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Background: Remote ischemic conditioning (RIC) has shown great advantages in protecting organs from ischemia-reperfusion loss and applied research on RIC continues to increase. We performed a systematic review and meta-analysis to comprehensively investigate the value of RIC for different organ transplantation., Methods: We searched PubMed, EMBASE, and the Cochrane Library from inception to November 1, 2023, for randomized controlled trials investigating whether RIC has an advantage in organ transplantation (including heart, lung, liver, and kidney) compared with controls. The primary outcomes varied according to the transplanted organ, including liver transplantation (graft loss, early allograft dysfunction, acute kidney injury, days in hospital, and mortality); kidney transplantation (delayed graft function, acute rejection (AR), graft loss, 50% decrease in serum creatinine, glomerular filtration rate, days in hospital, and mortality); heart and lung transplantation (AR, mortality). Two investigators independently selected suitable trials, assessed trial quality, and extracted the data., Results: A total of 11 randomized controlled trials were included in this study, including six kidney transplants, three liver transplants, and one heart and lung transplant each, with 561 RIC cases and 564 controls, and a total of 1125 patients. The results showed that RIC did not reduce mortality in transplant patients compared with controls (liver transplant: RR0.9, 95% confidence interval [0.31-2.66]; kidney transplant: RR 0.76, 95% confidence interval [0.17-3.33]), graft failure rate (liver transplantation: RR 0.3, 95% confidence interval [0.07, 1.19]; kidney transplantation: RR 0.89, 95% confidence interval [0.35, 2.27]), length of hospital stay (liver transplantation: standard mean difference [SMD] 0.14, 95% confidence interval [-0.15, 0.42]; kidney transplantation: SMD -0.1, 95% confidence interval [-0.3, 0.11]). In addition, RIC did not improve early liver function after liver transplantation (RR 0.97, 95% confidence interval [0.55,1.7]), acute kidney injury after liver transplantation (RR 1.17 95% confidence interval [0.9, 1.54]), delayed functional recovery after renal transplantation (RR 0.84, 95% confidence interval [0.62, 1.15]), AR rate (RR 1.04, 95% confidence interval [0.72, 1.49]), 50% serum creatinine decline rate (RR 1.1, 95% confidence interval [0.88, 1.37]), glomerular filtration rate 3 months after surgery (SMD 0.13, 95% confidence interval [-0.05, 0.31]) and postoperative 12 months glomerular filtration rate (SMD 0.13, 95% confidence interval [-0.06, 0.31])., Conclusion: Remote ischemic modulation does not improve clinical outcomes in patients undergoing organ transplantation (heart, lung, liver, and kidney)., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Propofol is widely used in general anesthesia, and it has been reported to protect various organs against ischemia-reperfusion injury (IRI), including liver. To evaluate the hepatoprotective effects of ischemic preconditioning (IP) under propofol anesthesia, we investigated the possible underlying mechanisms in rats., Methods: Male Sprague-Dawley rats were randomly assigned to 3 groups: sham group (n = 5), non-IP group (n = 9; 45 minutes of hepatic ischemia followed by 2 hours of reperfusion), and IP group (n = 9; IP applied as 10 minutes of hepatic ischemia followed by 15 minutes of reperfusion before 45 minutes of ischemia). Anesthesia was maintained with intravenous (IV) infusion of propofol (800 μg/kg/min). Liver enzymes, histopathological changes, and cytokine expression were examined., Results: The IP group showed significantly lower liver enzyme levels (aspartate aminotransferase, P = .045; alanine aminotransferase, P = .006) and reduced the histologic grades of hepatic injury 2 hours after reperfusion (P = .004) compared to the non-IP group. Lactate dehydrogenase activity (P < .001) and interleukin-6 mRNA levels were significantly higher in the non-IP group than in the sham and IP groups (P = .002, both groups)., Conclusions: Our results demonstrate that IP under propofol anesthesia significantly attenuated hepatic IRI. The principal mechanism of the protective effects appeared to involve reduced expression of the IL-6 pro-inflammatory cytokine and subsequent reduction of the degree of necrosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Ischemic preconditioning (IPC) was developed to diminish ischemia-reperfusion injury (IRI). There are two main ways of performing it: direct ischemic-preconditioning (DIP) and remote ischemic-preconditioning (RIP). The objectives of this study were to investigate local and systemic effects of DIP and RIP in liver IRI., Methods: Thirty-two weaning rats (50-70 g body weight; 21 days old) were divided into 4 groups: control (C); ischemia followed by reperfusion (IR); DIP followed by ischemia and reperfusion; and RIP followed by ischemia and reperfusion. In the IR group, the vascular pedicles of medial and left lateral liver lobes were clamped for 60 minutes and then unclamped. In the DIP group, a 10-minute cycle of ischemia followed by a 10-minute reperfusion of the same lobes was performed before 60 minutes of ischemia. In the RIP group, three 5-minute cycles of clamping and unclamping of the femoral vessels were performed before liver ischemia. The animals were euthanized 24 hours after the surgical procedures., Results: The serum levels of liver enzymes were significantly lower in the RIP group compared to the control and IR groups and to the DIP group. The scores of histologic hepatic lesions were significantly lower in RIP animals than those of IR animals (P = .002) and similar to the C group animals. The Bax/BCl-xl relation was lower in the DIP group than that in the RIP group (P = .045) and no differences were observed in histologic analyses of kidney, lung, intestine, and heart., Conclusion: In young animals, the beneficial effects of RIP are more evident than those of DIP., (Published by Elsevier Inc.)

