Time to angiographic reperfusion in acute ischemic stroke: decision analysis.

PubMed

Vagal, Achala S; Khatri, Pooja; Broderick, Joseph P; Tomsick, Thomas A; Yeatts, Sharon D; Eckman, Mark H

2014-12-01

Our objective was to use decision analytic modeling to compare 2 treatment strategies of intravenous recombinant tissue-type plasminogen activator (r-tPA) alone versus combined intravenous r-tPA/endovascular therapy in a subgroup of patients with large vessel (internal carotid artery terminus, M1, and M2) occlusion based on varying times to angiographic reperfusion and varying rates of reperfusion. We developed a decision model using Interventional Management of Stroke (IMS) III trial data and comprehensive literature review. We performed 1-way sensitivity analyses for time to reperfusion and 2-way sensitivity for time to reperfusion and rate of reperfusion success. We also performed probabilistic sensitivity analyses to address uncertainty in total time to reperfusion for the endovascular approach. In the base case, endovascular approach yielded a higher expected utility (6.38 quality-adjusted life years) than the intravenous-only arm (5.42 quality-adjusted life years). One-way sensitivity analyses demonstrated superiority of endovascular treatment to intravenous-only arm unless time to reperfusion exceeded 347 minutes. Two-way sensitivity analysis demonstrated that endovascular treatment was preferred when probability of reperfusion is high and time to reperfusion is small. Probabilistic sensitivity results demonstrated an average gain for endovascular therapy of 0.76 quality-adjusted life years (SD 0.82) compared with the intravenous-only approach. In our post hoc model with its underlying limitations, endovascular therapy after intravenous r-tPA is the preferred treatment as compared with intravenous r-tPA alone. However, if time to reperfusion exceeds 347 minutes, intravenous r-tPA alone is the recommended strategy. This warrants validation in a randomized, prospective trial among patients with large vessel occlusions. © 2014 American Heart Association, Inc.

Involvement of Rho-kinase in cold ischemia-reperfusion injury after liver transplantation in rats.

PubMed

Shiotani, Satoko; Shimada, Mitsuo; Suehiro, Taketoshi; Soejima, Yuji; Yosizumi, Tomoharu; Shimokawa, Hiroaki; Maehara, Yoshihiko

2004-08-15

Reperfusion of ischemic tissues is known to cause the generation of reactive oxygen species (ROS) with resultant tissue damage. However, the sources of ROS in reperfused tissues are not fully characterized. We hypothesized that the small GTPase Rho and its target effector Rho-kinase/ROK/ROCK are involved in the oxidative burst in reperfused tissue with resultant reperfusion injury. In an in vivo rat model of liver transplantation using cold ischemia for 12 hr followed by reperfusion, a specific Rho-kinase inhibitor, fasudil (30 mg/kg), was administered orally 1 hr before the transplantation. Fasudil suppressed the ischemia-reperfusion (I/R)-induced generation of ROS after reperfusion (P<0.01) and also suppressed the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta) 3 hr after reperfusion, resulting in a significant reduction of I/R-induced hepatocellular injury (P<0.05), necrosis, apoptosis (P<0.01), and neutrophil infiltration (P<0.0001) 12 hr after reperfusion. All animals receiving a graft without fasudil died within 3 days, whereas 40% of those receiving fasudil survived (P<0.001). The present study demonstrates that Rho-kinase-mediated production of ROS and inflammatory cytokines are substantially involved in the pathogenesis of hepatocellular necrosis and apoptosis induced by cold I/R in vivo and that Rho-kinase may be regarded as a novel therapeutic target for the disorder.

[Free radicals and hepatic ischemia-reperfusion].

PubMed

Szijártó, Attila

2015-11-22

The critical importance of the ischemic-reperfusive injury is well documented with regards to numerous organs and clinical conditions. Oxygen free radicals play a central role in the mediation of the injury, which dominantly influences the prevalence of postoperative complications, (long term) organ damage, and the potential manifestation of systemic reactions. The both anatomically and pathophysiologically unique ischemic-reperfusive injury of the liver, which is expressively vulnerable to free radicals, is of utmost importance in liver surgery. Several techniques (adaptive maneuvers, chemical agents) are known to ameliorate the reperfusive injury. Based on the prior research of the workgroup of the author, the aim of the current article is to overview the set of measures capable of attenuating ischemic-reperfusive injury (ischemic preconditioning, -perconditioning, administration of adenosine, -inosine, -levosimendan, and -poly-ADP-ribose-polymerase inhibitor), with special attention to the ischemic-reperfusive injury of the liver, as well as the special pathophysiological role of free radicals in mediating hepatic damage.

DIFFERENT PROTOCOLS OF POSTCONDITIONING DOES NOT ATTENUATE MESENTERIC ISCHEMIA-REPERFUSION INJURY AFTER SHORT-TERM REPERFUSION

PubMed Central

BRITO, Marcus Vinicius Henriques; YASOJIMA, Edson Yuzur; MACHADO, Andressa Abnader; SILVEIRA, Matheus Paiva Pacheco Reis; TEIXEIRA, Renan Kleber Costa; YAMAKI, Vitor Nagai; COSTA, Felipe Lobato da Silva

