Ischemic Preconditioning Group Research Articles

Protective effect of ischemia preconditioning on ischemia-reperfusion injury in rat liver transplantation.

We explored the protective effect of ischemia preconditioning (IP) on ischemia-reperfusion injury in rat liver transplantation. An orthotopic liver transplantation model was utilized in the study. A total of 54 Sprague-Dawley rats were divided into a control group (group A, no liver transplantation), liver transplantation group (group B, heparin Ringer's lactate solution was perfused via the portal vein before donor liver collection), and liver transplantation with IP group (group C, IP was performed for different time periods before donor liver collection). Liver function, B-cell lymphoma 2 expression in hepatic cells, cell apoptosis, and cellular ultrastructure changes were detected after surgery. After surgery, serum alanine aminotransferase activity was significantly higher in group B than in group A, while it was not clearly enhanced in group C and decreased progressively with increasing cycles of IP as bile capacity gradually increased. Compared with group B, group C showed alleviated injury of hepatic cells, increased B-cell lymphoma 2 expression, and a lower apoptosis index. IP had a protective effect on ischemia-reperfusion injury in rat liver transplantation, and the mechanism correlated with increased B-cell lymphoma 2 expression in hepatic cells and inhibition of cell apoptosis.

Ischemic preconditioning ameliorates intestinal injury induced by ischemia-reperfusion in rats.

To evaluate preventative effects of ischemic preconditioning (IP) in a rat model of intestinal injury induced by ischemia-reperfusion (IR). Male Sprague-Dawley rats (250-300 g) were fasted for 24 h with free access to water prior to the operation. Eighteen rats were randomly divided into three experimental groups: S group (n = 6), rats were subjected to isolation of the superior mesenteric artery (SMA) for 40 min, then the abdomen was closed; IR group (n = 6), rats were subjected to clamping the SMA 40 min, and the abdomen was closed followed by a 4-h reperfusion; IP group (n = 6) rats underwent three cycles of 5 min ischemia and 5 min reperfusion, then clamping of the SMA for 40 min, then the abdomen was closed and a 4-h reperfusion followed. All animals were euthanized by barbiturate overdose (150 mg/kg pentobarbital sodium, i.v.) for tissue collection, and the SMA was isolated via median abdominal incision. Intestinal histologic injury was observed. Malondialdehyde (MDA), myeloperoxidase (MPO) and tumor necrosis factor (TNF)-α concentrations in intestinal tissue were measured. Intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression, as well as nuclear factor (NF)-κB activity and expression in intestinal tissue were also determined. Compared with the IR group, IP reduced IR-induced histologic injury of the intestine in rats (2.00 ± 0.71 vs 3.60 ± 0.84, P < 0.05). IP significantly inhibited the increase in MDA content (5.6 ± 0.15 μmol/L vs 6.84 ± 0.18 μmol/L, P < 0.01), MPO activity (0.13 ± 0.01 U/L vs 0.24 ± 0.01 U/L, P < 0.01), and TNF-α levels (7.79 ± 2.35 pg/mL vs 10.87 ± 2.48 pg/mL, P < 0.05) in the intestinal tissue of rats. IP also markedly ameliorated the increase in ICAM-1 (204.67 ± 53.27 vs 353.33 ± 45.19, P < 0.05) and VCAM-1 (256.67 ± 58.59 vs 377.33 ± 41.42, P < 0.05) protein expression in the intestinal tissues. Additionally, IP remarkably decreased NF-κB activity (0.48 ± 0.16 vs 0.76 ± 0.22, P < 0.05) and protein expression (320.23 ± 38.16 vs 520.76 ± 40.53, P < 0.01) in rat intestinal tissue. IP may protect against IR-induced intestinal injury by attenuation of the neutrophil-endothelial adhesion cascade via reducing ICAM-1 and VCAM-1 expression and TNF-α-induced NF-κB signaling pathway activity.