Background: Ischemia-reperfusion injury is an unavoidable aspect of transplantation, as well as an important cause of acute kidney injury in clinical practice. Pre- and post-ischemic conditioning are strategies that may provide organs with resistance to major ischemic events. This study evaluates the effects of ischemic preconditioning and ischemic postconditioning, either separately or in combination, after an acute ischemia-reperfusion kidney injury., Methods: Forty Wistar rats received isoflurane anesthesia and were randomized into 5 groups: 1. the sham group underwent laparotomy; 2. the control group underwent laparotomy and 30 minutes of renal ischemia followed by reperfusion; 3. the preconditioning group underwent laparotomy, ischemic preconditioning, and 30 minutes of renal ischemia followed by reperfusion; 4. the preconditioning and postconditioning group underwent laparotomy, ischemic preconditioning, 30 minutes of renal ischemia, and ischemic postconditioning followed by reperfusion; and 5. the postconditioning group underwent laparotomy, 30 minutes of renal ischemia, and ischemic postconditioning followed by reperfusion. Serum analyses of creatinine and neutrophil gelatinase-associated lipocalin (NGAL) were performed, and renal histology was examined 24 hours later., Results: Severe tubular injury and increases in creatinine were observed in all groups except the sham group. The control group and all ischemic conditioning groups were no different in the degree of renal injury and values of NGAL and creatinine after the injury., Conclusions: Ischemic preconditioning and ischemic postconditioning, together or separately, are unable to preserve kidney function or exert a protective effect against tubular cell injury after an acute ischemia-reperfusion kidney injury., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In clinical islet transplantation, hepatic ischemia and insufficient neovascularization of transplanted islets are barriers to islet survival and function. However, hepatocytes have a potency to protect themselves against ischemia. We hypothesized that ischemia/reperfusion preconditioning (IRP) of hepatocytes might beneficially affect islet cells in a coculture system. Primary islets were cocultured with primary hepatocytes, and hepatocyte IRP was conducted by subjecting cells to hypoxic conditions for single 15-minute/30-minute hypoxia, or 2 tandem 15-minute/30-minute hypoxic treatments (hypoxic-normoxic-hypoxic). We show that gene expression levels of insulin-like growth factor 1 (IGF-1), hepatocyte growth factor (HGF), transforming growth factor-α (TGF-α), and TGF-β1 in hepatocytes were increased by IRP. IRP hepatocytes secreted hepatocyte growth factor and insulin-like growth factor-1. Coculture of islets with IRP hepatocytes enhanced islet insulin secretion in glucose challenge test and expression of the survival-related gene Bcl-2 and the regenerating gene-1α (Reg-1α). Islets cocultured with the 30-minute double-IRP hepatocytes displayed significantly higher viability in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase dUTP nick end labeling stain compared with that of islets subjected to 30 minutes of hypoxia. These results suggest that islet coculture with IRP hepatocytes can improve islet survival and insulin secretion., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The liver may be injured in situations where it is submitted to ischemia, such as partial hepatectomy and liver transplantation. In all cases, ischemia is followed by reperfusion and, although it is essential for the reestablishment of tissue function, reperfusion may cause greater damage than ischemia, an injury characterized as ischemia-reperfusion (I/R) damage. The aim of this work was to analyze the effect of ischemic preconditioning with the use of methylene blue (MB; 15 mg/kg) 5 or 15 minutes before I/R (IRMB5' and IRMB15', respectively) on the hepatic injury occurring after I/R., Methods: Twenty-eight male Wistar rats were used, and liver samples submitted to partial ischemia (IR) or not (NI) were obtained from the same animal. The samples were divided into 7 groups. Data were analyzed statistically by means of the nonparametric Mann-Whitney test and Wilcoxon Matched test, with the level of significance set at 5% (P < .05)., Results: The rate of oxygen consumption by state 3 mitochondria was inhibited in all ischemic groups compared with the sham group (SH vs IR: P = .0052; SH vs IRMB5': P = .0006; SH vs IRMB15': P = .0048), which did not occur in the nonischemic contralateral portion of the same liver (SH vs NI: P = .7652; SH vs NIMB5': P = .059; SH vs NIMB15': P = .3153). The inhibition of the rate of oxygen consumption by state 3 mitochondria was maintained in the presence of MB (IR vs IRMB5': P = .4563; IR vs IRMB15': P = .9021). The respiratory control ratio was reduced in all ischemic groups compared with the sham group, owing to the inhibition of oxygen consumption in state 3 (SH vs IR: P = .0151; SH vs IRMB5': P = .005; SH vs IRMB15': P = .0007)., Conclusions: Methylene blue had no effect on the mitochondrial respiratory parameters studied, but was able to reduce lipid peroxidation, preventing the production of reactive oxygen species (SH vs IRMB15': P = .0210)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: In hepatectomy or liver transplantation, preconditioning is a procedure indicated to protect the organ from ischemia-reperfusion injury (I-R)., Objective: Evaluate the effect of preconditioning after hepatic I-R in Wistar rats, through mitochondrial respiration, liver histology, and profile., Method: Twenty male Wistar rats, weighing on average 307.1 g, were anesthetized with sodium thiopental (25 mg/kg) intravenously and xylazine hydrochloride (30 mg/kg) intramuscularly. The animals were divided into 2 groups: the preconditioning group (PCG), which contained 10 animals, and the hepatic pedicle was isolated and submitted to clamping with microvascular clamp (10 minutes of ischemia and 10 minutes of reperfusion, followed by 30 minutes of ischemia and 30 minutes of reperfusion); and the simulated operation group (SOG), which contained 10 animals submitted to manipulation of the hepatic pedicle and observation for the same length of time, with blood collected for transaminase dosage measurements, and liver biopsy for evaluation of mitochondrial respiration and histologic liver analysis and after sacrificed under anesthesia. The project was approved by the Ethics Committee on Animal Experimentation CEEA/UNICAMP under protocol number 3905-1., Result: The PCG mitochondria showed the same respiration level as the SOG, when stimulated with the addition of adenosine diphosphate or carbonyl cyanide p-trifluoromethoxyphenylhydrazone. In the respiratory control ratio and resting of velocity of respiration the groups behaved in a similar way. The PCG presented high aspartate and alanine transaminases (P < .03) and about 60% of sinusoidal congestion and venous congestion in the histologic analysis when compared with SOG., Conclusion: We found that ischemia with preconditioning in Wistar rats can lead to mild histologic and biochemical dysfunction without leading to impairment of mitochondrial respiration., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Various volatile anesthetics and ischemic preconditioning (IP) have been demonstrated to exert protective effect against ischemia/reperfusion (I/R) injury in liver. We aimed to determine whether application of IP under isoflurane and sevoflurane anesthesia would confer protection against hepatic I/R injury in rats., Methods: Thirty-eight rats weighing 270 to 300 grams were randomly divided into 2 groups: isoflurane (1.5%) and sevoflurane (2.5%) anesthesia groups. Each group was subdivided into sham (n = 3), non-IP (n = 8; 45 minutes of hepatic ischemia), and IP (n = 8, IP consisting of 10-minute ischemia plus 15-minute reperfusion before prolonged ischemia) groups. The degree of hepatic injury and expressions of B-cell lymphoma 2 (Bcl-2) and caspase 3 were compared at 2 hours after reperfusion., Results: Hepatic ischemia induced significant degree of I/R injuries in both isoflurane and sevoflurane non-IP groups. In both anesthetic groups, introduction of IP dramatically attenuated I/R injuries as marked by significantly lower aspartate aminotransferase and aminotransferase levels and better histologic grades compared with corresponding non-IP groups. There were 2.3- and 1.7-fold increases in Bcl-2 mRNA levels in isoflurane and sevoflurane IP groups, respectively, compared with corresponding non-IP groups (both P < .05). Caspase 3 level was significantly high in the isoflurane non-IP group compared with the sham group; however, there were no differences among the sevoflurane groups., Conclusions: The degree of hepatic I/R injury was significantly high in both isoflurane and sevoflurane groups in rats. However, application of IP significantly protected against I/R injury in both volatile anesthetic groups to similar degrees, and upregulation of Bcl-2 might be an important mechanism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: It has been reported that nafamostat mesilate (NM) inhibits inflammatory injury via inhibition of complement activation in ischemic heart, liver, and intestine. However, it is unclear if NM also inhibits apoptosis in ischemia-reperfusion (IR)-injured kidney. We therefore investigated whether NM attenuates IR renal injury that involves inhibition of apoptosis., Methods: HK-2 cells and male C57BL/6 mice were used for this study. C57Bl/6 mice were divided into 4 groups: sham, NM (2 mg/kg) + sham, IR injury (IR injury; reperfusion 27 minutes after clamping of both the renal artery and vein), and NM + IR injury. Kidneys were harvested 24 hours after IR injury, and functional and molecular parameters were evaluated. For in vitro studies, HK-2 cells were incubated for 6 hours with mineral paraffin oil to induce hypoxic injury, and then treated with various doses of NM to evaluate the antiapoptotic effects., Results: Blood urea nitrogen, serum creatinine levels, and renal tissue injury scores in NM + IR-injured mice were significantly lower than those of control IR mice (all P < .01). NM significantly improved cell survival in hypoxic HK-2 cells (P < .01), significantly decreased renal Bax expression (P < .05), and increased renal Bcl-2 protein levels in IR kidneys and hypoxic HK-2 cells compared with those of the sham and control groups. The numbers of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling- and 8-oxo-2'-deoxyguanosine-positive cells were significantly lower in NM + IR-injured kidneys compared with those in control IR-injured mice (P < .05); NM treatment decreased the expression of inducible and endothelial nitric oxide synthase in IR-injured mice (P < .05)., Conclusions: NM ameliorates IR renal injury via inhibition of apoptosis by, at least in part, lowering nitric oxide overproduction, reducing Bax, and increasing Bcl-2., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Hepatic ischemia-reperfusion injury (IRI) is considered a major cause of hepatic damage in liver surgery. The aim of this study was to investigate the effect of the remote ischemic perconditioning method on hepatic IRI in a rat model., Methods: Seventeen rats underwent hepatic IRI for 30 minutes followed by reperfusion, and were divided into 3 groups: group I, only hepatic IRI (n = 5); group II, hepatic IRI with remote perconditioning (n = 7); and group III, hepatic IRI with remote postconditioning (n = 5)., Results: For Bax/β-actin, mean values of the 3 groups (±standard deviation) were 1.29 ± 0.26 (group I), 0.89 ± 0.15 (group II), and 1.02 ± 0.23 (group III). The level of Bax/β-actin in group II was significantly lower than in group I (P < .01). The cleaved Caspase-3/β-actin ratio for groups I, II, and III was 0.93 ± 0.22, 0.46 ± 0.16, and 0.63 ± 0.22, respectively. The level of cleaved Caspase-3/β-actin in groups II and III were significantly lower than in group I (P < .01 and P < .05, respectively). The Bcl-2/β-actin ratio for groups I, II, and III was 1.01 ± 0.09, 1.19 ± 0.39, and 1.20 ± 0.12, respectively. However, there were no significant difference between groups II and III and group I., Conclusions: The remote perconditioning on rat hepatic IRI downregulated the Bax and cleaved Caspase-3 expression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Intestinal ischemia-reperfusion injury occurs after different surgical treatments, including intestinal transplantation. This harmful process may have an effect in remote organs, leading to multiple organ dysfunction syndrome and death. Therefore, to establish strategies to attenuate local and remote damage constitutes a challenge for experimental and clinical surgeons in the intestinal surgical field., Methods: We evaluated the effect of ischemic preconditioning and tacrolimus pretreatment applied alone and in combination against local and remote damage caused by prolonged intestinal ischemia-reperfusion injury in a mouse model of warm ischemia., Results: Ischemic preconditioning applied alone and in combination with tacrolimus decreased histological damage (P < .05), number of apoptotic cells (P < .05), nitrosative stress (P < .01), and serum lactate dehydrogenase activity (P < .05) and lowered uremia (P < .05) compared with untreated post-reperfused intestines. Regarding remote organ damage, combination therapy was the unique condition able to attenuate lung (mainly neutrophil infiltration and hemorrhage), liver (sinusoidal congestion and hepatic vacuolization), and kidney (acute tubular necrosis and hydropic degeneration) histological alterations (P < .05), compared with the untreated group., Conclusions: These results support the application of these strategies in combination to minimize the impact of ischemia-reperfusion injury in the whole organism as a strategy to prevent multiple organ dysfunction syndromes and minimize the clinical impact., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: This study evaluated the effects of allopurinol (ALP), a xanthine oxidase inhibitor, and apocynin (APC), a NADPH oxidase inhibitor, administered alone or together, on kidney damage caused by renal ischemia-reperfusion (IR) in rats., Methods: Thirty rats were randomly assigned to 5 groups. Group 1 was a sham group. Group 2 was the renal IR control group (30-min ischemia followed by 24-h reperfusion). In groups 3 and 4, ALP or APC, respectively, was administered 1 h before the ischemia. In group 5, ALP and APC were co-administered. Blood urea nitrogen (BUN) and serum creatinine (Cr), renal tissue malondialdehyde (MDA) and superoxide dismutase (SOD), and histological changes were evaluated., Results: A significant increase in BUN and Cr level, and histological damage was seen in the IR control group, indicating renal injury. Elevated MDA and decreased SOD levels in the IR control group demonstrated that renal damage occurred through oxidative stress. Pretreatment with ALP or APC alone or together prevented IR-induced renal damage. However, there was no significant difference between treatment with a single drug and co-administration of ALP and APC., Conclusions: The use of ALP and/or APC before ischemia may be beneficial to ameliorate renal IR injury., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Heme oxygenase-1 (HO-1) has a protective role against ischemia/reperfusion (I/R) injury., Methods: We produced an HO-1 fusion protein mediated by cell penetrated peptide PEP-1, also known as PEP-1-HO-1 fusion protein, and investigated its role in renal I/R injury in rats. Male Sprague-Dawley rats were subjected to 45 minutes of ischemia by occluding the bilateral renal arteries and 6 hours of reperfusion to prepare the model of renal I/R. Animals were randomized to receive PEP-1-HO-1 fusion protein or equal volume of physiologic saline 30 minutes before ischemia., Results: Administration of PEP-1-HO-1 fusion protein resulted in a significant increase in HO-1 expression. His-probe expression (1 part of the PEP-1-HO-1 fusion protein) was only observed in PEP-1-HO-1-treated animals. I/R caused renal dysfunction and increases in malondialdehyde level and cell apoptosis, and decreased superoxide dismutase activity. Treatment of PEP-1-HO-1 fusion protein reversed these changes. Furthermore, administration of PEP-1-HO-1 inhibited the I/R-induced increase in nuclear factor-κB activation., Conclusions: These findings suggest that transduction of PEP-1-HO-1 attenuates renal I/R injury in rats, which might be partly attributable to its antioxidant and antiapoptotic effects., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. The pathogenetic mechanisms of renal I/R injury involve inflammation, oxidative stress, and apoptosis. Osthole, a natural coumarin derivative, has potential anti-inflammatory effects. This study investigated the effect of osthole on renal I/R injury and its potential mechanism., Methods: We induced renal I/R injury by clamping the left renal artery for 45 min followed by reperfusion, along with a contralateral nephrectomy. We randomly assigned 30 rats to 3 groups (n = 10): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intra-peritoneally with osthole (40 mg/kg) or vehicle (40 mg/kg) 45 min before renal ischemia. We harvested serum and kidneys at 24 h after reperfusion. Renal function and histological changes were assessed. The expression of tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6) in renal tissue and serum were examined by means of RT-PCR and ELISA, respectively. The expression of p-p85, p85, p-Akt, Akt, p-p65, and p65 were measured by means of Western blotting., Results: Osthole pre-treatment significantly attenuated renal dysfunction, renal histological changes, NF-κB activation, and the expression of TNF-α, IL-8, and IL-6 induced by I/R injury, but the activation of PI3K/Akt signaling was further increased., Conclusions: Osthole pre-treatment protects rats against renal I/R injury by suppressing NF-κB activation, which is involved in PI3K/Akt signaling activation. Thus, osthole may be a novel practical strategy to prevent renal I/R injury., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: The inflammatory response plays an important role in liver dysfunction after hepatic ischemia/reperfusion (I/R), which is tightly regulated by the Toll-like receptor 2 (TLR2)/nuclear factor (NF)-κB pathway; suppression of TLR2/NF-κB signaling has therefore become a promising target for anti-inflammatory treatment in hepatic I/R injury. Erythropoietin (EPO) is a glycoprotein cytokine produced primarily by the kidney that has anti-inflammatory activities. The purpose of the present study was to investigate the effect of EPO preconditioning, if any, against hepatic I/R injury in rats and its underlying mechanisms., Materials and Methods: Male Sprague-Dawley rats were subjected to partial (70%) hepatic ischemia for 45 minutes after pretreatment with either saline or EPO followed by 24-hour reperfusion. Hepatic injury was evaluated according to biochemical and histopathologic examinations. The expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were measured by using enzyme-linked immunosorbent assay and real-time polymerase chain reaction. The expression of nuclear translocation and phosphorylation of NF-κB p65, EPOR receptor (EPOR), p-EPOR, p-IκB-α, IκB-α, and TLR2 were determined by using Western blot analysis., Results: EPO treatment significantly improved hepatic function and histology, as indicated by reduced transaminase levels and pathologic changes. The expression of TNF-α, IL-1β, IL-6, p-IκB-α, and TLR2 was significantly decreased with up-regulation of p-EPOR by EPO. Moreover, EPO pretreatment also reduced I/R-induced the phosphorylation and nuclear translocation of NF-κB p65 subunits in liver tissue, but EPO had no influence on the expression of p65 and IκB-α., Conclusions: These results suggest that EPO pretreatment ameliorates hepatic I/R injury, which is involved in suppressing TLR2/NF-κB-mediated inflammation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hepatic ischemic/reperfusion injury (HIRI) is a major complication of liver resection and transplantation. Octreotide, a somatostatin analogue, has been used to treat hepatic fibrosis and portal hypertension; however, its function against HIRI remains unclear. To elucidate the effect of octreotide in HIRI, we investigated the hepatocellular protein profiles in response to octreotide preconditioning in a rabbit model by using proteomic analysis. Twenty-four rabbits were divided into 3 groups: the sham operative group (control), the ischemia/reperfusion group (IR), and the ischemia/reperfusion + octreotide group (IR+Oct). They were subjected to 30 minutes of normothermic ischemia followed by 120 minutes of reperfusion by using Pringle's maneuver method. Proteomic studies were then performed to compare the protein profiles of their left liver lobe. A total of 16 differential proteins were successfully identified. These findings suggest that octreotide might exert an effect against HIRI through up-regulating the expression of the anti-injury substances, such as heat-shock proteins 70 and 27 (confirmed by using Western blot analysis); significantly raising the phosphatidylethanolamine-binding protein that alleviates IR-related apoptosis; and down-regulating mitochondrial metabolic enzymes such as NADH2 dehydrogenase and triosephosphate isomerase., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study was evaluate the beta blocker atenolol (AT) and ischemic preconditioning (IPC) strategies for tissue protection against systemic effects of intestinal ischemia (I) and reperfusion (R) injury. Forty-two rats were pretreated with AT (1.5 mg · kg(-1)), 0.9% saline solution (SS; 0.1 mL), or IPC and then subjected to prolonged occlusion of the superior mesenteric artery for 60 minutes leading to I followed or not by 120 minutes of R, according to the group. For IPC, 5 minutes of I prior to 10 minutes of R were established. After this process of I or I-R, the right lung of each animal was adequately prepared for staining with hematoxylin and eosin and subsequent histologic analysis for quantification of inflammatory infiltrate was done. The left lung was frozen and prepared for assessment of oxidative stress by the quantification of thiobarbituric acid-reactivity substances (TBARS). Histologic analysis showed an important inflammatory infiltrate in the I-R + SS (I-R + SS = 4.5), which was significantly (P < .05) reduced by IPC (I-R + IPC = 3.0) or AT (I-R + AT = 3.0). Likewise, the TBARS levels were decreased by both strategies (I-R + SS = 0.63; I-R + IPC = 0.23; I-R + AT = 0.38; P < .05). Our results showed that AT and IPC attenuate pulmonary lesions caused by intestinal I and R process., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Liver regeneration has great importance for transplantation, especially in children; however, it has not been studied sufficiently in development animals. Ischemia-reperfusion injury is a problem, and strategies such as ischemic preconditioning and postconditioning are not well defined regarding regeneration., Objective: This study sought to evaluate liver regeneration with modulation by ischemic preconditioning and postconditioning in prepubertal rats subjected to total ischemia and reperfusion., Methods: Thirty-five 5-week-old female Wistar rats were divided into groups of 7 animals each: control group (SHAM), 70% hepatectomy (HEP), total ischemia 30 minutes before hepatectomy (IR), ischemic preconditioning 10/10 minutes before ischemia (PRE), and two 30/30-second ischemic postconditioning cycles after ischemia and hepatectomy (POS). All animals were subjected to 24-hour reperfusion. Aspartate aminotransferase and alanine aminotransferase activity were measured to evaluate liver damage, and histological analysis, proliferating cell nuclear antigen (PCNA) and regenerated mass liver were used to evaluate liver regeneration. Statistical analyses were performed using ANOVA and Kruskal-Wallis test., Results: Alanine aminotransferase and aspartate aminotransferase levels were significantly lower in conditioned groups than in the IR group. Regarding mitotic index, IR > control group and HEP (P < .05), PRE and POS were not significantly different from IR, and POS > HEP (P < .05). PCNA analysis showed that IR > HEP (P < .01), PRE < IR (P < .01), and no significant differences were observed between POS and IR groups. No significant differences in regenerated mass liver were observed between conditioned groups and HEP., Conclusions: Ischemic postconditioning prevented ischemic injury, promoted greater liver regeneration, and should be further investigated as an alternative better than ischemic preconditioning., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Minimizing the inflammatory events that follow intestinal transplantation may influence immediate graft function and improve outcome. Ischemic preconditioning (IPc) has been shown to ameliorate early inflammatory responses, and it may also attenuate the potentially damaging inflammation after intestinal transplantation. Herein, we examine the influence of intestinal IPc on inflammatory indices (tissue expression of ICAM-1, CD11a, and CD44 and serum levels of the soluble ICAM-1, sICAM-1) after heterotopic intestinal transplantation., Methods: Lewis rats received full-length preconditioned or non-preconditioned Brown Norway intestinal allografts in the absence of immunosuppression. Preconditioned grafts were subjected to 1 cycle of 10 minutes of ischemia-reperfusion. Preconditioned and non-preconditioned isografts acted as controls. Blood was collected on alternate days post-transplant, and graft tissue harvested on sacrifice. ICAM-1, CD44, and CD11a expression was determined by immunohistochemistry, and the area of staining was quantified using image analysis. Serum soluble ICAM-1 levels were determined using an R&D Systems Quantikine enzyme immunoassay., Results: (1) IPc ameliorated serum levels of sICAM-1 until severe rejection (day 7) overcame this down-regulation when compared to non-preconditioned allografts (day 3: 34,304 vs 40,479 pg/mL; day 5: 52,441 vs 61,593 pg/mL; day 7: 75,114 vs 73,309 pg/mL; day 9: 72,872 vs 76,314 pg/mL, respectively). (2) ICAM-1 expression was significantly lower in preconditioned allografts (1.02 vs 2.01 mm(2)). (3) CD44 tissue levels were also found to be lower in preconditioned allografts (0.86 vs 1.13 mm(2)). (4) There was a significant relationship between tissue ICAM-1 expression and serum levels of soluble ICAM-1 (P < .02)., Conclusions: IPc improves inflammatory indices in the early stages following intestinal transplantation, and this might lead to a preserved cellular, architectural, and functional graft status. Furthermore, our results support the use of soluble ICAM-1 as a marker of endothelial activation, and thence of inflammation and developing rejection., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to compare the protease inhibitor gabexate with widely used inosine for reducing renal ischemia-reperfusion injury., Method: A total of 48 rats were divided into 4 groups of 12 and administered gabexate, inosine, normal saline (NS), or nothing by injection through the vena dorsalis of the penis. Then all rats were subjected to right nephrectomy and 30-minute warm ischemia of the left kidney. At 24 and 48 hours after reperfusion, blood samples were collected from the inferior vena cava and serum creatinine (SCr) was assayed. Left kidney tissue was homogenized and used to assay malondialdehyde (MDA) and superoxide dismutase (SOD). The tissue was also analyzed using hematoxylin-eosin (HE) staining, TUNEL staining, and NF-κB immunohistochemistry., Results: SCr level decreased after reperfusion more in the gabexate group than in the other groups. Reperfused kidney tissue in the gabexate group showed lower MDA levels but higher SOD activity than did tissue in the inosine and saline groups, as well as lower pathology scores based on HE staining, lower necrosis index, and lower levels of NF-κB expression (all P < .05). Tissue in the inosine and saline groups showed similar necrosis index and NF-κB expression (P > .05)., Conclusion: Preconditioning with gabexate is superior to preconditioning with inosine for ameliorating rat renal ischemia-reperfusion injury. Future studies are needed to verify the effects of gabexate in the clinic, especially for kidney transplantation., (Published by Elsevier Inc.)