2017-01-01

ABSTRACT Background: Mesenteric ischemia is a challenging diagnosis. Delay in diagnosis can lead to extent bowel necrosis and poor outcomes. Ischemia and reperfusion syndrome plays an important role in this scenario. Aim: To access effects of different post-conditioning cycles on mesenteric ischemia-reperfusion syndrome. Method: Twenty-five rats were assigned into five groups: Sham, used to establish normal parameters; control group, submitted to mesenteric ischemia for 30 min; in groups GP3, GP1 and GP30, ischemia was followed by post-conditioning protocol, which consisted of 1 cycle of 3 min (GP3), 3 cycles of 1 min (GP1) or 6 cycles of 30 s (GP30), respectively. Ileum samples were harvested after one hour of reperfusion. Intestinal mucosal injury was evaluated through histopathological analysis. Results: The average of mesenteric injury degree was 0 in the sham group, 3.6 in the control group, 3.4 in GP3, 3.2 in GP1, and 3.0 in GP30; villous length average was 161.59 in sham group, 136.27 in control group, 135.89 in GP3, 129.46 in GP1, and 135.18 in GP30. Was found significant difference between sham and other groups (p<0.05); however, there was no difference among post-conditioning groups. Conclusion: Post-conditioning adopted protocols were not able to protect intestinal mucosa integrity after mesenteric ischemia and short term reperfusion. PMID:28489164

Global brain ischemia and reperfusion.

PubMed

White, B C; Grossman, L I; O'Neil, B J; DeGracia, D J; Neumar, R W; Rafols, J A; Krause, G S

1996-05-01

Brain damage accompanying cardiac arrest and resuscitation is frequent and devastating. Neurons in the hippocampus CA1 and CA4 zones and cortical layers III and V are selectively vulnerable to death after injury by ischemia and reperfusion. Ultrastructural evidence indicates that most of the structural damage is associated with reperfusion, during which the vulnerable neurons develop disaggregation of polyribosomes, peroxidative damage to unsaturated fatty acids in the plasma membrane, and prominent alterations in the structure of the Golgi apparatus that is responsible for membrane assembly. Reperfusion is also associated with vulnerable neurons with prominent production of messenger RNAs for stress proteins and for the proteins of the activator protein-1 complex, but these vulnerable neurons fail to efficiently translate these messages into the proteins. The inhibition of protein synthesis during reperfusion involves alteration of translation initiation factors, specifically serine phosphorylation of the alpha-subunit of eukaryotic initiation factor-2 (elF-2 alpha). Growth factors--in particular, insulin--have the potential to reverse phosphorylation of elF-2 alpha, promote effective translation of the mRNA transcripts generated in response to ischemia and reperfusion, enhance neuronal defenses against radicals, and stimulate lipid synthesis and membrane repair. There is now substantial evidence that the insulin-class growth factors have neuron-sparing effects against damage by radicals and ischemia and reperfusion. This new knowledge may provide a fundamental basis for a rational approach to "cerebral resuscitation" that will allow substantial amelioration of the often dismal neurologic outcome now associated with resuscitation from cardiac arrest.

Electrocardiography as a Tool for Validating Myocardial Ischemia–Reperfusion Procedures in Mice

PubMed Central

Preda, Mihai B; Burlacu, Alexandrina

2010-01-01

This paper evaluates the modifications induced by ischemia and ischemia–reperfusion in mice after permanent or transient, respectively, ligation of the left coronary artery and establishes a correlation among the extent of ischemia, electrocardiograph features, and infarct size. The left coronary artery was ligated 1 mm distal from the tip of the left auricle. Histologic analysis revealed that 30-min ischemia (n = 9) led to infarction involving 9.7% ± 0.5% of the left ventricle, whereas 1-h ischemia (n = 9) resulted in transmural infarction of 16.1% ± 4.6% of the left ventricle. In contrast, 24-h ischemia (n = 8) and permanent ischemia (n = 8) induced similarly sized infarcts (33% ± 2% and 31.8% ± 0.7%, respectively), suggesting ineffective reperfusion after 24-h ischemia. Electrocardiography revealed that ligation of the left coronary artery led to ST height elevation (204 compared with 14 μV) and QTc prolongation (136 compared with 76 ms). Both parameters rapidly normalized on reperfusion, demonstrating that electrocardiography was important for validating correct ligation and reperfusion. In addition, electrocardiography predicted the severity of the myocardial damage induced by ischemia. Our results show that electrocardiographic changes present after 30-min ischemia were reversed on reperfusion; however, prolonged ischemia induced pathologic electrocardiographic patterns that remained even after reperfusion. The mouse model of myocardial ischemia–reperfusion can be improved by using electrocardiography to validate ligation and reperfusion during surgery and to predict the severity of infarction. PMID:21262130

Monitoring somatosensory evoked potentials in spinal cord ischemia-reperfusion injury

PubMed Central

Ji, Yiming; Meng, Bin; Yuan, Chenxi; Yang, Huilin; Zou, Jun

2013-01-01

It remains unclear whether spinal cord ischemia-reperfusion injury caused by ischemia and other non-mechanical factors can be monitored by somatosensory evoked potentials. Therefore, we monitored spinal cord ischemia-reperfusion injury in rabbits using somatosensory evoked potential detection technology. The results showed that the somatosensory evoked potential latency was significantly prolonged and the amplitude significantly reduced until it disappeared during the period of spinal cord ischemia. After reperfusion for 30–180 minutes, the amplitude and latency began to gradually recover; at 360 minutes of reperfusion, the latency showed no significant difference compared with the pre-ischemic value, while the somatosensory evoked potential amplitude in-creased, and severe hindlimb motor dysfunctions were detected. Experimental findings suggest that changes in somatosensory evoked potential latency can reflect the degree of spinal cord ischemic injury, while the amplitude variations are indicators of the late spinal cord reperfusion injury, which provide evidence for the assessment of limb motor function and avoid iatrogenic spinal cord injury. PMID:25206629

Hepatic apoptotic activity following transient normothermic inflow occlusion and reperfusion in the swine model.

