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EFFECT OF OLPRINONE, A PHOSPHODIESTERASE III INHIBITOR, ON HEPATIC ISCHEMIA-REPERFUSION INJURY IN RATS

Yamaguchi, Keisuke*; Kawahara, Toshiyasu; Kumakura, Seiichiro; Hua, Jian§; Kugimiya, Toyoki*; Nagaoka, Isao§; Inada, Eiichi*

doi: 10.1097/SHK.0b013e3181be3d7a
Basic Science Aspects
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I/R injury is the main cause for hepatic dysfunction and failure after liver transplantation and liver resection. Therefore, reduction of I/R injury is the most important goal to improve the outcome of these procedures. Olprinone is a newly developed selective phosphodiesterase III inhibitor, which has been reported to ameliorate renal I/R injury in rats. However, no clear evidence for the actions of olprinone on inflammatory response after hepatic I/R injury has been disclosed thus far. Our study was designed to evaluate the action of olprinone on the hepatic I/R injury in rats. Olprinone increased the cyclic adenosine monophosphate level in injured liver tissue and ameliorated the liver injury after hepatic I/R. Moreover, olprinone suppressed the activation of p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-κB, cytokine production (TNF-α, IL-6, and cytokine-induced neutrophil chemoattractant factor 1), and intercellular adhesion molecule 1 expression in liver after hepatic I/R. These observations suggest that olprinone protects liver against I/R injury via the elevation of cyclic adenosine monophosphate level and suppression of intercellular adhesion molecule 1 expression and cytokine production (TNF-α, IL-6, and cytokine-induced neutrophil chemoattractant factor 1), possibly by interfering with the signaling pathways of p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-κB in rats.

Departments of *Anesthesiology and Pain Medicine, and Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine; Division of Anesthesiology and Pain Medicine, Juntendo Nerima Hospital; and §Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, Tokyo, Japan

Received 29 May 2009; first review completed 24 Jun 2009; accepted in final form 20 Jul 2009

Address reprint requests to Keisuke Yamaguchi, MD, Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail: keisuke@juntendo.ac.jp.

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INTRODUCTION

Olprinone is a newly developed selective phosphodiesterase (PDE) type III inhibitor with combined positive inotropic and vasodilating properties through the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels in vascular smooth muscle cells and cardiomyocytes by preventing the degradation of cAMP (1). In Japan, this agent is extensively used in the treatment of acute heart failure and myocardial depression after cardiac surgery.

I/R injury is the main cause for primary liver dysfunction and organ failure after liver transplantation (2), liver resection (3), and hemorrhagic shock (4). Although the precise mechanism of I/R injury remains to be defined, it is believed that several mediators such as reactive oxygen species (2), proinflammatory cytokines (5), chemokines (6), adhesion molecules (7), and excess NO contribute to this injury (4, 8, 9). Therefore, pharmacological agents that attenuate the production or expression of these molecules are expected to reduce I/R injury (10).

Recently, it has been observed that activation of A2A-adenosine receptor reduced I/R-induced renal injury by increasing intracellular cAMP and consequently activating protein kinase A (11, 12). Consistent with this, increasing the intracellular cAMP level reduces neutrophil accumulation in I/R-induced renal injury (13). Moreover, amrinone, a PDE III inhibitor, reportedly increases cAMP concentration in the liver and exerts beneficial effects on the hepatic injury after I/R by suppressing neutrophil infiltration, intercellular adhesion molecule 1 (ICAM-1) expression, and platelet aggregation (14), and the protective mechanism is likely to be based on the improvement of hepatic microcirculation during reperfusion via the elevation of cAMP level (14-16). Olprinone has been demonstrated to reduce the I/R-induced acute renal injury in rats by inhibiting leukocyte activation (17). However, no clear mechanism for the action of olprinone on inflammatory response after I/R injury has been disclosed thus far.

Based on the previously discussed background, we hypothesize that olprinone could be useful for relieving the I/R-induced liver injury by suppressing inflammatory response. To test our hypothesis, this study was designed to evaluate the pharmacological action of olprinone on the I/R-induced liver injury in rats by investigating the production of inflammatory cytokines, expression of an adhesion molecule (ICAM-1), and activation of intracellular signaling molecules.