Ischemic preconditioning protects hippocampal pyramidal neurons from transient ischemic injury via the attenuation of oxidative damage through upregulating heme oxygenase-1

Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic injury by activating specific mechanisms. In this study, we tested the hypothesis that IPC attenuates postischemic neuronal death via heme oxygenase-1 (HO-1). Animals used in this study were randomly assigned to 4 groups; sham-operated group, ischemia-operated group, IPC plus (+) sham-operated group and IPC+ischemia-operated group. IPC was induced by subjecting gerbils to 2min of ischemia followed by 1 day of recovery. A significant loss of neurons was observed in pyramidal neurons of the hippocampal CA1 region (CA1) in the ischemia-operated groups at 5 days postischemia. In the IPC+ischemia-operated groups, CA1 pyramidal neurons were well protected. The level of HO-1 protein and its activity increased significantly in the CA1 of the IPC+sham-operated group, and the level and activity was maintained in all the time after ischemia–reperfusion compared with the ischemia-operated groups. HO-1 immunoreactivity was induced in the CA1 pyramidal neurons in both IPC+sham-operated- and IPC+ischemia-operated groups. We also found that levels or immunoreactivities of superoxide anion, 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal were significantly decreased in the CA1 of both IPC+sham-operated- and IPC+ischemia-operated groups. Whereas, treatment with zinc protoporphyrin IX (a HO-1 inhibitor) into the IPC+ischemia-operated groups did not preserve the IPC-mediated increase of HO-1 and lost beneficial effects of IPC by inhibiting ischemia-induced DNA damage and lipid peroxidation. In brief, IPC protects CA1 pyramidal neurons from ischemic injury by upregulating HO-1, and we suggest that the enhancement of HO-1 expression by IPC may be a legitimate strategy for a therapeutic intervention of cerebral ischemic damage.

Effect of ischemia preconditioning and leech therapy on cutaneous pedicle flaps subjected to prolonged ischemia in a mouse model.

We sought to determine the effect of ischemic preconditioning (IPC) and hirudotherapy (leech therapy) on cutaneous pedicle flaps after they underwent prolonged ischemia (global ischemia) in a mouse model. Twenty cutaneous pedicle flaps were elevated in 20 mice, and the animals were randomized into four groups: sham, control, IPC and leech (5 flaps in each group). Except in the sham group, all flaps were subjected to global ischemia for 5 h via pedicle clamping. The control group did not receive any treatment before or after global ischemia. In the IPC group, global ischemia was preceded by three 10-min episodes of ischemia, each followed by 10 min of reperfusion. In the leech therapy group, after global ischemia, hirudotherapy was performed. Flap survival area and histopathological changes were evaluated on the 10th day after surgery. Flap survival areas were significantly higher in both the IPC and leech groups than in the control group and were significantly higher in the leech group than in the IPC group (p < 0.05). In conclusion IPC and hirudotherapy had definite effects on the survival area of cutaneous pedicle flaps that underwent prolonged ischemia in a mouse model.

Ischemic preconditioning reduces the severity of ischemia-reperfusion injury of peripheral nerve in rats

Background and aimAllow for protection of briefly ischemic tissues against the harmful effects of subsequent prolonged ischemia is a phenomennon called as Ischemic Preconditioning (IP). IP has not been studied in ischemia-reperfusion (I/R) model of peripheral nerve before. We aimed to study the effects of acute IP on I/R injury of peripheral nerve in rats.Method70 adult male rats were randomly divided into 5 groups in part 1 experimentation and 3 groups in part 2 experimentation. A rat model of severe nerve ischemia which was produced by tying iliac arteries and all idenfiable anastomotic vessels with a silk suture (6-0) was used to study the effects of I/R and IP on nerve biochemistry. The suture technique used was a slip-knot technique for rapid release at time of reperfusion in the study. Cytoplasmic vacuolar degeneration was also histopathologically evaluated by light microscopic examination in sciatic nerves of rats at 7th day in part 2 study.Results3 hours of Reperfusion resulted in an increase in nerve malondialdehyde levels when compared with ischemia and non-ischemia groups (p < 0.001 and p < 0.0001 respectively). IP had significantly lower nerve MDA levels than 3 h reperfusion group (p < 0.001). The differences between ischemic, IP and non-ischemic control groups were not significant (p > 0.05). There was also a significant decrease in vacoular degeneration of sciatic nerves in IP group than I/R group (p < 0.05).ConclusionIP reduces the severity of I/R injury in peripheral nerve as shown by reduced tissue MDA levels at 3 th hour of reperfusion and axonal vacoulization at 7 th postischemic day.