PubMed

Helling, T S; Edwards, C A; Helling, T S; Chang, C C; Hodges, M C; Dhar, A; VanWay, C

1999-09-01

Accelerated hepatic apoptosis was first described in portal vein-ligated livers but has since been reported in a variety of liver injuries. Because porto-prival states can induce apoptosis we sought to determine whether transient ischemic periods followed by reperfusion would trigger such cell death. The cytokines TNF-alpha and TGF-beta are known to facilitate apoptosis and are released in response to a number of stimuli including ischemia. We also investigated alterations in plasma and tissue levels of these cytokines which might lend support to their role in increased apoptotic activity following ischemia/reperfusion. Female pigs were used as the experimental model. Inflow occlusion of portal and hepatic arterial blood was performed to a portion of the swine liver directing the entire splanchnic flow to the remaining hepatic lobes for a period of 2 h. The livers were then reperfused and plasma and tissue samples taken for determination of apoptotic activity utilizing cell death immunoperoxidase staining of 3'-OH DNA ends generated by fragmentation and ELISA assay of histone-associated DNA fragments. Plasma and tissue levels of TNF-alpha and plasma levels of TGF-beta were determined by ELISA assay. An increase in apoptotic activity following reperfusion was seen at Day 2 and Day 4 compared to preischemic values by the cell death stain. The ELISA cell death assay showed an increase in apoptotic activity at 60 min, Day 2, and Day 4. Moreover, the ELISA cell death assay showed enhanced apoptotic activity in "hyperperfused" hepatic lobes compared to preischemic, or resting, liver. This was also observed when compared to sham-operated animals. Surprisingly, there was no detectable increase in plasma TNF-alpha or TGF-beta levels following ischemia/reperfusion, although homogenized liver TNF-alpha levels were increased at 60 min and Day 2 following reperfusion. We conclude that transient hepatic inflow occlusion followed by reperfusion can induce increased apoptotic

Reduced ischemia-reperfusion injury with isoproterenol in non-heart-beating donor lungs.

PubMed

Jones, D R; Hoffmann, S C; Sellars, M; Egan, T M

1997-05-01

Transplantation of lungs retrieved from non-heart-beating donors could expand the donor pool. Recent studies suggest that the ischemia-reperfusion injury (IRI) to the lung can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, as measured by Kfc, in lungs retrieved from non-heart-beating donors and reperfused with or without isoproterenol (iso). Using an in situ isolated perfused lung model, lungs were retrieved from non-heart-beating donor rats ventilated with O2 or not at varying intervals after death. The lungs were reperfused with or without iso (10 microM). Kfc, lung viability, and pulmonary hemodynamics were measured, and tissue levels of adenine nucleotides and cAMP were measured by HPLC. Iso-reperfusion decreased Kfc significantly (P < 0.05) compared to non-iso-reperfused groups at all postmortem ischemic times, irrespective of preharvest ventilation status. Pulmonary arterial pressures and resistances increased and venous resistances decreased with iso-reperfusion. Total adenine nucleotide (TAN) levels correlated with Kfc in non-iso-reperfused (r = 0.65) and iso-perfused (r = 0.84) lungs. cAMP levels increased significantly with iso-reperfusion. cAMP levels correlated with Kfc (r = 0.87) in iso-reperfused lungs. Iso-reperfusion of lungs retrieved from non-heart-beating donor rats results in decreased capillary permeability and increased lung tissue cAMP levels. Pharmacologic augmentation of tissue TAN and cAMP levels may further ameliorate the increased capillary permeability seen in lungs retrieved from non-heart-beating donors.

Edaravone prevents lung injury induced by hepatic ischemia-reperfusion.

PubMed

Uchiyama, Munehito; Tojo, Kentaro; Yazawa, Takuya; Ota, Shuhei; Goto, Takahisa; Kurahashi, Kiyoyasu

2015-04-01

Lung injury is a major clinical concern after hepatic ischemia-reperfusion (I/R), due to the production of reactive oxygen species in the reperfused liver. We investigated the efficacy of edaravone, a potent free-radical scavenger, for attenuating lung injury after hepatic I/R. Adult male Sprague-Dawley rats were assigned to sham + normal saline (NS), I/R + NS, or I/R + edaravone group. Rats in the I/R groups were subjected to 90 min of partial hepatic I/R. Five minutes before reperfusion, 3 mg/kg edaravone was administered to the I/R + edaravone group. After 6 h of reperfusion, we evaluated lung histopathology and wet-to-dry ratio. We also measured malondialdehyde (MDA), an indicator of oxidative stress, in the liver and the lung, as well as cytokine messenger RNA expressions in the reperfused liver and plasma cytokine concentrations. Histopathology revealed lung damages after 6 h reperfusion of partial ischemic liver. Moreover, a significant increase in lung wet-to-dry ratio was observed. MDA concentration increased in the reperfused liver, but not in the lungs. Edaravone administration attenuated the lung injury and the increase of MDA in the reperfused liver. Edaravone also suppressed the reperfusion-induced increase of interleukin-6 messenger RNA expressions in the liver and plasma interleukin-6 concentrations. Edaravone administration before reperfusion of the ischemic liver attenuates oxidative stress in the reperfused liver and the subsequent lung injury. Edaravone may be beneficial for preventing lung injury induced by hepatic I/R. Copyright © 2015 Elsevier Inc. All rights reserved.