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MATERIALS AND METHODS

Materials

Olprinone was obtained from Eisai Pharmaceutical Co. (Tokyo, Japan). Ethylenediaminetetraacetate was purchased from Sigma Chemical Co. (St. Louis, Mo).

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Animal model of liver I/R

All procedures were performed according to the Institutional Animal Care and Committee Guideline of Juntendo University School of Medicine. Adult male Fisher rats (Charles River Laboratories, Yokohama, Japan) weighing 170 to 200 g were housed in a temperature-controlled (22°C) room with alternating 12-h light/dark cycles and fed standard laboratory food and water ad libitum. The animals were allowed to breathe room air spontaneously.

The animals were divided into three groups: sham group (n = 5), control group without olprinone administration (n = 5), and olprinone group with olprinone administration (n = 5). All rats were anesthetized with light ether inhalation. After the abdomen was shaved and disinfected, a midline incision was made, and rats underwent either sham surgery or I/R. For hepatic ischemia, the portal vein was partially clamped with a noncrushing microvascular clamp, and then the wound was closed with 3-0 silk suture. After 55 min of clamping, 20 μg/kg olprinone and the same volume of saline were administered from testicular vein for the olprinone and control groups as a bolus injection, respectively. A dose of olprinone (20 μg/kg) was determined based on the previous research evaluating the cardioprotective effect of olprinone using animal modes (dogs and rats) (18, 19). After 60 min of partial hepatic ischemia, the clamp was removed to initiate hepatic reperfusion, and then the wound was closed with 3-0 silk suture. The animals were then returned to their cages and allowed free access to food and water.

After 3 h of reperfusion, the animals were anesthetized again. Blood samples were collected from inferior vena cava with EDTA-anticoagulation and centrifuged at 3,000 g for 10 min at 4°C. The plasma samples were then stored at −80°C until use for biochemical analysis. After collecting blood samples, liver specimens were collected. For extracting soluble proteins from liver tissues, the liver samples were weighed and homogenized with phosphate-buffered saline (137 mM NaCl, 2.7 mM KCl, 8.1 mM Na2HPO4, 1.5 mM KH2PO4, pH 7.4) using a BioMasher tissue homogenizer (Cartagen Molecular Systems, Seattle, Wash) for 60 s at 100 g. After centrifugation, the extracted protein was collected and then stored at −80°C until use after the quantification of protein contents using a protein assay kit (Bio-Rad Laboratories, Hercules, Calif) according to the manufacturer's instruction.

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Measurement of liver enzymes

Concentrations of plasma aspirate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) were determined with a Spot Chem kit (Spotchem Co., Kyoto, Japan) (20).

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Measurement of cAMP in liver tissue and plasma

For measuring cAMP levels, plasma and liver extracted protein were analyzed with a cAMP assay kit (R&D Systems, Minneapolis, Minn). Cyclic adenosine monophosphate levels in plasma and liver tissue were expressed as picomoles of cAMP per milliliter and per milligram tissue, respectively.

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Measurement of cytokines in liver tissue and plasma

For measuring cytokine levels, plasma and liver extracted protein were analyzed by a sandwich enzyme-linked immunosorbent assay (ELISA) with a Ready-Set-Go ELISA set for TNF-α (eBioscience, San Diego, Calif) and DuoSet ELISA Development kits (R&D Systems) for IL-6 and cytokine-induced neutrophil chemoattractant factor 1 (CINC-1; CXC chemokine family). Cytokine levels were expressed as picograms of cytokines per milliliter or per milligram tissue.

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Western blotting

Western blot analysis was performed as described previously (21). In brief, liver extracted protein (30 μg) was electrophoresed on a 10% sodium dodecyl sulfate-polyacrylamide gel and then transferred to a Immobilon-P polyvinylidene difluoride membrane (Millipore Corporation, Bedford, Mass). Phosphorylated p38 mitogen-activated protein kinase (MAPK), phosphorylated JNK, Iκ-B, and ICAM-1 were detected using mouse antiphosphorylated p38 MAPK monoclonal antibody (pT180/pY182; BD Biosciences Pharmingen, San Diego, Calif), rabbit antiphosphorylated JNK antibody (T183/Y185; Cell Signaling Technology, Danvers, Mass), rabbit anti-IκB-α antibody (Cell Signaling), and goat anti-ICAM-1 antibody (M-19; Santa Cruz Biotechnology, Santa Cruz, Calif), respectively. Furthermore, to confirm that equal amounts of proteins were analyzed in each sample, p38 MAPK protein was detected as a loading control by using mouse anti-p38 MAPK monoclonal antibody (p38/SAPK2α; BD Biosciences Pharmingen).