Objectives: We designed studies to test the hypotheses that hyperbaric oxygen (HBO) therapy should protect liver against subsequent ischemia/reperfusion (I/R) injury are scarce and controversial. The purpose of this study was to clarify some questions about the association of HBO with the processes of liver I/R., Methods: We divided Wistar rats into 5 groups: (1) SHAM operation, (2) I/R, rats submitted to total pedicle ischemia for 30 minutes followed by 5 minutes of reperfusion; (3) HBO60I/R and (4) HBO120I/R, rats respectively submitted to 60 and 120 minutes of HBO therapy at 2 absolute atmospheres and immediately after submitted to the experimental protocol of I/R; (5) HBO120, rats submitted to 120 minutes of HBO therapy at 2 absolute atmospheres and then immediately after humanely killed. The experimental protocol included (1) serum levels of aspartate and alanine aminotransferase; (2) mitochondrial function; (3) tissue malondialdehyde (MDA); and (4) plasma nitrite/nitrate. Data were analyzed using the Mann-Whitney test and were considered significant P < 5%., Results: The processes of liver ischemia/reperfusion caused tissue injury with hepatic mitochondrial functional impairment. A single exposure to 120 minutes of HBO caused an increase of tissue MDA. The time of HBO exposure as preconditioning before hepatic I/R is critical in the prevalence of beneficial or deleterious effects. Sixty minutes of hyperoxic preconditioning before liver I/R presents systemic benefits, but no significant tissue preservation. One hundred twenty minutes of hyperoxic preconditioning tissue liver benefits predominate compared with systemic benefits., Conclusions: The HBO preconditioning therapeutic benefits to liver I/R injury are time dependent, suggesting a therapeutic window that needs to be clearly defined in future studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: To investigate the protective role of nitric oxide (NO) induced by ischemic preconditioning (IP) on cold ischemic-reperfusion (IR) injury of rat liver grafts., Methods: One hundred twenty-eight male Sprague Dawley rats used for orthotopic liver transplantation were randomly divided into four groups (n = 32): administering heparin before ischemic reperfusion (control group); IP with 10-minute ischemia and 10-minute reperfusion before IR (IP group); adenosine before IR (Ade group); and L-NAME (NG-nitro-L-arginine methyl ester) + IP before IR (NAME group). Half of each group were used to investigate 1-week recipient survival rate, and another to obtain blood and hepatic tissue samples after 2-hour reperfusion., Results: One-week survival bile production, serum NO, and antioxidase activity were higher but serum alanine aminotransferase, tumor necrosis factor-α, and superoxide levels in hepatic tissue were lower in the IP group and Ade group versus the control group or NAME group. Liver sinusoidal endothelial cells in the IP and Ade groups showed less injury than the other groups., Conclusion: NO induced by IP can improve 1-week survival and rat liver function as well as protect liver sinusoidal endothelial cells., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To investigate the effect on intrahepatic cholangiocytes mediated by hypoxic preconditioning (HP) after liver transplantation and the role of vascular endothelial growth factor (VEGF)., Materials and Methods: This experiment was based on a model of rat orthotopic liver autotransplantation. Sprague-Dawley rats were randomly divided into 3 groups: normal control, autotransplantation (AT), and HP. The HP group was subjected to 8% oxygen atmosphere for 90 minutes before surgery. At 6, 12, 24, and 48 hours after autotransplantation, the rats were killed for testing .Serum total bilirubin, direct bilirubin, and alkaline phosphatase concentrations were determined. The microstructure of cholangiocytes and the ultramicrostructure of cholangioles were determined. Immunohistochemistry was used to detect the expression of VEGF and the proliferation rate of cholangiocytes., Results: Total bilirubin, direct bilirubin, and alkaline phosphatase concentrations in the AT group increased considerably more than in the HP group during the entire interval (P < .05). Light microscopy demonstrated that the microstructure of cholangiocytes in the AT group was damaged more seriously than in the HP group. At transmission electron microscopy, the ultramicrostructure of cholangioles was changed more obviously than in the HP group. The expression of VEGF on cholangiocytes and the proliferation rate of cholangiocytes were higher in the HP group than in the AT group over the entire experiment (P < .05)., Conclusion: Hypoxic preconditioning has a protective effect on cholangiocytes after liver autotransplantation. The mechanism may be related to HP-induced overexpression of VEGF on cholangiocytes., (2010 Elsevier Inc. All rights reserved.)

