVP was strikingly reduced to normal values. A 3-fold enhancement in bile production and 1.5-fold increase in TAN of the liver tissue were also observed. Conclusion: NHBD livers are prone to severe reoxygenation injury promoted by oxygen free radicals, massive nitrite oxide production and peroxynitrite-induced apoptosis within the sinusoids. Antioxidant medication with SOD should be considered as a useful means of preserving NHBD livers.

Meloxicam, a COX-2 inhibitor, ameliorates ischemia/reperfusion injury in non-heart-beating donor livers.

Background/Aims: Chronic organ donor shortage has led to the consideration to expand the donor pool with livers from non-heart-beating donors (NHBD), although a higher risk of graft dys- or nonfunction is associated with these livers. We examined the effects of selective cyclooxygenase-2 (COX-2) inhibition on hepatic warm ischemia (WI) reperfusion (I/R) injury of NHBD. Methods: Male Wistar rats were used as donors and meloxicam (5 mg/kg body weight) was administered into the preservation solution. Livers were excised after 60 min of WI in situ, flushed and preserved for 24 h at 4°C. Reperfusion was carried out in vitro at a constant flow for 45 min. During reperfusion (5, 15, 30 and 45 min), enzyme release of alanine aminotransferase and glutamate lactate dehydrogenase were measured as well as portal venous pressure, bile production and oxygen consumption. The production of malondialdehyde was quantified and TUNEL staining was performed. Quantitative PCR analyzed COX-2 mRNA. COX-2 immunohistochemistry and TxB2 detection completed the measurements. Results: Meloxicam treatment led to better functional recovery concerning liver enzyme release, vascular resistance and metabolic activity over time in all animals. Oxidative stress and apoptosis were considerably reduced. Conclusion: Cold storage using meloxicam resulted in significantly better integrity and function of livers retrieved from NHBD. Selective COX-2 inhibition is a new therapeutic approach achieving improved preservation of grafts from NHBD.

Contents Vol. 53, 2014

I. Alwayn, Halifax D.K. Bartsch, Marburg C. Bassi, Verona W.O. Bechstein, Frankfurt am Main J.A. Bradley, Cambridge M. Cikirikcioglu, Geneva P.-A. Clavien, Zurich R.W.F. de Bruin, Rotterdam C. Eipel, Rostock S. Fichtner-Feigl, Regensburg H. Friess, Munich G. Galata, London D.J. Gouma, Hilversum J.K. Habermann, Lübeck M. Heberer, Basel M. Heger, Amsterdam T. Hubert, Lille W.R. Jarnagin, New York, N.Y. J.C. Kalff, Bonn M.W. Laschke, Homburg/Saar H.-A. Lehr, Lausanne C.M. Malata, Cambridge T. Minor, Bonn M. Morino, Torino J. Pirenne, Leuven A. Schachtrupp, Melsungen R. Schramm, Munich L. Steinstraesser, Bochum A. Szijártó, Budapest R.H. Tolba, Aachen T.M. van Gulik, Amsterdam M.A. Venermo, Helsinki D.C. Winter, Dublin Y. Yamamoto, Akita Clinical and Experimental Surgery

A Case of Vena Cava Filter for Colon Cancer Complicated by Pulmonary Thromboembolism.

肺塞栓症にて入院加療中に結腸癌を診断され, 予防的下大静脈フィルターを用いて手術しえた症例を経験した.症例は78歳の女性で, 呼吸困難にて来院, 肺塞栓症の診断にて入院中, 貧血を指摘され結腸癌が発見された.術前に抗凝固療法施行, かつ下大静脈フィルターを留置し, 肺塞栓再発予防や肺機能の改善に努め, 入院第37日目に根治手術を行った.術後も抗凝固療法を行い, 肺塞栓症の再発もなく術後第18日目に退院した.以後2年経過したが, 再発は認めていない.肺塞栓症合併患者の周術期管理上, 肺塞栓症再発が問題となるが, 周術期管理について詳細に論じた報告は見当たらない.そこでこの症例を踏まえ, 肺塞栓症合併患者の周術期管理について考察した.抗凝固療法や下大静脈フィルター留置施行は再発を防止し, 特に, 下大静脈フィルターは周術期管理上有用であった.