Cardiac Effect of Ischemic Preconditioning and Heparin Following Intestinal Ischemia and Reperfusion in Rats

To study the role of heparin and ischemic preconditioning (IPC) in cardiac injury after intestinal ischemia (I) and reperfusion (R), 54 rats underwent 60 minutes of I, which was produced by occlusion of the superior mesenteric artery, and/or 120 minutes of R. The IPC group had the I procedure stimulation for 5 minutes and R for 10 minutes. The control group was subjected to sham surgery only, and the other groups were injected with saline solution (SS; 0.1 mL) or heparin (100 IU/kg) via the inferior cava vein 5 minutes before I and 5 minutes before R and 55 minutes after the R begins in I-R groups. In all animals, cardiac samples were stained with hematoxylin and eosin for optical microscopy analysis, and other sample was processed for lipid peroxidation determination. In I-R groups, both heparin and IPC showed significant protection compared to the SS group; conversely, in animals subjected only to I, no protection was observed. Moreover, when heparin was associated with IPC, I-R protection was compromised and the ischemic injury increased. Data showed that IPC and heparin attenuated cardiac dysfunction caused by intestinal I and I-R, but when used in association did not show beneficial effects.

Effect of lung ischemic preconditioning on expression of aquaporin-1 during lung ischemia-reperfusion induced by cardiopulmonary bypass in dogs

Objective To investigate the effect of lung ischemic preconditioning (IP) on the expression of aquaporin-1 (AQP1) during lung ischemia-reperfusion (I/R) induced by cardiopulmonary bypass (CPB) in dogs.Methods Twelve adult mongrel dogs,weighing 15-20 kg,were randomly divided into 2 groups (n =6 each):lung I/R (group I/R) and ischemic preconditioning group (group IP).The left pulmonary artery was occluded at 10 min of off-pump CPB and mechanical ventilation was stopped in the left lung,60 min later occlusion was released,and mechanical ventilation was recovered to establish the model of left lung ischemia-reperfusion injury induced by CPB.In group IP,lung ischemic preconditioning was induced by 2 cycles of 5 min ischemia followed by 5 min reperfusion before occlusion of the left pulmonary artery.Before CPB (T1),immediately after occlusion of the left pulmonary artery (T2),at the end of CPB (T3),and at 2 h after the end of CPB (T4),pulmonary specimens were collected for determination of wet to dry lung weight ratio (W/D ratio) and expression of AQP1 and for examination of the pathological changes of lungs which were scored.Respiration index (RI),oxygenation index (OI),and alveolar-arterial oxygen tension difference (P(A-a)O2) were calculated at T1,T3 and T4,and the left pulmonary alveolar fluid clearance (AFC) was calculated at T4.Results Compared with group I/R,P(A-a) O2 and RI were significantly decreased,OI was increased,W/D ratio and pathological scores were decreased,the expression of AQP1 was up-regulated,and the AFC was increased at T3 and T4 in group IP.The pathological changes of the lung were significantly attenuated in group IP as compared with group I/R.Conclusion The mechanism by which lung ischemic preconditioning mitigates lung I/R injury induced by CPB is related to upregulation of the expression of AQP1 in dog lung tissues. Key words: Ischemic preconditioning; Cardiopulmonary bypass ; Reperfusion injury ; Lung ; Aquaporin 1

Conditioning techniques and ischemic reperfusion injury in relation to on-pump cardiac surgery

Objectives. The objective was to investigate the potential protective effects of two conditioning methods, on myocardial ischemic and reperfusion injury in relation to cardiac surgery. Design. Totally 68 patients were randomly assigned to either a control group (n = 23), a remote ischemic preconditioning (RIPC) group (n = 23) or a glucagon-like peptide-1 (GLP-1) analogue group (n = 22). The RIPC protocol consisted of three cycles of upper limb ischemia. The GLP-1 analogue protocol consisted of intravenous infusion with exenatide. The primary endpoint was postoperative cardiac enzyme release. The other secondary endpoints were metabolic parameters related to myocardial ischemia, measured using microdialysis technique, as well as other operative- and postoperative data. Results. Postoperative cardiac enzyme release indicated a possible beneficial effect of the interventions, but the difference did not reach statistical significance. RIPC showed a trend toward lower levels (p = 0.07). We managed to establish a functional myocardial microdialysis model, but we were unable to demonstrate clear protective effects. Conclusions. We were in this prospective randomized proof-of-concept trial, unable to show distinct protective effects of the studied conditioning methods. However, this trial can hopefully contribute to generate a productive discussion concerning limitations and future use of cardiac conditioning as well as microdialysis technique.

