Daisuke Yoshinari

Effects of a dual inhibitor of tumor necrosis factor-α and interleukin-1 on lipopolysaccharide-induced lung injury in rats : Involvement of the p38 mitogen-activated protein kinase pathway

ObjectiveSepsis is a major cause of adult respiratory distress syndrome. In this study, we evaluated the effect of FR167653, which is a potent suppressant of tumor necrosis factor (TNF)-&agr; and interleukin (IL)-1 production, on lipopolysaccharide (LPS)-induced lung injury and lethality in rats, and we examined the involvement of p38 mitogen-activated protein (MAP) kinase in the action of FR167653. DesignProspective, randomized study. SettingAnimal research facility in a university. SubjectsMale Sprague-Dawley rats weighing 200–270 g. InterventionsAll the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg·kg−1·hr−1, commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs. Measurements and Main Results LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group. Serum concentrations of TNF-&agr; and IL-1&bgr; and plasma concentrations of thromboxane B2 were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues. ConclusionsFR167653 administration decreased serum TNF-&agr; and IL-1&bgr; concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-&agr; and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.

Effects of a p38 mitogen-activated protein kinase inhibitor as an additive to university of wisconsin solution on reperfusion injury in liver transplantation.

BACKGROUND Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the development of ischemia/reperfusion injury in nonhepatic organs, such as the heart. However, the role of p38 MAPK activation in the liver is unclear. We examined the effects of FR167653, a novel p38 MAPK inhibitor, as an additive to University of Wisconsin (UW) solution in rat liver transplantation. METHODS Rat orthotopic liver transplantation was performed after 30 hr of cold storage using UW solution with or without FR167653. Ten-day survival rates, serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels, liver tissue blood flow, histological findings, and activities of p38 MAPK and p46/p54 c-Jun N-terminal kinase (JNK) in liver grafts were evaluated. RESULTS The addition of FR167653 significantly increased animal survival rates. FR167653 significantly suppressed serum ALT and LDH levels and improved liver tissue blood flow after transplantation. FR167653 also ameliorated histological damage to the liver graft. Neither p38 MAPK nor p46/p54 JNKs was activated during cold storage, whereas both were markedly activated within 30 min of reperfusion and remained activated until 60 min after reperfusion. FR167653 inhibited the activation of p38 MAPK both 30 and 60 min after reperfusion, but it did not affect the activation of p46/p54 JNKs. CONCLUSIONS The addition of FR167653 to UW solution improved liver graft viability and animal survival rates associated with the inhibition of p38 MAPK activation. These results suggest that inhibiting the activation of p38 MAPK may attenuate ischemia/reperfusion injury in liver transplantation.

FR167653 attenuates ischemia and reperfusion injury of the rat lung with suppressing p38 mitogen-activated protein kinase

BACKGROUND FR167653 is a potent suppressant of tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1) production, and was shown to attenuate ischemia and reperfusion (I/R) organ injury in our previous experiment. Because p38 mitogen-activated protein (MAP) kinase has been reported to regulate the production of TNF-alpha and IL-1, we examined the effects of FR167653 in the rat lung I/R model and determined the expression and activation of p38 MAP kinase. METHODS Experiment 1: After 1 hour of ischemia, p38 MAP kinase, phosphorylated p38 MAP kinase (active form), histologic changes of the lung, and serum levels of TNF-alpha and IL-1beta were examined. Experiment 2: After 2 hours of reperfusion, arterial oxygen content (PaO(2)) and saturation (SaO(2)), serum TNF-alpha and IL-1beta levels, and histologic changes in the lung were examined. Rats were divided into three groups in Experiment 1. In the control group, a saline solution was administered and, in the FR group, 0.1 mg/kg per hour of FR167653 was administered, intravenously throughout the experiment, beginning 30 minutes before ischemia. In the non-ischemic group, samples were taken soon after thoracotomy. The rats were divided into control and FR groups in Experiment 2. RESULTS Experiment 1: One hour of ischemia induced almost no changes in the lung or serum cytokine levels. Meanwhile, FR167653 markedly attenuated the expression of phosphorylated p38 MAP kinase. Experiment 2: SaO(2) and PaO(2) were improved, serum cytokines were lower, and lung damage was less extensive in the FR group than in the control group. CONCLUSION FR167653 attenuates I/R injury of the lung and this attenuation is associated with suppression of p38 MAP kinase activation.

Effects of a p38 mitogen-activated protein kinase inhibitor as an additive to Euro-Collins solution on reperfusion injury in canine lung transplantation1.