Failure of antiarrhythmic drugs to prevent experimental reperfusion ventricular fibrillation.

PubMed

Naito, M; Michelson, E L; Kmetzo, J J; Kaplinsky, E; Dreifus, L S

1981-01-01

Ninety-nine adult mongrel dogs underwent acute ligation of the proximal left anterior descending coronary artery. Thirty minutes later, the occlusion was released to evaluate the effectiveness of five antiarrhythmic protocols in eliminating reperfusion ventricular fibrillation. The five protocols included: protocol 1 --i.v. lidocaine, preligation and prerelease (n = 19); protocol 2 -- i.v. lidocaine, prereperfusion only (n = 22); protocol 3 -- chronic, oral, daily amiodarone for 2 weeks preligation (n = 19); protocol 4 -- i.v. procainamide, preligation and prereperfusion (n = 21); and protocol 5 -- i.v. verapamil, prereperfusion (n = 18). Each regimen was evaluated with respect to the incidence of reperfusion ventricular fibrillation in dogs that survived to reperfusion, and the results were compared to 77 control dogs that underwent identical coronary artery occlusion and release procedures without drug therapy. The incidence of reperfusion ventricular fibrillation was as follows: protocol 1 -- seven of 15 dogs (47%); protocol 2 -- six of 18 (33%); protocol 3 -- 11 of 16 dogs (69%); protocol 4 -- eight of 17 dogs (47%); and protocol 5 -- 10 of 17 dogs (59%), compared with 36 of 60 (60%) in control dogs. Using chi-square analysis, protocol 2 was beneficial (p < 0.05). The dogs were then stratified into high- and low-risk subgroups based on the arrhythmic events of the antecedent coronary artery ligation periods, and predictive risk indexes for the occurrence of reperfusion ventricular fibrillation were developed. the Mantel-Haenszel method of statistical analysis revealed that none of these protocols resulted in a statistically significant reduction in the incidence of reperfusion ventricular fibrillation. Thus, use of these predictive indexes plus appropriate statistical methods has revealed, unexpectedly, limitations in the efficacy of a spectrum of antiarrhythmic agents in preventing reperfusion ventricular fibrillation.

HDAC Inhibition Blunts Ischemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy

PubMed Central

Xie, Min; Kong, Yongli; Tan, Wei; May, Herman; Battiprolu, Pavan K.; Pedrozo, Zully; Wang, Zhao; Morales, Cyndi; Luo, Xiang; Cho, Geoffrey; Jiang, Nan; Jessen, Michael E.; Warner, John J.; Lavandero, Sergio; Gillette, Thomas G.; Turer, Aslan T.; Hill, Joseph A.

2014-01-01

Background Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that SAHA, a histone deacetylase (HDAC) inhibitor FDA-approved for cancer treatment, will blunt reperfusion injury. Methods and Results Twenty-one rabbits were randomized into 3 groups: a) vehicle control, b) SAHA pretreatment (one day prior and at surgery), and c) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (I/R, 30min coronary ligation, 24h reperfusion). Additionally cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated I/R (sI/R) to probe mechanism. SAHA reduced infarct (those reduction inhibitor, SAHA, infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during I/R occur, at least in part, through induction of autophagic flux. assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to sI/R, SAHA pretreatment reduced cell death by 40%. This eduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA's cardioprotective effects. Conclusions The FDS-approved anti-cancer HDAC inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during I/R occur, at least in part, through induction of autophagic flux. PMID:24396039

Selenium Ameliorate Peripheral Nerve Ischemic-Reperfusion Injury via Decreased TNF-α.

PubMed

Zendedel, Abolfazl; Gharibi, Zahra; Anbari, Khatereh; Abbaszadeh, Abolfazl; Khayat, Zahra Khanipour; Khorramabadi, Reza Mohammadrezaei; Soleymaninejad, Maryam; Gholami, Mohammadreza

2017-04-01

Selenium is considered as a trace element that plays antioxidant role in the body. So, the aim of this study was to evaluate the effect of selenium on ameliorating of sciatic nerve ischemia-reperfusion injury. Eighty (80) adult male Wistar rats weighing 250-300 g were used. They were divided into 10 groups (n = 8). Then, femoral vessels were obstructed by using 4/0 silk and splitknot techniques. After 3-h ischemia for all the groups, reperfusion was applied for different periods: 3, 7, 14, and 28 days. In half of each experimental group, 0.2 mg/kg selenium was injected intraperitoneally, coinciding with ischemia. After reperfusion, according to the grouping, rats were killed by using high dose of anesthetic drug and then sciatic nerve was removed and fixed. Then, tissue samples were processed and subsequently stained with hematoxylin-eosin, apoptosis, and immunohistochemistry stains. On the third day of reperfusion, the amount of TNF-α as an inflammatory marker of ischemia-reperfusion acute phase increased. On the seventh day of reperfusion, the amount of NF-кB as an apoptotic index and infiltration of mast cells increased in the tissue as a result of development of inflammation. But, on the 14th day of reperfusion, the amount of NF-кB as an apoptotic index decreased to the lowest amount. On the 28th day of reperfusion, the amount of TNF-α as an inflammatory marker decreased to its lowest level. Prescription of selenium concurrent with development of ischemia can reduce the damage caused by sciatic nerve ischemia-reperfusion.

Postconditioning: "Toll-erating" mesenteric ischemia-reperfusion injury?