Pivotal role of mast cell carboxypeptidase A in mediating protection against small intestinal ischemia–reperfusion injury in rats after ischemic preconditioning

Aim of the studyMast cell (MC) degranulation contributes to the protection mediated by ischemic preconditioning (IPC); however, the precise mechanisms underlying this protection remain largely unknown. Mast cell carboxypeptidase A (MC-CPA) is released solely from MCs and plays a critical role in degrading toxins and endothelin 1 (ET-1). The present study sought to explore whether MC-CPA is involved in the process of IPC in a rodent model of small intestinal ischemia reperfusion (IIR) injury. Materials and methodsIIR injuries were induced in Sprague–Dawley rats by clamping the superior mesenteric artery for 60 min followed by reperfusion for 2 h. One cycle of 10 min intestinal ischemia and 10 min of reperfusion was used in the IPC group, and the MC stabilizer cromolyn sodium and MC potato carboxypeptidase inhibitor were administered before the start of IPC. At the end of experiment, intestine tissue was obtained for assays of the MC-CPA3, tumor necrosis factor-α, interleukin-6, and ET-1 contents and myeloperoxidase activities. Intestinal histologic injury scores and MC degranulation were assessed. Apoptosis indices and cleaved caspase- 3 protein expressions were quantified. ResultsIIR resulted in severe injury, as evidenced by significant increases in injury scores and MC-CPA3, tumor necrosis factor-α, interleukin-6, and ET-1 contents that were accompanied with concomitant elevations in cleaved caspase 3 expression, apoptosis indices, and myeloperoxidase activities. IPC induced a significant increase in MC-CPA3, induced MC degranulation, and attenuated IIR injury by downregulating IIR-induced biochemical changes, whereas cromolyn sodium and potato carboxypeptidase inhibitor abolished the IPC-mediated changes. ConclusionsThese data suggest that IPC protected against IIR injury via the MC degranulation-mediated release of MC-CPA.

Effect of ischemic preconditioning on expression of intracellular adhesion molecule-1 in brain tissues following traumatic brain injury in rats

Objective To investigate the effect of ischemic preconditioning (IPC) on expression of intracellular adhesion molecule-1 (ICAM-1) in brain tissues following traumatic brain injury (TBI) in rats.Methods Sixty male SD rats weighing 220-250 g were randomly divided into three groups (n =20 for each):sham operation group,TBI group,and IPC group.Cerebral IPC models were induced by transient occlusion of the bilateral common carotid arteries; TBI models were induced by Feeney's freefalling method; rats in sham operation group were only performed exposure of dura of the right parietal lobe.Ten rats were sacrificed respectively at 6 and 72 hours after TBI and injured brain tissues were harvested to estimate wet/dry weight (W/D) ratio for the brain,determine ICAM-1 expression by immunohistochemistry and perform microscopic examination.Results Brain W/D ratio was significantly increased in TBI group compared with sham operation group (6 h:4.2 ± 0.4 vs 2.7 ± 0.4 ; 72 h:5.0 ±0.1 vs 3.1 ± 0.2,P ＜ 0.05).ICAM-1 expression was up-regulated in TBI group compared with sham operationgroup (6h:25.4±3.5vs8.6±1.3; 72 h:36.5±5.4 vs8.4±1.6,P＜0.05).W/D ratio was significantly decreased in IPC group compared with TBI group (6 h:3.5 ±0.6 vs 4.2 ±0.4; 72 h:3.7 ± 0.4 vs 5.0 ± 0.1,P ＜ 0.05).ICAM-1 expression was down-regulated in IPC group compared with TBI group (6 h:16.5 ± 2.7 vs 25.4 ± 3.5 ; 72 h:24.3 ± 4.6 vs 36.5 ± 5.4,P ＜ 0.05).Milder injury to brain tissues was observed in IPC group than in TBI group.Conclusion IPC can attenuate TBI in rats by down-regulating the expression of ICAM-1. Key words: Brain injuries; Ischemic preconditioning; Cell adhesion molecules

Ischemic preconditioning provides no additive clinical value in liver resection of cirrhotic and non-cirrhotic patients under portal triad clamping: A prospective randomized controlled trial

The clinical value of ischemic preconditioning (IP) on patients undergoing hepatectomy under portal triad clamping (PTC) is uncertain, especially for patients with liver cirrhosis. Hence, we conducted a prospective randomized controlled trial to test whether IP could protect liver against ischemic reperfusion (IR) injury after hepatectomy under PTC. One hundred patients, including 67 with cirrhosis, undergoing hepatectomy with PTC were randomly divided into IP and control groups. Liver function tests at postoperative days 1, 3, and 7 as well as postoperative morbidity, mortality, and duration of hospitalization were compared between the two groups. The general clinical characteristics between both groups were comparable. The duration of the operation, the amount of intraoperative blood loss, and the need and amount of perioperative blood transfusion were similar in both groups. The postoperative levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and albumin were not statistically different between the two groups. In addition, the morbidity and mortality rates and the duration of hospitalization were similar in both groups. IP did not improve liver tolerance to IR injury after hepatectomy under PTC. Therefore, the clinical use of IP cannot be recommended as a standard procedure before PTC.