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Histopathological examination of liver tissue

After 3 h of reperfusion, liver specimens were collected and fixed in 10% formalin. The tissues were dehydrated, embedded in paraffin, cut into 5-μm section, and mounted. After deparaffinization, the tissues were stained with hematoxylin and eosin for histological study. To investigate the accumulation of polymorphonuclear cells (neutrophils) in the liver, the tissues were stained with naphthol AS-D chloroacetaste esterase (Sigma) (22).

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Statistical analysis

Data are expressed as mean ± SD. Statistical analyses were performed using unpaired t test or one-way ANOVA (Prism, Graphpad Software, Inc., San Diego, Calif). A P value less than 0.05 was considered statistically significant.

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RESULTS

Effect of olprinone on the cAMP levels in the I/R-induced hepatic injury

Olprinone has been demonstrated to elevate cAMP level in vascular smooth muscle cells and cardiomyocytes (1). To investigate the effect of olprinone on I/R-induced hepatic injury, we measured the cAMP concentrations in hepatic tissue and plasma after 3 h of reperfusion. As shown in Figure 1, the reduced level of cAMP in hepatic tissue after I/R was significantly elevated by olprinone administration (control versus olprinone; P < 0.05). In contrast, there were no statistical differences in plasma cAMP levels among sham-operated, control, and olprinone groups after 3 h of reperfusion (Fig. 1).

Fig. 1

Fig. 1

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Effect of olprinone on the I/R-induced liver dysfunction

To test the effect of olprinone on the I/R-induced hepatic dysfunction, we measured AST, ALT, and LDH in plasma. As shown in Figure 2, olprinone significantly suppressed the elevation of AST, ALT, and LDH after 3 h of reperfusion (control versus olprinone; P < 0.05), suggesting that olprinone exerts a protective action on I/R injury. Furthermore, the suppressive effect of olprinone on AST, ALT, and LDH levels was observed even after 24 h of reperfusion (data not shown).

Fig. 2

Fig. 2

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Effect of olprinone on the I/R-induced cytokine levels in liver tissue

It is thought that several mediators, proinflammatory cytokines (5), and chemokines (7) contribute to I/R injury. To elucidate the mechanism for the protective action of olprinone on I/R hepatic injury, we measured TNF-α, IL-6, and CINC-1 in hepatic tissue after 3 h of reperfusion. As shown in Figure 3, the levels of TNF-α, IL-6, and CINC-1 were significantly reduced by olprinone administration (control versus olprinone; P < 0.05).

Fig. 3

Fig. 3

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Effect of olprinone on I/R-induced ICAM-1 expression in liver tissue

It has been reported that cell adhesion molecules play a crucial role in I/R injury by mediating the interaction of neutrophils with endothelium (23, 24), and a PDE III inhibitor (amrinone) suppresses ICAM-1 expression in the liver injury after hepatic I/R (14). To confirm the effect of olprinone on ICAM-1 expression in the liver injury, we evaluated the ICAM-1 expression in hepatic tissue after 3 h of reperfusion by Western blotting. As shown in Figure 4, the increased expression of ICAM-1 was suppressed by olprinone in the liver after 3 h of reperfusion.

Fig. 4

Fig. 4

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Effect of olprinone on I/R-induced activation of p38 MAPK and JNK

p38 MAPK, JNK, and nuclear factor-κB (NF-κB) are reported to be activated by a variety of cellular stresses such as inflammatory cytokines, LPS, heat shock, osmotic stress, and I/R injury. In particular, activation of p38 MAPK and JNK pathways has been implicated in the generation of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8 (25, 26). To clarify the mechanism for the action of olprinone, we investigated the activation of p38 MAPK and JNK in liver tissue by Western blot analysis. As shown in Figure 4, olprinone suppressed the I/R-induced activation (phosphorylation) of p38 MAPK and JNK in the liver after 3 h of reperfusion. Moreover, olprinone inhibited the activation of NF-κB, as assessed by the degradation of IκB, an NF-κB inhibitor (Fig. 4).