Objectives: Ischemic preconditioning (IP) affords resistance to liver ischemia-reperfusion (IR) injury, providing an early phase of protection. Development of delayed IP against IR injury was assessed using partial IR in rat liver., Methods: The IP manuver (10 minutes of ischemia and up to 72 hours of reperfusion) was induced before 1 hour of ischemia and 20 hours of reperfusion. At the end of the reperfusion period, blood and liver samples were analyzed for serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), haptoglobin and tumor necrosis factor-alpha (TNF-alpha) levels, hepatic histology, protein carbonyl and glutathione (GSH) contents as well as nuclear factor-kappaB (NF-kappaB), and activating protein-1 (AP-1) DNA binding., Results: The IP manuver significantly increased protein carbonyl/GSH ratios (275%), serum ALT (42%), and AST (58%); these changes normalized after 12 hours. Serum AST, ALT, and LDH levels were significantly increased by IR (4-, 5.6-, and 7.0-fold, respectively), with significant changes in liver histology, protein carbonyl/GSH ratio (481% enhancement), and serum TNF-alpha (6.1-fold increase). Delayed IP in IR animals reduced serum AST (66%), ALT (57%), and LDH (90%) and liver GSH depletion (89%), with normalization of protein carbonyl content, serum TNF-alpha levels, and liver histology. Enhanced AP-1/NF-kappaB DNA binding ratios and diminished haptoglobin expression induced by IR were normalized by IP., Conclusion: These data support that delayed IP suppresses IR-induced liver injury, oxidative stress, and TNF-alpha response, which coincide with recovery of IR-altered signaling functions represented by normal AP-1/NF-kappaB DNA binding ratios and acute phase responses.