Ischemic versus pharmacologic hepatic preconditioning

BackgroundHepatic ischemia–reperfusion injury has a significant impact on liver resection and transplantation. Many strategies have been developed to reduce the effects of ischemia–reperfusion injury, including pharmacologic and ischemic preconditioning; however, studies comparing these two methods are lacking. Material and methodsAn experimental study was performed in a swine model. Eighteen swine were randomly assigned to three different groups: an ischemic preconditioning (IschPC) group, a pharmacologic preconditioning (PharmPC) group, and a control group. All animals underwent a 40-min liver ischemia, followed by 40 min of reperfusion. The IschPC group received a short period of ischemia (10 min) and a short period of reperfusion (15 min) before prolonged ischemia. The PharmPC group received inhaled sevoflurane for 30 min before prolonged ischemia. The control group did not receive any intervention before prolonged ischemia. Blood samples and liver tissue were obtained after ischemic and reperfusion periods. Injury was evaluated by measure of DNA damage (using COMET assay) and serum biochemical markers (transaminases, alkaline phosphatase, amylase, bilirubin, and C-reactive protein [CRP]). ResultsNo significant difference was found in serum biochemical markers, except for the C-reactive protein level that was lower in the PharmPC group than in the control group soon after hepatic ischemia. Soon after prolonged ischemia, DNA damage index, both in blood samples and in liver tissue samples, was similar among the groups. However, an increase in DNA damage after reperfusion was higher in the control group than in the PharmPC group (P < 0.05). The increase in DNA damage in the IschPC group was half of that observed in the control, but this difference was not statistically significant. ConclusionsOur results suggest an early protective effect of PharmPC (lower levels of C-reactive protein soon after ischemia). The protective effect observed after reperfusion was higher with PharmPC than with ischemic preconditioning. The simultaneous use of both methods could potentiate protection for ischemia–reperfusion.

Effect of One-Cycle Remote Ischemic Preconditioning to Reduce Myocardial Injury During Percutaneous Coronary Intervention

Up to 1/3 of percutaneous coronary interventions (PCIs) are complicated by troponin release. Remote ischemic preconditioning (IPC) confers effective cardioprotection; however, a 30-minute remote IPC protocol may be difficult to implement during ad hoc PCI. This study was performed to assess the ability of a brief remote IPC protocol to attenuate cardiac troponin I (cTnI) release after ad hoc PCI. Ninety-four patients undergoing ad hoc PCI for stable coronary artery disease, with undetectable preprocedural cTnI, were recruited and randomized to receive remote IPC (induced by one 5-minute inflation of a blood pressure cuff to 200 mm Hg around the upper arm) or control after the decision for PCI was made. The primary outcome was the difference between cTnI levels 24 hours after PCI and cTnI levels before coronary angiography (ΔcTnI). ΔcTnI in the remote IPC group was significantly lower compared with the control group (0.04 ng/ml [interquartile range 0.01 to 0.14] vs 0.19 ng/ml [interquartile range 0.18 to 0.59], p <0.001). The incidence of PCI-related myocardial infarction (MI) was greater in the control group (42.6% vs 19.1%, p = 0.014). In multivariate analysis, remote IPC was independently associated with ΔcTnI and PCI-related MI. In conclusion, our results suggest that even 1 cycle of remote IPC immediately before ad hoc PCI attenuates periprocedural cTnI release and reduces the incidence of type 4a MI.