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Effects of olprinone on the I/R-induced histopathological changes

Histopathologically, widespread areas of coagulative hepatic necrosis with polymorphonuclear cell (neutrophil) infiltration were observed in the live specimens from rats with hepatic I/R (Fig. 5, A and C). In contrast, olprinone treatment obviously repressed the I/R-induced pathological changes, and the liver tissue was less damaged in the olprinone group compared with that in the control group (Figs. 5, B and D).

Fig. 5

Fig. 5

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DISCUSSION

In the present study, we tried to evaluate the effect of olprinone, a newly developed PDE III inhibitor, on hepatic I/R injury in rats.

The results indicated that olprinone up-regulated cAMP in injured liver tissue, suppressed the elevation of plasma AST, ALT, and LDH, and reduced the hepatic tissue damage after 3 h of reperfusion in hepatic I/R rats. Moreover, olprinone repressed the activation of p38 MAPK, JNK, and NF-κB, cytokine production (TNF-α, IL-6, and CINC-1), and ICAM-1 expression in the injured liver.

Hepatic I/R injury often occurs in the setting of hepatic resectional surgery, transplantation, and hemorrhagic shock, and may lead to local and remote organ failure with significant rates of morbidity and mortality (2-4). During the initial stages of reperfusion, Kupffer cells are activated and release a large amount of inflammatory cytokines such as TNF-α and IL-6, which is associated with ischemic damage and lack of tissue protection (27). Furthermore, in hepatic I/R injury, CINC-1, which belongs to the IL-8 superfamily, a potent neutrophil chemoattractant in rats (28), is produced by activated Kupffer cells (29). In this study, TNF-α, IL-6, and CINC-1 production was suppressed in the rat liver with hepatic I/R injury by olprinone. Thus, these observations suggest that olprinone may exert an anti-inflammatory action in a rat liver I/R model by suppressing the production of inflammatory mediator such as TNF-α, IL-6, and CINC-1.

Moreover, ICAM-1 is one of the adhesion molecules that is present at low levels on endothelial cells (30) and up-regulated by inflammation and I/R injury (31). Blocking the ICAM-1 adhesion receptors with monoclonal antibody has been shown to protect the liver against I/R injury (32, 33). Kobayashi et al. (14) showed that the expression of ICAM-1 mRNA and protein in the injured liver was suppressed in rats by amrinone, another type of PDE III inhibitor. Consistent with this, our results revealed that olprinone suppressed ICAM-1 expression in rats with liver I/R injury. In addition, during reperfusion, neutrophils are activated by TNF-α and migrated toward IL-8, adhering to the vascular endothelium with ICAM-1 receptor to release various inflammatory mediators, such as neutrophil elastase and reactive oxygen species, and damage endothelial cells and increase hepatic vascular permeability (6). In this study, we found that olprinone administration suppressed the neutrophil infiltration into the liver. Together, these observations suggest that olprinone may attenuate the activation, adhesion, and migration of neutrophils in rat I/R liver by suppressing TNF-α, IL-6, CINC-1, and ICAM-1 expression.

Mitogen-activated protein kinase family members are activated by phosphorylation in response to extracellular stimuli. Once phosphorylated, these kinases are translocated to the nucleus, where they phosphorylate and activate different transcription factors such as NF-κB. Furthermore, NF-κB regulates the production of inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8 in I/R tissues, suggesting that MAPKs and NF-κB play a crucial role in inflammatory responses during I/R injury (6). Among these, p38 MAPK and JNK are reported to be activated by a variety of cellular stresses such as I/R injury (34-36). The inhibition of p38 MAPK suppresses the I/R-induced apoptosis of cardiomyocyte and myocardial neutrophil accumulation and improves the cardiac function in a rabbit myocardial I/R model (37, 38). Similarly, the inhibition of JNK represses the cardiomyocyte apoptosis and infarct size after myocardial I/R in anesthetized rats and improves I/R injury in rat lungs (39, 40). Moreover, TNF-α activates NF-κB in rat liver by rapidly degrading IκB (an inhibitor of NF-κB), which prevents the translocation of NF-κB from cytoplasm to nucleus (41, 42). In our rat I/R model, we revealed that the activation of p38 MAPK, JNK, and NF-κB (assessed by the suppression of IκB degradation) and production of TNF-α, IL-6, and CINC-1 were inhibited by olprinone. Thus, these observations likely suggest that olprinone interferes with p38 MAPK, JNK, and NF-κB signaling pathways, thereby suppressing the production of inflammatory cytokines (TNF-α, IL-6, and CINC-1).