Objective: The present study was designed to examine whether ischemic preconditioning could play a protective role on cold ischemia and reperfusion injury associated with intestinal transplantation in rats., Methods: The 48 male Sprague Dawley (SD) rats were randomly assigned to 2 groups. Ischemic preconditioning was performed in experimental but not control rats by preserving the self donor small bowel in Ringer lactate solution at 4 degrees C for 3 hours (n = 6), 6 hours (n = 6), 12 hours (n = 6), or 18 hours (n = 6). One hour reperfusion was performed for every rat after orthotopic transplantation of donor small bowel. Small bowel samples were obtained for histological examination and immunohistochemistry analysis of nuclear factor kappaB (NF-kappaB) expression., Result: The small intestinal villus was arranged more regularly in experimental compared with control rats. Ischemia preconditioning also decreased edema in the muscule layer and increased Chiu score in experimental rats. Immunohistochemistry analysis revealed that ischemic preconditioning down-regulated the expression of NF-kappaB in the epithelia of experimental rats., Conclusion: Ischemic preconditioning improved intestinal transplantation in rats from cold ischemia and reperfusion injury by down-regulating the expression of NF-kappaB.

Background: The role of ischemia/reperfusion injury in the pathogenesis of acute pancreatitis is still ill-defined. It is accepted, however, that ischemia/reperfusion induces the development of postimplantation pancreatitis that is responsible for considerable morbidity. Preconditioning by brief exposure to ischemia protects the organ against damage evoked by subsequent severe ischemia. This study was undertaken to examine whether two brief ischemic periods protect the pancreas against severe ischemia/reperfusion-induced pancreatitis., Materials and Methods: This study was performed on 30 rats in three groups. The first group (control) underwent a laparatomy without clamping of any artery. The second group underwent 30-minute clamping of the inferior splenic artery followed by 1-hour reperfusion of the pancreas, and the third group underwent clamping of inferior splenic artery (2 x 5 minutes with 5-minute interval) as ischemic preconditioning and then 30-minute clamping of inferior splenic artery followed by 1-hour reperfusion., Results: Exposure to 30-minute pancreatic ischemia followed by 1-hour reperfusion led to the development of severe alterations greater than the other group that underwent ischemic preconditioning and then ischemia/reperfusion. Ischemia preconditioning applied prior to induction of pancreatitis reduced plasma lipase and interleukin-1beta concentrations as well as less histological signs of pancreatic damage., Conclusion: We concluded that pancreatic ischemic preconditioning reduced the severity of ischemia/reperfusion-induced pancreatitis. This effect seemed to be related at least in part to the release of the proinflammatory mediator interleukin-1beta.