Role of protein kinase C in reduction of mitochondrial injury during myocardial ischemia-reperfusion by ischemic preconditioning in rats

Objective To evaluate the role of protein kinase C （PKC ） in reduction of mitochondrial injury during myocardial ischemia-reperfusion （I/R） by ischemic preconditioning in rats .Methods Forty male Sprague-Dawley rats ,aged 12-13 weeks ,weighing 280-320 g ,were randomly divided into 4 groups （ n=10 each） using a random number table：sham operation group （S group） ,I/R group ,ischemic preconditioning group （IP group） and PKC inhibitor chelerythrine group （C group） .Myocardial I/R was produced by 35 min occlusion of left anterior descending branch of coronary artery followed by 120 min reperfusion .Ischemic preconditioning was induced by 3 episodes of 5 min occlusion of left anterior descending branch at 5 min intervals before myocardial ischemia . Chelerythrine 1 mg/kg was injected intravenously via the caudal vein before ischemic preconditioning in group C . At 120 min of reperfusion ,the animals were sacrificed and the hearts were immediately removed .Mitochondrial suspension was prepared for determination of activities of succinate dehydrogenase （SDH ） , xanthine oxidase （XOD ） , glutathione peroxidase （GSH-Px ） and Ca2＋-ATPase , content of Ca2＋ , myocardial mitochonerial permeability transition pore （mPTP） opening and membrane potential （Δψm ） .Results Compared with S group , the activities of XOD and Ca2＋-ATPase ,content of Ca2＋ and mPTP opening were significantly increased ,and the＆nbsp;activities of SDH and GSH-Px and Δψm were decreased in I/R group （ P〈0.05） .Compared with I/R group ,the activities of XOD and Ca2＋-ATPase , content of Ca2＋ and mPTP opening were significantly decreased , and the activities of SDH and GSH-Px and Δψm were increased in IP group （ P〈0.05） .Compared with IP group ,the activities of XOD and Ca2＋-ATPase , content of Ca2＋ and mPTP opening were significantly increased , and the activities of SDH and GSH-Px and Δψm were decreased in C group （ P〈0.05） .Conclusion PKC is involved in reduction of mitochondrial injury during myocardial I/R by ischemic preconditioning in rats . Key words: Protein kinase C; Ischemic preconditioning; Myocardial reperfusion injury; Mitochondria

Comparison of ischaemic preconditioning with surgical delay technique to increase the viability of single pedicle island venous flaps: An experimental study

The aim of the present study was to investigate the effect of ischaemic preconditioning compared with the surgical delay procedure in an effort to increase the survival rate of single pedicle island venous flaps. Eighteen male Wistar albino rats (250–350 g) were included. A 3 × 4 cm flap was planned at the right lower abdomen of the rat. Superficial epigastric vein constituted the pedicle of the flap. The rats were divided into three groups, each consisting of six rats. In the control group, a single pedicle venous island flap was elevated on each rat and no other surgical procedure was performed. In the ischaemic preconditioning group, ischaemic preconditioning was performed and, in the surgical delay procedure group, the surgical delay technique was performed before flap elevation. The mean necrosis areas were 56.85 ± 14.60%, 28.73 ± 15.60%, and 12.08 ± 3.65% in the control, ischaemic preconditioning, and surgical delay procedure groups, respectively. The necrosis areas were significantly smaller in the ischaemic preconditioning group and surgical delay procedure groups compared to the control group (p = 0.004 and p < 0.001, respectively). The necrosis areas were similar in the ischaemic preconditioning and surgical delay procedure groups. Histopathological parameters including necrosis, abscess formation, and skin ulceration scores were significantly lower in the ischaemic preconditioning group than in the control group, whereas the study groups were similar. In conclusion, ischaemic preconditioning may serve as an adjuvant technique in increasing venous island flap viability.

Different roles of hepatic hypothermic ischemia and ischemic preconditioning in chemically induced hepatocarcinogenesis in rats

BackgroundHepatic ischemia–reperfusion (IR) injury, an unfavorable complication of hepatectomy, could be prevented by hypothermic ischemia and ischemic preconditioning (IPC). However, the effects of these two approaches on hepatocarcinogenesis have not been examined. The aim of the study was to investigate roles of hypothermic ischemia and IPC in a chemically induced rat liver tumor model. MethodsTwenty-four Sprague–Dawley rats were treated with diethylnitrosamine and phenobarbital to induce hepatocellular carcinoma. Rats underwent hepatic ischemic injury, hypothermic ischemia, and IPC. Twenty-eight-wk-old rats were sacrificed to evaluate the morbidity and growth of liver tumor. Cytokines were measured at the protein and messenger RNA level. ResultsIR injury significantly promoted liver tumor development. Intriguingly, hypothermic ischemia, but not IPC, delayed liver carcinogenesis, although both of them suppressed the hepatic IR injury. IPC-treated rats showed elevated interleukin (IL)-6 concentration in the serum and messenger RNA expression in liver. In addition, higher levels of IL-6 activated signal transducer and activator of transcription 3 in the liver of IPC-treated rats. The hepatic expression of target genes of signal transducer and activator of transcription 3 signaling, cyclin D1, c-myc, c-fos, and c-jun, all of which might participate in tumor progression, increased in IPC group, compared with that of IR group. ConclusionsThese data indicated hypothermic ischemia could ameliorate both IR injury and liver tumor development. However, IPC, another effective method to prevent hepatic IR injury, might exacerbate liver tumor growth. The elevated level of IL-6 was one of the reasons for the different effects of hypothermic ischemia and IPC on hepatocarcinogenesis in rats.