Production of TNF-α by Kupffer cells after I/R has long been thought to be the initiating event for primarily propagating hepatic inflammatory response (43). The precise mechanism by which olprinone reduces I/R-induced TNF-α production is unknown at present. However, it has been shown that dibutyryl cAMP, a cAMP analog, enhances the tissue cAMP concentration in a renal I/R model and reduces the I/R-induced TNF-α up-regulation in renal tissue. Moreover, Meng et al. (44) demonstrated that the elevation of cellular cAMP either by promotion of generation or by inhibition of degradation suppressed LPS-induced TNF-α production in vitro. Consistent with the previously mentioned studies, olprinone up-regulates cAMP level and reduces TNF-α production in our hepatic I/R model, indicating that olprinone enhances cAMP levels in hepatic I/R injury rats as a PDE III inhibitor, thereby reducing the I/R-induced TNF-α production. In addition, TNF-α has been reported to strongly activate p38 MAPK and JNK in vitro (36-38), and the blockade of TNF-α reduces NF-κB activation, ICAM-1 up-regulation, and myocardial injury in an in vivo canine I/R model (45). In the present study, we revealed that the activation of p38 MAPK, JNK, and NF-κB after hepatic I/R injury was inhibited by olprinone. Thus, the protective effect of olprinone on I/R injury seems to be partly explained by the up-regulation of cAMP in the liver, which consequently suppresses the production of TNF-α- and TNF-α-induced activation of p38 MAPK, JNK, and NF-κB.

Several limitations of this study should be noted. First, we studied only a single dose of olprinone because the cardioprotective effect of olprinone was originally evaluated using animal modes (dogs and rats) at a dose of 20 μg/kg (18, 19). Thus, in the present study, we administered the same dose of olprinone (20 μg/kg) into rats to examine the effect of olprinone on the hepatic I/R injury. It is unfortunate that we could not present the dose-response curve of olprinone for hepatocellular protection. Second, we did not directly compare the effects of olprinone with older PDE inhibitors such as milrinone or amrinone, which are widely used in clinical medicine outside of Japan. Among PDE III inhibitors, milrinone reportedly exhibits the liver protection after I/R injury in rats (46), and amrinone suppresses hepatic I/R injury in rats (14). Moreover, olprinone, a newly developed PDE III inhibitor, has been shown to improve the hepatosplanchnic blood flow more significantly after cardiac surgery compared with other PDE III inhibitor such as amrinone and milrinon, thus being beneficial in protecting the hapatosplanchnic organs (47). However, we could not provide the direct data supporting this contention.

In conclusion, olprinone increased the cAMP level and suppressed the ICAM-1 expression in injured liver tissue, accompanied with the decreased liver injury in hepatic I/R rats. Moreover, olprinone repressed cytokine production (TNF-α, IL-6, and CINC-1) in the liver injury, possibly by inhibition of the activation of p38 MAPK, JNK, and/or NF-κB signaling pathways, and exhibited the protective action on the hepatic I/R injury. Thus, olprinone is expected to have potential to clinically prevent and treat I/R injury, which is associated with liver dysfunction and organ failure after liver transplantation, liver resection, and hemorrhagic shock. However, the clinical effect of olprinone on I/R injury should be cautiously evaluated in the future.

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Keywords:

Phosphodiesterase inhibitor; cyclic adenosine monophosphate; I/R injury; liver; cytokine; adhesion molecule; p38 mitogen-activated protein kinase; c-Jun N-terminal kinase

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