The ischemia/reperfusion (I/R) model in rats allows pharmacological investigation of protective renal effects of certain agents to thereby diminish the incidence of delayed graft function (DGF). The aim of this study was to determine the effects of preconditioning with triiodothyronine (T(3)) on renal function and oxidative status in renal I/R injury. Forty male Wistar rats were preconditioned with T(3) (100 microg/kg) or control (normal saline) at 24 hours prior to 45 minutes of renal ischemia, followed by a 4-hour (groups C-4h and T(3)-4h) or 24-hour (groups C-24h and T(3)-24h) reperfusion period. We determined renal function parameters (urea, creatinine, and proteinuria), oxidative stress biomarkers in plasma (malondialdehyde [MDA], glutathione [GSH], and superoxide dismutase [SOD]), urine (hydrogen peroxide [H(2)O(2)]), and renal tissue (GSH and MDA), and poly(ADP-ribose) polymerase (PARP-1) expression. Proteinuria was significantly lower in the T(3)-treated group (4.63 +/- 1.9 vs 9.27 +/- 0.72 mg/mL/100 g body weight). Pretreated rats showed lower levels of plasma and tissue MDA and urine H(2)O(2) (50.57 +/- 1.17 vs 71.16 +/- 1.14 micromol/100 g body weight). The T(3) treatment was associated with lower postischemia GSH concentrations (3.82 +/- 1.16 vs 4.89 +/- 0.68 nmol/mg protein) and higher SOD levels at 24 hours (11.27 +/- 0.86 vs 9.92 +/- 1.77 nmol/mg protein). Preconditioning with the hormone also reduced PARP-1 tissue expression by 18% (P

Purpose: The purpose of this study was to establish morphologically the best time of vascular occlusion to induce ischemic preconditioning (IPC) for rat small bowel undergoing ischemia and reperfusion injury., Methods: After approval by the Ethics Committee, 36 EPM-1 young adult Wistar rats from 300-350 g were distributed into 6 groups: sham (S); ischemia and reperfusion (IR), with 50 minutes of cranial mesenteric artery occlusion and 30 minutes of reperfusion; IPC with 1 cycle of 2 minutes (IPC-2), 5 minutes (IPC-5), 10 minutes (IPC-10), or 15 minutes (IPC-15), followed by sustained IR. The animals anesthetized with ketamine (60 mg/kg) and xylazine (10 mg/kg) intramuscular (IM), were maintained on mattress heat, hydrated with saline (80 mL/kg), and injected with 100 IU heparin. Samples of jejunum were stained with hematoxylin and eosin (HE) and classified according to Park et al. Statistical analysis of results was performed using Kruskal-Wallis tests (P < .05)., Results: The histological evaluation showed no difference between IR and IPC15 rats (5.2 and 5, respectively; P = .84). Greater jejunal injury was observed with IPC15 (5) compared with other groups (IPC2 = 3, P = .03; IPC5 = 3.2, P = .05; IPC10 = 2.8, P = .02, respectively). There was no difference between groups IPC2 x IPC5 x IPC10., Conclusion: Morphologically, IPC with short times promoted greater intestinal protection against the IR lesion in rats.

Purpose: The purpose of this study was to evaluate estradiol serum levels and follicular development in rats subjected to ovarian autologous transplantation with or without remote ischemic preconditioning (R-IPC)., Methods: Seventy-two adult female Wistar EPM-1 rats were distributed into 3 groups: (1) controls; (2) ovarian transplantation; and (3) ovarian transplantation + R-IPC. The groups were divided into subgroups, according to the prefixed date for euthanasia: 24 hours, 48 hours, 72 hours, and 7th postoperative day (PO). R-IPC was performed by clamping the common iliac artery for a 15-minute period of ischemia followed by 15 minutes of reperfusion, before undergoing ovarian transplantation. The graft was fixed to the retroperitoneum with a simple 8-0 prolene thread. Blood samples were collected from the vena cava. For evaluation of follicular development, the ovarian follicles were classified as immature and mature follicles besides corpora lutea. Only the viable follicles and functioning corpora lutea were counted., Results: At 72 hours, the R-IPC group showed higher estradiol values than the other groups, which were similar. After 24 hours the mean values were similar among all groups, and at 48 hours the R-IPC group was similar to the transplanted group without IPC. Animals undergoing R-IPC showed superior morphologic aspects, but 7 days after transplantation the morphology was worse in all groups. R-IPC enhanced the number of immature follicles at 48 hours (P > .05) and number of mature follicles from 24 hours to 48 hours after transplantation (P < .01). Functioning corpora lutea number was increased as well., Conclusion: R-IPC increased the estradiol levels in autologous ovarian transplants associated with better graft morphology and more mature follicles.

Increasing evidence supports the beneficial effects of ischemic preconditioning (IPC) of organs on subsequent ischemia. The aim of this study was to assess the effects of IPC of the pancreas on islet cell recovery after cold preservation using a rat model. The pancreas was deprived of perfusion (celiac artery and superior mesenteric artery occlusion) for 10 minutes followed by 10 minutes of reperfusion. Islet isolation was performed after 18 hours of cold ischemia. Glands undergoing IPC yielded significantly greater numbers of islets than controls. Following overnight culture, a significantly greater proportion of islets was recovered from IPC-treated pancreata. Microarray genomic analysis of pancreatic tissue revealed a significant differential expression of approximately 600 unique mRNA strands within IPC pancreata compared to only <100 unique mRNA strands within non-IPC pancreata (>2-fold change; P < .05). Proteomic analysis revealed significant differential expression of at least 5 proteins >1.5-fold change; P < .05) within the IPC vs control group. Our data indicated that IPC of the pancreas prior to cold preservation was associated with improved islet cell recovery after cold ischemia. IPC of the pancreas may represent a viable therapeutic intervention to increase islet transplantation success from a single donor and to maximize organ utilization.

Objective: Our aim was to investigate the mechanisms of early protection by ischemic preconditioning (IPC) of transplanted rat kidneys., Materials and Methods: Thirty-six male donor and recipient Sprague-Dawley (SD) rats were randomly divided into 3 groups: sham-operated (A), transplantation (B), and IPC treatment (C) groups. Group A underwent exploratory laparotomy, group B received orthotopic transplantation, and group C, 15 minutes of ischemia followed by 10 minutes of reperfusion before transplantation. We measured the serum creatinine (SCr), blood urea nitrogen (BUN), and degree of kidney graft ischemic/reperfusion injury (IRI) by tumor necrosis factor-alpha (TNF-alpha) IkappaB kinase beta (IKK-beta) nuclear factor-kappa beta (NF-kappabeta) p65 subunit mRNA expressions., Results: The SCr and BUN levels in groups C and B were higher than those in the sham-operated group (P < .01), without a significant difference between groups C and B at 24 hours after transplantation (P > .05). The degree of renal graft tubular injury in group C was significantly lower than that in group B (P < .01). TNF-alpha transcription levels at 24 hours after transplantation were significantly lower compared with the non-IPC group (P < .01). However, we failed to note a significant difference in IKK-beta or p65 mRNA expressions between groups C and B (P > .05)., Conclusions: One cycle of preconditioning (15 min/10 min) attenuated renal graft IRI in the early phase. The inhibiting effects on TNF-alpha and the positive feedback signaling of TNF-alpha/NF-KB pathways may play important roles in renal graft protection.

Objective: The aim of this study was to investigate the early protection of ischemic preconditioning (IPC) and its mechanisms in transplanted rat kidneys., Materials and Methods: Thirty-six male Sprague-Dawley (SD) rat donors and recipients were randomly divided into the following groups: sham-operated group (A; n = 6); untreated transplantation group (B; n = 6); and treatment group (C; n = 6). Group A was subjected to exploratory laparotomy. Group B received orthotopic transplantation. Group C underwent a 15-minute period of ischemia followed by a 10-minute reperfusion before orthotopic transplantation. We assessed the serum creatinine (SCr), blood urea nitrogen (BUN), and to evaluate the degree of kidney graft ischemia/reperfusion injury: tumor necrosis factor-alpha (TNF-alpha), IkappaB kinase-beta (IKK-beta), and nuclear factor-kappa B (NF-kappaB) P65 subunit mRNA expressions., Results: The levels of SCr and BUN in groups C and B were greater than in the sham-operated group (P < .01), but there was no significant difference between the C and B groups at 24 hours after transplantation (P > .05). The degree of renal graft tubular injury in group C was significantly less compared with group B (P < .01). TNF-alpha transcription levels at 24 hours after transplantation were significantly less compared with the non-IPC group (P < .01). However, no significant difference was observed in IKK-beta mRNA and P65 mRNA expressions between groups C and B (P > .05)., Conclusions: A 1-cycle schedule of preconditioning (15 min/10 min) attenuated renal graft ischemia/reperfusion injury in the early phase. IPC can improve rat kidney allograft function after ischemia/reperfusion injury. The inhibitory effects on TNF-alpha and on positive feedback signaling of TNF-alpha/NF-kappaB pathways may play important roles in renal graft protection in the early stage.