PubMed

Rosero, Olivér; Ónody, Péter; Kovács, Tibor; Molnár, Dávid; Fülöp, András; Lotz, Gábor; Harsányi, László; Szijártó, Attila

2017-04-01

Postconditioning may prove to be a suitable method to decrease ischemia-reperfusion injury of intestine after mesenteric arterial occlusion. Toll-like-receptor-4 is involved in the pathophysiology of organ damage after ischemia-reperfusion; therefore, the aim of our study was to investigate the effect of postconditioning on the mucosal expression of toll-like-receptor-4. Male Wistar rats (n = 10/group) underwent 60 minutes of superior mesenteric artery occlusion followed by 6 hours of reperfusion in 3 groups: sham-operated, ischemia-reperfusion, and a postconditioned group. Postconditioning was performed by 6 alternating cycles of 10 seconds of reperfusion/reocclusion. Blood and tissue samples were collected at the end of reperfusion. Intestinal histopathologic changes and immunohistochemical expression of mucosal caspase-3, antioxidant status, and protein levels of high-mobility group box-1 and toll-like-receptor-4 were assessed. Immunofluorescent labeling and confocal microscopic analysis of toll-like-receptor-4 were performed. Mucosal and serum levels of interleukin-6 and tumor necrosis factor-α protein were measured. Histologic alterations in the postconditioned group were associated with decreased caspase-3 positivity, less toll-like-receptor-4 mRNA, and less protein expression of high-mobility group box-1 and toll-like-receptor-4 in the intestinal villi compared with the ischemia-reperfusion group. Furthermore, a significantly improved antioxidant state of the intestinal mucosa and less mucosal and serum protein levels of interleukin-6 and tumor necrosis factor-α were detected in the postconditioned group. Small intestinal ischemia-reperfusion injury in male Wistar rats caused by the occlusion of the superior mesenteric artery was ameliorated by the use of postconditioning, showing a more favorable inflammatory response, which may be attributed to the decreased mucosal expression of toll-like-receptor-4. Copyright © 2016 Elsevier Inc. All rights

Receptor for advanced glycation end products involved in lung ischemia reperfusion injury in cardiopulmonary bypass attenuated by controlled oxygen reperfusion in a canine model.

PubMed

Rong, Jian; Ye, Sheng; Liang, Meng-ya; Chen, Guang-xian; Liu, Hai; Zhang, Jin-Xin; Wu, Zhong-kai

2013-01-01

Controlled oxygen reperfusion could protect the lung against ischemia-reperfusion injury in cardiopulmonary bypass (CPB) by downregulating high mobility group box 1 (HMGB1), a high affinity receptor of HMGB1. This study investigated the effect of controlled oxygen reperfusion on receptor for advanced glycation end products (RAGE) expression and its downstream effects on lung ischemia-reperfusion injury. Fourteen canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest followed by 90 minutes of reperfusion. Animals were randomized to receive 80% FiO2 during the entire procedure (control group) or to a test group receiving a controlled oxygen reperfusion protocol. Pathologic changes in lung tissues, RAGE expression, serum interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated. The lung pathologic scores after 25 and 90 minutes of reperfusion were significantly lower in the test group compared with the control group (p < 0.001). RAGE expression, TNF-α, and IL-6 were downregulated by controlled oxygen treatment (p < 0.001). RAGE might be involved in the lung ischemia-reperfusion injury in canine model of CPB, which was downregulated by controlled oxygen reperfusion.

Lipoate ameliorates ischemia-reperfusion in animal models.

PubMed

Freisleben, H J

2000-01-01

Ischemia and reperfusion were studied in isolated working rat hearts and in exarticulated rat hind limbs. Free radicals are known to be generated in ischemia/reperfusion and to propagate complications. To reduce reperfusion injury, conditions were ameliorated including the treatment with antioxidants, lipoate or dihydrolipoate. In isolated working rat hearts, cardiac and mitochondrial parameters are impaired during hypoxia and partially recover in reperfusion. Dihydrolipoate, if added into the perfusion buffer at 0.3 microM concentration, keeps the pH higher (7.15) during hypoxia, as compared to controls (6.98). This compound accelerates and stabilizes the recovery of the aortic flow. With dihydrolipoate, ATP synthesis is increased, ATPase activity (ATP hydrolysis) reduced, intracellular creatine kinase activity maintained and thus phosphocreatine contents are higher than in controls. For exarticulated rat hind limbs, the dihydrolipoate group contained 8.3 microM in the modified reperfusate. Recovery of the contractile function was 49% vs. 34% in controls and muscle flexibility was maintained whereas it decreased by 15% in the controls. Release of creatine kinase from cells was significantly lower with dihydrolipoate. Lipoate/dihydrolipoate effectively reduced reperfusion injury in isolated working rat hearts and in exarticulated rat hind limbs after extended ischemia. Finally, the compound was successfully applied in an in vivo pig hind limb model.

Milrinone and levosimendan administered after reperfusion improve myocardial stunning in swine.