Background. The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the development of ischemia/reperfusion injury. FR167653 is a novel p38 MAPK inhibitor. This study evaluated the effects of p38 MAPK inhibition during cold ischemia on subsequent reperfusion injury using FR167653 as an additive to Euro-Collins solution in canine lung transplantation. Methods. Canine orthotopic left lung transplantation was performed after 12-hr cold storage using Euro-Collins solution, with or without FR167653. Fifteen minutes after reperfusion, the right pulmonary artery and the right stem bronchus were ligated, and the animals were observed for 4 hr after reperfusion. Left pulmonary vascular resistance (L-PVR), cardiac output (CO), arterial oxygen pressure (Pao2), and alveolar-arterial oxygen pressure difference (A-aDo2) were measured. Lung specimens were harvested for wet-to-dry lung weight ratio (WDR) measurements, histopathologic studies, and polymorphonuclear neutrophil (PMN) counts. The activities of p38 MAPK in lung grafts were evaluated. Results. The addition of FR167653 significantly (P <0.05) improved Pao2, A-aDo2, L-PVR, CO, and WDR and suppressed PMN infiltration after transplantation. FR167653 also ameliorated histologic damage to the lung graft. During cold storage, p38 MAPK was not activated in the lung graft, whereas it was markedly activated 30 min after reperfusion. FR167653 significantly (P <0.05) inhibited p38 MAPK activation 30 min after reperfusion. Conclusions. The addition of FR167653 to Euro-Collins solution improved lung graft viability associated with the inhibition of p38 MAPK activation. These results suggest that inhibiting p38 MAPK activation may attenuate ischemia/reperfusion injury in lung transplantation.

2-Arachidonoylglycerol Increases in Ischemia–Reperfusion Injury of the Rat Liver

Several studies have implicated endocannabinoids in various forms of shock. However, the role of endocannabinoids in hepatic ischemia–reperfusion injury remains unclear. The purpose of this study was to evaluate the changes of two endocannabinoids in hepatic ischemia–reperfusion injury: anandamide (ANA) and 2-arachidonoylglycerol (2-AG). Male Sprague–Dawley rats were divided into 2 groups: the short (15 min) ischemic group and the long (60 min) ischemic group in the segmental (70%) hepatic tissue. Blood levels of aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), ANA, and 2-AG were examined. Serum levels of AST, ALT, and LDH were significantly higher in the long-ischemia group than in the short-ischemia group. Plasma levels of 2-AG showed similar augmentation prior to and after reperfusion in both the short- and long-ischemia groups, although plasma 2-AG levels tended to be higher in the long-ischemia group than in the short-ischemia group. Plasma levels of ANA were augmented in the early phase of reperfusion in the short-ischemia group and did not differ significantly from the normal level with time after reperfusion in the long-ischemia group. These results suggest that the endocannabinoid 2-AG increases in hepatic ischemia–reperfusion injury of rats, rather than ANA.

Three-dimensional computed tomography for analyzing the vascular anatomy in laparoscopic surgery for right-sided colon cancer.

Background: The mesenteric vessels have many branching patterns. This study clarified the anatomic relationship between the superior mesenteric vein (SMV), the right colic artery (RCA), and the ileocolic artery (ICA) using 3-dimensional computed tomography (3D-CT). The relationship between the RCA and the right colic vein (RCV) was also examined. Methods: Between April 2006 and July 2011, all patients with colorectal cancer underwent multidetector computed tomography (MDCT) before laparoscopic surgery. The 100 most recent consecutive cases were analyzed. 3D-CT images were made by combining arterial angiography, venous angiography, colonography, tumor, lymph node, and duodenal images. Results: The RCA branched from the SMA in 37 cases (37%); of these, 21 had an ICA that crossed anterior to the SMV and 16 had an ICA that crossed posterior. When the ICA crossed anterior to the SMV, all had an RCA that crossed anterior to the SMV, and no posterior RCA was seen. Furthermore, the RCV joined the SMV in 10 cases (27%) and the gastrocolic trunk in 27 cases (73%). Conclusions: Our study clarified the anatomic variety of the vessels in right-sided colon cancer. Preoperative 3D-CT is useful for understanding the anatomy to ensure a safe, precise operation.