Purpose: Verify the optimum remote vascular occlusion time to reduce ovarian injury in autologous transplants in rats., Methods: Twenty-four adult female rats were assigned to four groups: GC (control group): bilateral oophorectomy followed by ovary transplant; GIPC (ischemic preconditioning group): remote ischemic preconditioning at the iliac artery for 5, 10, and 15 minutes (GIPC-5, GIPC-20, and GIPC-15) previous to bilateral oophorectomy and ovarian transplantation. The right ovary was fixed in the retroperitoneum. Euthanasia was performed 4 days after the surgical procedure. The follicles were counted and classified as developing versus atretic. The immunohistochemical assay identified vascular factor of endothelial growth (VEGF) in the ovarian stroma and assessed the proliferation capacity by means of the Ki-67 in the ovarian follicles., Results: Every group showed an inflammatory infiltrate, luteous body, and ovarian follicles in several phases of development. The ischemic preconditioning groups displayed greater amounts of viable ovarian follicles and increased vascularization and vasodilatation than the control group. GIPC-15 showed the highest amount of viable follicles compared to the others (P < .05 GIPC-15 vs GC; GIPC-15 vs GIPC-5). More VEGF-labeled cells were observed in GIPC-10 than the control group (P < .05, GIPC-10 vs GC). The proliferation index assessed by Ki-67 marking showed GC: 80%; GIPC-5: 76%; GIPC-10: 67%; and GIPC-15: 64% (P > .05)., Conclusions: The PCI-15 cohort seem to be the most adequate timing to achieve functional support and preservation of a greater number of viable ovarian follicles.

Increasing evidence has shown that reactive oxygen species (ROS) are important mediators in liver ischemia/reperfusion injury(IRI). ROS include hydrogen peroxide (H(2)O(2)), superoxide anion (O(-2)), and hydroxyl radical (HO(-)), which may be generated by activated Kupffer cells in the liver, contributing to reperfusion injury. Hepatic IRI is a multistep process that damages liver graft function. To establish a series of therapeutic strategies to improve the outcome of liver transplantation, a good understanding of the mechanisms of IRI is essential. However, the detail mechanisms of how ROS lead to hepatocyte damage in IRI remains unclear. The aim of this review was to describe recent developments in the field of oxidative stress research. The first part of this review focused on the key roles and possible mechanisms of ROS in hepatic IRI. The second part of this review summarizes some findings including novel and classic antioxidant methods to ameliorate the hepatocyte damage during IRI.

To minimize bleeding during major liver resections or liver transplantation, surgical measures have been adopted that induce ischemia-reperfusion injury (I/R) which may significantly contribute to morbidity and mortality of partial liver resections. Several methods have sought to minimize I/R hepatic lesions. The present project assessed the protective role of ischemic preconditioning (IPC) in rat livers. The IPC was accomplished by clamping the hepatic pedicle for 5 minutes, followed by a 5-minute reperfusion (R) period before a 2-hour ischemia. Thereafter, reperfusions of 1, 3, and 24 hours were compared among IPC and control groups without IPC. Liver biopsy and blood samples were measured for mitochondrial respiratory control ratio (RCR), serum aspartate aminotransferase (AST), and alanine aminotransferase (ALT). IPC protected liver mitochondrial function. Serum aminotransferase levels were significantly lower among animals undergoing IPC compared with groups without IPC. Thus, we verified the effects of IPC for hepatocellular protection against I/R lesions.

Purpose: We investigated whether pharmacologically induced up-regulation of heme oxygenase 1 by pyrrolidine dithiocarbamate (PDTC) conferred protection against subsequent ischemia-reperfusion injury (IRI) to the rat liver after temporary vascular occlusion of 70% of the organ., Methods: Female Wistar rats (200 to 250 g body weight) anesthetized with pentobarbitone were cannulated in the carotid artery and jugular vein. After laparotomy, a rubber band was applied around the entire vascular supply to the median and left lateral lobes, enabling vascular occlusion of 70% of the liver. A laser Doppler miniprobe was placed on the left lateral lobe to monitor peripheral liver blood flow (PLBF). Immediately upon completion of the surgery, the rats were administered either PDTC (50 mg/kg intravenously; n = 8) or its solvent (isotonic NaCl; n = 8). After 60 minutes, regional ischemia was induced for 30 minutes. The animals were then monitored for 2 hours of reperfusion. Blood samples for alanine transferase (ALT) estimation (as a measure of parenchymal injury) were drawn immediately prior to ischemia and reperfusion, as well as 60 and 120 minutes after reperfusion; PLBF was calculated at these times., Results: ALT increased in the course of the experiments but there was no difference between the groups. The reduction in PBLF due to ischemia-reperfusion was significantly lower in the PDTC group: about 16% versus 40%, after 2 hours of reperfusion., Conclusion: Pretreatment with PDTC attenuated the disturbance of hepatic microcirculation, but not parenchymal injury, in the early phase of IRI.

Unlabelled: In this study we examined the effect of remote ischemic preconditioning (RIPC) on liver ischemia-reperfusion (IR) injury. Anesthetized Wistar rats (200 to 250 g body weight, n = 32) had the right femoral artery (FA) dissected. Protocol I. The hepatic artery (HA) was clamped for 60 minutes; peripheral liver blood flow (PLBF) and alanine aminotransferase (ALT) were measured prior to clamping as well as 60 minutes after reperfusion. The cohorts were group 1 (no RIPC; n = 10) and group 2 (RIPC; n = 10) 35 minutes after surgery, the FA was clamped for 10 minutes. After 15 minutes, the HA was clamped as in group 1. In protocol II, a rubber band was applied around the entire vascular supply to about 70% of the liver, yielding group 3 (no RIPC; n = 6) that 60 minutes after surgery, had vascular occlusion performed for 30 minutes and group 4 (RIPC; n = 6) with the FA clamped as above, in a procedure otherwise identical to that of group 3., Results: In protocol I, there was no significant difference in PLBF between the two groups after reperfusion, but the increased ALT levels in the RIPC group were reduced (.70 +/- .05 vs. 1.0 +/- .15 microkat/L, P = .049). In protocol II, we observed no significant differences in ALT levels or PLBF between the two groups. Thus, a beneficial effect of RIPC was demonstrated in protocol I with relative hypoxemia to the liver. However, the effect could not be demonstrated in protocol II, which induced a more severe IR injury.

Ischemic preconditioning (IPC), which is obtained by exposure to brief periods of vascular occlusion, improves organ tolerance to prolonged ischemia. The aim of this study was to evaluate the threshold level of NF-kB activation in small intestine during an IPC procedure. Various intestinal IPC were performed on 20 Wistar rats in seven groups: group I (GI, nonpreconditioned); group II (GII, 1-minute ischemia and 1-minute reperfusion); group III (GIII, two cycles of 1-minute ischemia and 1-minute reperfusion); group IV (GIV, 2-minutes ischemia and 2-minutes reperfusion); group V (GV, two cycles of 2-minute ischemia and 2-minute reperfusion); group VI (GVI, 5-minute ischemia and 10-minute reperfusion); group VII (GVII, two cycles of 5-minute ischemia and 10-minute reperfusion). Bowel biopsies were collected after laparotomy (control) as well as at 30, 60, and 120 minutes following IPC. We determined the cytoplasmic and nuclear NF-kB by a chemiluminescence-based ELISA method. Our results showed low, constant NF-kB levels in GI. In the preconditioned groups (GII-GVII), NF-kB was significantly elevated at 30 minutes following IPC (P < .05 vs control). After 1 hour, NF-kB activity decreased to the control level. However, 2 hours after IPC both forms of NF-kB were elevated significantly again, which was independent of the number of IPC cycles (P < .05 vs control). Our experiments revealed that one cycle of 1-minute ischemia and 1-minute reperfusion is a critical threshold level for NF-kB activation during small bowel IPC. Longer and more IPC cycles did not result in further elevation of NF-kB activation.