PubMed

Shibata, Itsuko; Cho, Sungsam; Yoshitomi, Osamu; Ureshino, Hiroyuki; Maekawa, Takuji; Hara, Tetsuya; Sumikawa, Koji

2013-02-01

We assessed the effect of milrinone application timing after reperfusion against myocardial stunning as compared with levosimendan in swine. Furthermore, we examined the role of p38 mitogen-activated protein kinase (p38 MAPK) in the milrinone-induced cardioprotection. All swine were subjected to 12-minutes ischemia followed by 90-minutes reperfusion to generate stunned myocardium. Milrinone or levosimendan was administered intravenously either for 20 minutes starting just after reperfusion or for 70 minutes starting 20 minutes after reperfusion. In another group, SB203580, a selective p38 MAPK inhibitor, was administered with and without milrinone. Regional myocardial contractility was assessed by percent segment shortening (%SS). Milrinone starting just after reperfusion, but not starting 20 minutes after reperfusion, improved %SS at 30, 60, and 90 minutes after reperfusion compared with that in the control group. SB203580 abolished the beneficial effect of milrinone. On the other hand, levosimendan starting 20 minutes after reperfusion, but not for 20 minutes starting just after reperfusion, improved %SS at 60 and 90 minutes after reperfusion. Milrinone should be administered just after reperfusion to protect myocardial stunning through p38 MAPK, whereas levosimendan improvement of contractile function could be mainly dependent on its positive inotropic effect.

Oxidative and inflammatory biomarkers of ischemia and reperfusion injuries.

PubMed

Halladin, Natalie Løvland

2015-04-01

clinical trials is very limited. In this PhD thesis we set out to explore the oxidative and inflammatory biochemical markers of ischemia and reperfusion injuries and the possible effect of melatonin on these markers. We have reviewed the literature on the tourniquet-related oxidative damage and found that ischemic preconditioning and the use of propofol could significantly reduce the release of such markers. However, the relevance of this reduction in terms of clinical outcomes is still to be investigated (paper 1). We undertook the characterization of a human ischemia-reperfusion model without the influencing factors of surgery and anesthesia, and subsequently found ways to improve this model (paper 2). In order to apply an intracoronary melatonin administration, we investigated whether melatonin could be dissolved in non-ethanol based buffers and still activate the melatonin receptors (paper 3). We found this to be possible, and in a porcine closed-chest model of acute myocardial infarction (AMI) we randomized the pigs to intracoronary and systemic melatonin or placebo in order to test whether melatonin could attenuate the oxidative and inflammatory biomarkers following reperfusion (paper 4). The outcomes were not optimal for this model, and the effect of melatonin still remains to be explored in a large animal model. We are currently still awaiting the results of the IMPACT-trial - a randomized, placebo-controlled, clinical trial exploring the effect of intracoronary and systemic melatonin given to patients suffering from AMI and undergoing primary percutaneous coronary intervention (pPCI) (paper 5). Though pPCI is undisputedly life-saving, it holds a built-in consequence of aggravating the ischemic injury, paradoxically due to the reperfusion. The optimization of existing treatments and the exploring of new suitable interventions, such as melatonin, for minimizing the ischemia-reperfusion injuries is therefore of great interest.

Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion.

PubMed

Diamond, Joshua M; Arcasoy, Selim; McDonnough, Jamiela A; Sonett, Joshua R; Bacchetta, Matthew; D'Ovidio, Frank; Cantu, Edward; Bermudez, Christian A; McBurnie, Amika; Rushefski, Melanie; Kalman, Laurel H; Oyster, Michelle; D'Errico, Carly; Suzuki, Yoshikazu; Giles, Jon T; Ferrante, Anthony; Lippel, Matthew; Singh, Gopal; Lederer, David J; Christie, Jason D

2017-01-01

Obesity is a risk factor for primary graft dysfunction (PGD), a form of lung injury resulting from ischemia-reperfusion after lung transplantation, but the impact of ischemia-reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from six subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were downregulated in the postreperfusion time compared with baseline. Long pentraxin-3, a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5-fold increase, p = 0.04). Fibronectin leucine-rich transmembrane protein-3, a gene associated with cell adhesion and receptor signaling, was the most downregulated gene (4.3-fold decrease, p = 0.04). Ischemia-reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of nonobese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

B-type natriuretic peptide as a predictor of ischemia/reperfusion injury immediately after myocardial reperfusion in patients with ST-segment elevation acute myocardial infarction.

PubMed

Arakawa, Kentaro; Himeno, Hideo; Kirigaya, Jin; Otomo, Fumie; Matsushita, Kensuke; Nakahashi, Hidefumi; Shimizu, Satoru; Nitta, Manabu; Takamizawa, Tetsu; Yano, Hideto; Endo, Mitsuaki; Kanna, Masahiko; Kimura, Kazuo; Umemura, Satoshi

2016-02-01

In animal models of acute myocardial infarction (AMI), B-type natriuretic peptide (BNP) administered before and during coronary occlusion limits infarct size. However, the relation between plasma BNP levels and ischemia/reperfusion injury remains unclear. 302 patients with ST-segment elevation AMI (STEMI) received emergency percutaneous coronary intervention within six hours from the onset. The patients were divided into two groups according to the plasma BNP level before angiography: group L (n=151), BNP ≤ 32.2 pg/ml; group H (n=151), BNP >32.2 pg/ml. The Selvester QRS-scoring system was used to estimate infarct size. The rate of ischemia/reperfusion injury immediately after reperfusion, defined as reperfusion ventricular arrhythmias (26% vs. 11%, p=0.001) and ST-segment re-elevation (44% vs. 22%, p=0.008), was higher in group L than in group H. Group L had a greater increase in the QRS score during percutaneous coronary intervention (3.55 ± 0.17 vs. 2.09 ± 0.17, p<0.001) and a higher QRS score 1 h after percutaneous coronary intervention (5.77 ± 0.28 vs. 4.51 ± 0.28, p=0.002). On multivariate analysis, plasma BNP levels in the lower 50th percentile were an independent predictor of reperfusion injury (odds ratio, 2.620; p<0.001). The odds ratios of reperfusion injury according to decreasing quartiles of BNP level, as compared with the highest quartile, were 1.536, 3.692 and 4.964, respectively (p trend=0.002). Plasma BNP level before percutaneous coronary intervention may be a predictor of ischemia/reperfusion injury and the resultant extent of myocardial damage. Our findings suggest that high plasma BNP levels might have a clinically important protective effect on ischemic myocardium in patients with STEMI who receive percutaneous coronary intervention. © The European Society of Cardiology 2015.