Ischemic preconditioning improves liver tolerance to congestion–reperfusion injury in mice

BackgroundCongestion–reperfusion injury (CRI) is a common complication after living donor liver transplantation, which has not been fully understood. It causes more severe inflammatory response as compared with ischemia–reperfusion injury (IRI). Ischemic preconditioning (IPC) has been endowed with powerful protective properties toward IRI. This study aimed to investigate whether IPC also has a protective effect against CRI and potential underlying mechanisms. Materials and methodsMice were randomly divided into sham operation, CRI, IPC-CRI, and congestion precondition (CPC-CRI) group. The hepatic vein of the left anterior hepatic lobe was occluded for 75 min followed by reperfusion in the CRI group. The blood inflow was previously clamped for 10 min followed by 10 min of reperfusion just before occluding the hepatic vein in the IPC-CRI group. To imitating IPC in the CPC-CRI group, 10 min of congestion followed by 10 min of reperfusion just before CRI was performed. The animals were sacrificed at 2, 6, 24, 48 h, and 7 d after reperfusion. The blood and liver samples were collected for hepatic function assay, histology, terminal deoxynucleotidyl transferase dUTP nick end labeling, myeloperoxidase, and real-time polymerase chain reaction analysis. ResultsMice in the CRI, IPC-CRI, and CPC-CRI group demonstrated elevated liver enzymes, histologic damage, cellular apoptosis, and inflammatory response compared with those in the sham operation group. Compared with the CRI group, mice in the IPC-CRI group expressed lower alanine transaminase activities (2 h: 839.2 ± 132.5 versus 384.2 ± 94.8, P < 0.01; and 6 h: 680 ± 142.4 versus 342.3 ± 99.7, P < 0.01) and lower myeloperoxidase levels (2 h: 7.1 ± 4.0 U/g versus 3.8 ± 1.6 U/g, P < 0.05; and 6 h: 8.1 ± 1.3 U/g versus 5.2 ± 3.0 U/g, P < 0.05). However, the alanine transaminase level in the CPC-CRI group was notably higher at 2 h (839.2 ± 132.5 versus 1087.5 ± 192.5, P < 0.05). Livers from mice in the IPC-CRI group showed better tissue integrity, diminished hepatocellular injury, and apoptosis at 2 and 6 h. The messenger RNA transcriptions of interleukin 1 and interleukin 6 were significantly lower after 2–24 h of reperfusion, whereas tumor necrosis factor α and monocyte chemoattractant protein 1 were significantly lower after 24 h of reperfusion in the IPC-CRI group. ConclusionsIPC can significantly improve liver tolerance to CRI by attenuating neutrophil infiltration, proinflammatory cytokine formation, and hepatocytes apoptosis. This pretreatment strategy holds greater prospect of being translated into clinical use in living donor liver transplantation.

Hepatic ischemic preconditioning increases portal vein flow in experimental liver ischemia reperfusion injury

Ischemic preconditioning (IPC) has been shown to decrease liver injury and to increase hepatic microvascular perfusion after liver ischemia reperfusion. This study aimed to evaluate the effects of IPC on hemodynamics of the portal venous system. Thirty-two rats were randomized into two groups: IPC group and control group. The rats of the IPC group underwent IPC by 10 minutes of liver ischemia followed by 10 minutes of reperfusion before liver ischemia, and the rats of the control group were subjected to 60 minutes of partial liver ischemia. Non-ischemic lobes were resected immediately after reperfusion. The animals were studied at 4 hours and 12 hours after reperfusion. Mean arterial pressure, heart rate, portal vein flow and pressure were analyzed. Blood was collected for the determination of the levels of aspartate aminotransferase, alanine aminotransferase, calcium, lactate, pH, bicarbonate, and base excess. IPC increased the mean portal vein flow at 4 hours and 12 hours after reperfusion. IPC recovered 78% of the mean portal vein flow at 12 hours after reperfusion. IPC decreased the levels of aspartate aminotransferase, alanine aminotransferase and lactate, and increased the levels of ionized calcium, bicarbonate and base excess at 12 hours after reperfusion. This study demonstrated that IPC increases portal vein flow and enhances hepatoprotective effects in liver ischemia reperfusion. The better recovery of portal vein flow after IPC may be correlated with the lower levels of transaminases and with the better metabolic profile.