The aim of this study was to assess the influence of ischemic preconditioning (IPC) on parenchymal liver blood flow during the early phase of reperfusion after 60 minutes of ischemia, additionally modified by adding N-nitro-L-arginine methyl ester (L-NAME). Our research involved 4 groups of rats (10 animals in each group), which underwent liver ischemia and 24 hours of reperfusion. Group I, ischemia/reperfusion (IR) was performed; group II, IPC, 10 minutes of ischemia and 10 minutes of reperfusion, and IR after that; group III, L-NAME (10 mg/kg intravenous [iv]), 10 minutes before IR; and group IV, L-NAME before IPC + IR. Activity of APAT, ALAT, GGTP, and FA was marked in serum in 90 minutes and 24 hours of reperfusion. In the liver biopsies at 24 hours of reperfusion, we analyzed reaction on adenosine-3-phosphatase stimulated by Mg++ and performed histological examination. The parenchymal perfusion was measured using a laser-doppler blood flowmeter (model PeriFlux System5000, Perimed Inc., United Kingdom). IPC during reperfusion led to minor injuries of the organ, with statistically significant normalization of enzymes compared with group 1, and a better reaction to the adenosine-3-phosphatase IPC produced faster and full return of perfusion to the 68.3 value at 24 hours (59.1 in the 60 minutes). In groups III and IV at 60 minutes, the perfusion was not statistically different from that in group 1. IPC causes full and faster blood return in the early phase of reperfusion and minor injury of liver parenchyma and liver sinus. The protective effect observed, especially in the first 60 minutes of reperfusion, was limited by L-NAME and was influenced by the action of nitric oxide.

Background: Heat exposure of isolated islets enhances resistance against inflammation but decreases islet graft function. In contrast, donor preconditioning by whole-body hyperthermia increases islet ischemic tolerance and improves viability of pancreatic isografts. This study aimed to compare yield, viability, and inflammatory resistance of rat islets subjected to heat shock prior to (pre-HS) or after isolation (post-HS)., Methods: Islets were isolated as previously described. HS (42 degrees C/45 min) was induced 12 hours before islet isolation (pre-HS, n = 31) or in freshly isolated islets prior to 12 hours of recovery at 37 degrees C (post-HS, n = 12). Islets continuously incubated at 37 degrees C served as controls (n = 33). Proinflammatory treatment included incubation with 0.05 mmol/L H(2)O(2), 1.0 mmol/L DETA-NO or cytokines (interleukin-1beta + tumor necrosis factoralpha + interferongamma)., Results: Purified islet yield was 1200 +/- 80 IEQ in unconditioned donors (n = 45) and 980 +/- 80 IEQ after pre-HS (ns). Islet viability was not affected by post-HS, but the glucose stimulation index (P < 0.001, P < 0.01) and formazan production (P < 0.05) were significantly lower compared to pre-HS or sham treatment. The expression of heat shock protein HSP70 in pre-HS islets was slightly higher compared to controls (ns) but lower compared to post-HS islets (P < 0.05), correlating with the resistance against H(2)O(2) and DETA-NO compared to post-HS islets (P < 0.05) or controls (ns). Cytokines did not affect mitochondrial formazan production., Conclusions: The findings indicate that hyperthermic islet treatment is less harmful if performed in the native pancreatic environment. This beneficial effect is associated with a decreased HSP70 expression resulting in a reduced resistance against inflammatory mechanisms.

Unlabelled: Ischemic preconditioning (IP) has been shown to ameliorate renal ischemia reperfusion injury. Using a rat kidney transplantation model we determined if IP improves graft function after prolonged cold storage., Materials and Methods: Syngeneic rat kidneys were divided into two groups. Prior to 42 hours of cold storage in UW and transplantation, one group (n = 10) received IP (15 minutes of warm ischemia/10 minutes of reperfusion), whereas another group (n = 10) received no treatment. Early graft function and 1-week recipient survival were assessed., Results: Recipient survival was not significantly different between groups [70% (IP) vs 40% (non-IP); P = .28]. IP treatment led to a quicker recovery of renal function. On PODs 3 and 6, serum creatinine levels in the IP group were significantly lower compared with the untreated group. In conclusion, one cycle of IP (15/10) accelerates recovery of renal graft function after severe ischemia reperfusion injury. This simple treatment modality may improve outcomes of renal transplants with prolonged cold storage.

Ischemic preconditioning (IP), obtained by exposure to brief periods of vascular occlusion, improves organ tolerance to prolonged ischemia. The aim of this study was to evaluate the effects of IP on intestinal morphology. Forty rats were subjected to sham surgery (n = 20, group I) or intestinal preconditioning (n = 20, group II) with a cycle of brief ischemia/reperfusion (10-minute occlusion of superior mesenteric artery [SMA], followed by 10-minute reperfusion) before prolonged ischemia produced by SMA occlusion (45 minutes). Five animals in each group were sacrificed 2, 12, 24, and 48 hours after reperfusion. Intestinal samples were processed for light and electron microscopy. A TUNEL assay was performed to detect apoptosis. Statistical analysis used Student t test and Kaplan-Meier survival curves. The overall mortality for the sham-operated group was 15%, while no animals of group II died (NS). Histological evaluation showed early detachment of epithelial cells from villous stroma accompanied by marked congestion and edema. Successive morphological changes were represented by leukocyte infiltration, focal necrosis, and marked villus denudation or loss. Group II animals showed significantly reduced inflammatory infiltrates in the lamina propria and a greater villus height compared to group I. The maximum number of apoptotic nuclei was observed in both groups, Following 2 hours of reperfusion group II animals showed significantly, greater apoptosis at 2 and 12 hours after reperfusion (P <.05). Electron microscopy showed severe mitochondrial and basement membrane damage. The findings from this study confirm that IP preconditioning attenuates morphological alterations that are invariably present after prolonged ischemia and reperfusion.

Ischemic preconditioning (IPC) has been defined as short periods of ischemia with intermittent reperfusion. IPC induces two phases of protection. We sought to investigate the effects of classic and delayed preconditioning on oxidative stress markers prior to autotransplantation. Total orthotopic intestinal autotransplantation was performed on 18 mongrel dogs in three groups: group I (GI, nonpreconditioned), group II (GII, classic preconditioned), and group III (GIII, delayed preconditioned). In GI 3-hour cold preservation in University of Wisconsin solution was followed by 1 hour of reperfusion. In GII before this procedure the intestine was preconditioned by occlusion of the mesenteric artery with four cycles each of 5 minutes of ischemia and 10 minutes of reperfusion (IPC protocol). In GIII on day 1 the animals underwent the IPC protocol, and autotransplantation was performed on day 2. Oxidative stress parameters included malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) measurements in tissue samples. Our results showed increased lipid peroxidation with decreased GSH level and SOD activity in GI (control: 254.38 +/- 18.32 IU/g; reperfused: 55.01 +/- 26.40 IU/g; P <.05). In GII MDA was slightly elevated, and the GSH concentration was increased markedly. Furthermore, better preservation of SOD activity was observed at the end of the reperfusion. Meanwhile, in GIII GSH was significantly increased, indicating the activation of the endogenous antioxidant protective system (control: 382.13 +/- 24.22 micromol/L per gram; reperfused: 515.25 +/- 26.36 micromol/L per gram; P <.05). Moreover, SOD surpassed the control activity. Our findings confirmed that both forms of preconditioning mitigate the severity of oxidative stress prior to preservation and autotransplantation. Delayed preconditioning is more effective to protect bowel tissue against oxidative injury.

Ischemic preconditioning renders the liver more tolerant to ischemia-reperfusion injury in warm and cold ischemia-reperfusion models. In general, the application of a 5 to 10-minute period of ischemia followed by 10 minutes of reperfusion confers early effective protection to the liver. Mechanisms responsible for this endogenous protective effect include: (1) transient nitric oxide production during liver preconditioning; (2) diminution of toxic reactive species generated on reperfusion; (3) remote effect on extrahepatic organs such as lung, kidney, and pancreas; (4) preservation of energy metabolism during ischemia; and (5) involvement of nuclear transcription factor and others.