[Effect and mechanism of icariin on myocardial ischemia-reperfusion injury model in diabetes rats].

PubMed

Hu, Yan-wu; Liu, Kai; Yan, Meng-tong

2015-11-01

To study the therapeutic effect and possible mechanism of icariin on myocardial ischemia-reperfusion injury ( MIRI) model in diabetes rats. The model of diabetic rats were induced by Streptozotocin (STZ), then the model of MIRI was established by ligating the reversible left anterior descending coronary artery for 30 min, and then reperfusing for 120 min. totally 40 male SD were randomly divided into five groups: the control group (NS), the ischemia reperfusion group (NIR), the diabetes control group (MS), the diabetic ischemia reperfusion group (MIR) and the diabetic ischemia reperfusion with icariin group (MIRI). The changes in blood glucose, body weight and living status were observed; the enzyme activity of serum CK-MB, LDH, GSH-Px and myocardium SOD and the content MDA and NO in myocardium were detected; the myocardial pathological changes were observed by HE staining; the myocardial Caspase-3, the Bcl-2, Bax protein expressions were detected by Western blot. The result showed that the diabetes model was successfully replicated; myocardial ischemia-reperfusion injury was more serious in diabetes rats; icariin can increase NO, SOD, GSH-Px, Bcl-2 protein expression, decrease MDA formation, CK-MB and LDH activities and Caspase-3 and Bcl-2 protein expressions and myocardial damage. The result suggested that icariin may play a protective role against ischemia reperfusion myocardial injury in diabetes rats by resisting oxidative stress and inhibiting cell apoptosis.

The effect of adhesion molecule blockade on pulmonary reperfusion injury.

PubMed

Levine, Adrian J; Parkes, Karen; Rooney, Stephen J; Bonser, Robert S

2002-04-01

Selectins are the molecules involved in the initial adhesion of the activated neutrophil on pulmonary endothelium. We investigated the efficacy of selectin blockade in a selective (monoclonal antibody RMP-1) and nonselective (Fucoidin) manner in pulmonary reperfusion injury. Groups of six rat lungs were flushed with University of Wisconsin solution then stored at 4 degrees C for 4 hours. They then underwent sanguinous reperfusion for 30 minutes during which functional measures (gas exchange, pulmonary artery pressure, and airway pressure) of lung performance were made. After reperfusion we estimated their capillary filtration coefficient (Kfc units g/cm water/minute/g wet lung tissue) using a gravimetric technique. Four groups were studied: group I had no reperfusion, group II had 30 minutes of reperfusion, group III had infusion of 20 mg/kg Fucoidin before reperfusion, and group IV had infusion of 20 microg/mL RMP-1 before reperfusion. Reperfusion injury was found between groups I and II by an increase in capillary filtration coefficient (1.048 +/- 0.316 to 3.063 +/- 0.466, p < 0.01). Groups III and IV had a significantly lower Kfc than group II (0.967 +/- 0.134 and 1.205 +/- 0.164, respectively, p < 0.01). There was no significant functional difference between groups II, III, and IV. Reperfusion-induced hyperpermeability was ameliorated by selective (RMP-1) and nonselective (Fucoidin) selectin blockade.

Role of platelet-activating factor in the reperfusion injury of rabbit ischemic heart

DOE Office of Scientific and Technical Information (OSTI.GOV)

Montrucchio, G.; Alloatti, G.; Mariano, F.

1990-07-01

This study shows that the administration of the PAF receptor antagonist SDZ 63.675 (5 mg/kg body weight) before reperfusion significantly reduced the hematologic and hemodynamic alterations, as well as the size of necrotic area in rabbits subjected to 40 minutes of coronary occlusion and reperfusion. Pretreatment with SDZ 63.675 prevented the reduction of platelet counts in the blood obtained from the right ventricle (86.6 +/- 2.8% of the control preischemia value) and the transient bradycardia (85.0 +/- 2.8%), the systemic hypotension (58.0 +/- 2.8%), and the increase in right ventricular pressure (125.0 +/- 3.6%) that were evident in the firstmore » minutes of reperfusion in untreated control rabbits. Two as well as 24 hours after reperfusion, the infarct size, judged by staining with tetrazolium, was significantly reduced in rabbits treated with SDZ 63.675 (infarct size in control animals, 66.0 +/- 2.9% and 63.46 +/- 2.09% of the risk region at 2 or 24 hours, respectively, compared with 38.9 +/- 5.2% and 37.11 +/- 2.44% of the risk region at 2 and 24 hours in rabbits treated with SDZ 63.675). This result was confirmed by histologic examination of cardiac tissue 24 hours after reperfusion. In addition, SDZ 63.675 markedly reduced the accumulation of 111In-oxine-labeled platelets that occurs 15 minutes after reperfusion in the central ischemic area of the heart and in the lungs. These results suggest that PAF plays a role in the evolution of myocardial injury observed during reperfusion.« less

[Investigation of postconditioning in intestinal ischemia-reperfusion experimental models].