Improved cardioprotection using a novel stepwise ischemic preconditioning protocol in rabbit heart

BackgroundThe current commonly used cardiac ischemic preconditioning (IPC) protocol, involving three 5-min cycles of ischemia–reperfusion (I/R), may not be clinically beneficial because of its acutely deleterious effects on hemodynamics. This study attempted to assess the effects of a novel stepwise IPC scheme on cardiac function, infarct size, and arrhythmogenesis in a rabbit model of prolonged I/R. MethodsAnesthetized open-chest rabbits were subjected to 60-min occlusion of a proximal branch of the left coronary artery followed by 180-min reperfusion. Animals were divided into five groups (n = 6 each): (1) control group (no IPC); (2) 2-min IPC group (three cycles of 2-min IPC); (3) 5-min IPC group (three cycles of 5-min IPC); (4) 10-min IPC group (three cycles of 10-min IPC); and (5) stepwise IPC group (2-, 5-, and 10-min I/R). ResultsCompared with control group, 2-, 5-, and 10-min IPC decreased arrhythmia score by 16%, 67%, and 33%, respectively. Remarkably, stepwise IPC resulted in a 78% reduction of arrhythmias. Stepwise IPC also produced the least ventricular infarct size when compared with 2-, 5-, and 10-min IPC groups (16.4% versus 39.3%, 28.1%, and 38.5%, P < 0.05). ConclusionsThese results suggest that stepwise IPC has better cardioprotective effects against prolonged I/R injury and may serve as an acceptable approach to clinical revascularization procedures on the heart, including catheter-based and surgical approaches.

Leg ischaemia before circulatory arrest alters brain leucocyte count and respiratory chain redox state

Remote ischaemic preconditioning and its neuroprotective abilities are currently under investigation and the method has shown significant effects in several small and large animal studies. In our previous studies, leucocyte filtration during cardiopulmonary bypass reduced cerebrocortical adherent leucocyte count and mitigated cerebral damage after hypothermic circulatory arrest (HCA) in piglets. This study aimed to obtain and assess direct visual data of leucocyte behaviour in cerebral vessels after hypothermic circulatory arrest following remote ischaemic preconditioning. Twelve native stock piglets were randomized into a remote ischaemic preconditioning group (n = 6) and a control group (n = 6). The intervention group underwent hind-leg ischaemia, whereas the control group received a sham-treatment before a 60-min period of hypothermic circulatory arrest. An intravital microscope was used to obtain measurements from the cerebrocortical vessel in vivo. It included three sets of filters: a violet filter to visualize microvascular perfusion and vessel diameter, a green filter for visualization of rhodamine-labelled leucocytes and an ultraviolet filter for reduced nicotinamide adenine dinucleotide (NADH) analysis. The final magnification on the microscope was 400. After the experiment, cerebral and cerebellar biopsies were collected and analysed with transmission electron microscope by a blinded analyst. In the transmission electron microscope analysis, the entire intervention group had normal, unaffected rough endoplasmic reticulum's in their cerebellar tissue, whereas the control group had a mean score of 1.06 (standard deviation 0.41) (P = 0.026). The measured amount of adherent leucocytes was lower in the remote ischaemic preconditioning group. The difference was statistically significant at 5, 15 and 45 min after circulatory arrest. Statistically significant differences were seen also in the recovery phase at 90 and 120 min after reperfusion. Nicotinamide adenine dinucleotide autofluorescence had statistically significant differences at 10 min after cooling and at 120 and 180 min after hypothermic circulatory arrest. Remote ischaemic preconditioning seems to provide better mitochondrial respiratory chain function as indicated by the higher NADH content. It simultaneously provides a reduction of adherent leucocytes in cerebral vessels after hypothermic circulatory arrest. Additionally, it might provide some degree of cellular organ preservation as implied by the electron microscopy results.