The Effects of Cyclooxygenase (COX)-2 Inhibition on Ischemia-Reperfusion Injury in Liver Transplantation

Purpose: Our objective was to evaluate whether COX-2 inhibition with FK3311, a selective cyclooxygenase (COX)-2 inhibitor, improves transplanted liver function. Methods: Inbred male Lewis rats weighing 200–260 g were used. The donor liver was perfused with cold University of Wisconsin (UW) solution and then stored in the same solution at 4°C for 18 hr. After the preservation period, orthotopic liver transplantation was performed. Animals were divided into three groups: the control group; the FK low-dose group (1 mg/kg FK3311 i.v. 20 min before reperfusion); and the FK high-dose group (3 mg/kg FK3311 i.v. 20 min before reperfusion). Survival rate, serum GOT and GPT levels, liver tissue blood flow, and serum thromboxane B2 (TxB2) levels were compared among groups. Results: Survival rate was significantly better (p <. 05) and serum GOT levels 30 min after reperfusion were significantly lower (p <. 05) in the FK high-dose group compared to the other two groups. Four hours after reperfusion, GPT levels and liver tissue flow were significantly (p <. 05) better in the FK high-dose group compared to the control. Both 30 min and 4 hr after reperfusion, serum TxB2 levels were significantly lower in the FK high-dose group compared to the control (p <. 05). Conclusion: COX-2 activity results in deteriorated liver function after I/R injury associated with transplantation, and selective COX-2 inhibition improved liver graft function.

NO donor ameliorates ischemia-reperfusion injury of the rat liver with iNOS attenuation.

This study investigated the effect of a spontaneous nitric oxide (NO) donor, FK409 (FK), in a rat model of segmental hepatic ischemia. Rats were allocated to four experimental groups. Two of the groups underwent segmental hepatic ischemia of 60 min duration and received FK (0.4 mg/kg, iv) or vehicle alone before inducing ischemia and again 5 min before reperfusion. Sham-FK and sham groups were treated identically, but did not have vascular occlusion. Serum aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) were measured, and the livers were examined for histological evidence of injury, polymorphonuclear neutrophil (PMN) infiltration, and immunohistochemical expression of inducible NO synthase (iNOS) before and 6 h after reperfusion. AST, ALT, and LDH levels were significantly (p <. 05) reduced 6 h after reperfusion in the FK-treated group compared with the vehicle-treated control group. FK treatment also reduced the degree of hepatic damage apparent on histopathology and reduced PMN infiltration and iNOS expression. Thus, FK treatment is protective against hepatic ischemia reperfusion injury and attenuates neutrophil infiltration and iNOS expression.

Effects of the COX-2 inhibitor FK3311 on ischemia - reperfusion injury in the rat lung.

Ischemia–reperfusion injury is induced by activation of the arachidonic acid cascade following the induction of cyclooxygenase-2. This study evaluated the effects of a selective cyclooxygenase-2 inhibitor, FK3311, on warm ischemia–reperfusion injury in the lung. Male Wistar rats were divided into two groups. In the FK3311 group (n = 27), FK3311 (4 mg/kg) was administered intravenously 5 min before ischemia, while in the control group (n = 27) only vehicle was injected. Warm ischemia was induced for 1 h by clamping the left hilus. The arterial oxygen pressure (PaO2) and saturation (SaO2) were measured 30 and 120 min after reperfusion. Serum thromboxane B2 and 6-keto-prostaglandin F1α were also measured 30 min after reperfusion. Lung specimens were harvested 120 min after reperfusion for histologic examination and polymorphonuclear counts, and immunostained with cyclooxygenase-2. The 1-week survival rate in the two groups was compared. PaO2 and SaO2 30 and 120 min after reperfusion were significantly (p <. 05) better in the FK3311 group. Serum thromboxane B2 levels were significantly (p <. 05) lower in the FK3311 group. However, there was no significant difference in 6-keto-prostaglandin F1α. Histologically, tissue damage was mild and polymorphonuclear infiltration was reduced in the FK3311 group compared to the control group. The expression of cyclooxygenase-2 in the alveolar epithelium based on immunostaining was suppressed in the FK3311 group. The 1-week survival rate was significantly (p <. 05) higher in the FK3311 group. We conclude that FK3311 has protective effects on pulmonary ischemia–reperfusion injury, and results in improvement in the 1-week survival rate.

Laparoscopic resection of a paraganglioma located on the border of the thoracic and abdominal cavities using a transabdominal-transdiaphragmatic approach

We treated a 64‐year‐old woman with high blood pressure. Catecholamine metabolite levels were elevated in the blood and urine. CT revealed a densely stained tumor on the right side of the descending aorta dorsal to the inferior vena cava. PET‐CT revealed abnormal accumulation of 18F‐fluorodeoxyglucose, and 123I‐meta‐iodo‐benzylguanidine uptake was apparent on scintigraphy. The tumor was determined to be a paraganglioma located on the border between the thoracic and abdominal cavities, and laparoscopic tumorectomy was performed. The patient was placed in the left lateral position. The right lobe of the liver was turned over, and we cut the diaphragm to expose the front of the tumor. We resected the straight artery flowing in from the aorta and removed the tumor safely. Herein, we describe the removal of a paravertebral paraganglioma located in the border of the thoracic and abdominal cavities with a laparoscopic transabdominal‐transdiaphragmatic approach.