PubMed

Rosero, Olivér; Onody, Péter; Stangl, Rita; Hegedus, Viktor; Lotz, Gábor; Blázovics, Anna; Kupcsulik, Péter; Szijártó, Attila

2011-02-01

The ischemic-reperfusion injury of the intestine, which occurs as a consequence of circulatory redistribution or occlusion of the superior mesenteric artery, is associated with high mortality rates. Postconditioning may reduce ischemic-reperfusion damage in such cases. Effects of this new surgical method were investigated in rats. Male Wistar rats underwent 60 minutes of superior mesenteric artery occlusion in four groups: sham-operated, control and two postconditioned groups with different algorithms. Postconditioning was performed immediately at the beginning of reperfusion, by repetitive cycles of reperfusion and reocclusion. 3 cycles of 1 minute and 6 cycles of 10 seconds were applied according to groups. Intestinal microcirculation was followed by laser Doppler flowmetry. Blood and tissue samples were taken after 60 minutes of reperfusion. Histological analayses of the small intestine, measurement of serum necroenzyme levels and IL-6, mesenterial venous blood gas analyses were preformed and antioxidant state of the mucosa was investigated. The microcirculation during the reperfusion showed significant improvement in both postconditioned groups. Histological damage, necroenzyme and IL-6 levels were significantly reduced, while antioxidant state was improved in the postconditioned groups. Postconditioning was capable of increasing the guts chance to survive ischemic-reperfusion injury caused by superior mesenteric artery occlusion.

Animal models of ischemia-reperfusion-induced intestinal injury: progress and promise for translational research

PubMed Central

Gonzalez, Liara M.; Moeser, Adam J.

2014-01-01

Research in the field of ischemia-reperfusion injury continues to be plagued by the inability to translate research findings to clinically useful therapies. This may in part relate to the complexity of disease processes that result in intestinal ischemia but may also result from inappropriate research model selection. Research animal models have been integral to the study of ischemia-reperfusion-induced intestinal injury. However, the clinical conditions that compromise intestinal blood flow in clinical patients ranges widely from primary intestinal disease to processes secondary to distant organ failure and generalized systemic disease. Thus models that closely resemble human pathology in clinical conditions as disparate as volvulus, shock, and necrotizing enterocolitis are likely to give the greatest opportunity to understand mechanisms of ischemia that may ultimately translate to patient care. Furthermore, conditions that result in varying levels of ischemia may be further complicated by the reperfusion of blood to tissues that, in some cases, further exacerbates injury. This review assesses animal models of ischemia-reperfusion injury as well as the knowledge that has been derived from each to aid selection of appropriate research models. In addition, a discussion of the future of intestinal ischemia-reperfusion research is provided to place some context on the areas likely to provide the greatest benefit from continued research of ischemia-reperfusion injury. PMID:25414098

Protective effects of osthole on intestinal ischemia-reperfusion injury in mice.

PubMed

Zhang, Zhen; Pan, Chen; Wang, Hong-zhi; Li, Yong-xiang

2014-06-01

The purpose of this study was to evaluate the effect of intravenous injection of osthole on intestinal ischemia-reperfusion injury and parameters of oxidative stress. In 45 Kunming male mice, treatment included sham surgery (15 mice); intestinal ischemia-reperfusion injury (clamping of the superior mesenteric artery, 2 h; clamp release, 1 h; 15 mice); or osthole treatment before and after ischemia-reperfusion injury (15 mice). Evaluation included histopathology, determination of intestinal wet/dry weight ratio, and measurement of levels of diamine oxidase, superoxide dismutase, malondialdehyde, interleukin 1β, tumor necrosis factor α, and interleukin 2. Intestinal barrier permeability was evaluated with Evans blue test. The mean wet-to-dry weight ratio, Evans blue content, and Chiu score were significantly greater in the ischemia-reperfusion than in the sham group and lower in the osthole-treated than the ischemia-reperfusion group. The mean serum diamine oxidase, malondialdehyde, interleukin 1β, and tumor necrosis factor α levels were significantly greater in the ischemia-reperfusion than in the sham group and lower in the osthole-treated than in the ischemia-reperfusion group. The mean superoxide dismutase activity and interleukin 2 levels were lower in the ischemia-reperfusion than in the sham group and greater in the osthole-treated than in the ischemia-reperfusion group. Treatment with osthole may protect against oxidative stress and tissue damage from intestinal ischemia-reperfusion injury.

Remifentanil ameliorates intestinal ischemia-reperfusion injury

PubMed Central

2013-01-01

Background Intestinal ischemia-reperfusion injury (IRI) can occur in clinical scenarios such as organ transplantation, trauma and cardio-pulmonary bypass, as well as in neonatal necrotizing enterocolitis or persistent ductus arteriosus. Pharmacological protection by pretreating (“preconditioning”) with opioids attenuates IRI in a number of organs. Remifentanil appears particularly attractive for this purpose because of its ultra-short duration of action and favorable safety profile. To date, little is known about opioid preconditioning of the intestine. Methods Young adult C57BL/6J mice were randomly assigned to receive tail vein injections of 1 μg/kg of remifentanil or normal saline and underwent either ischemia-reperfusion of the intestine or a sham laparotomy. Under isoflurane anesthesia, the mice were subjected to intestinal ischemia-reperfusion by occlusion (clamping) of the superior mesenteric artery for 30 min, followed by unclamping and 60 min of reperfusion. After completion of this protocol, tissue injury and lipid peroxidation in jejunum and ileum were analyzed by histology and malondialdehyde (MDA), respectively. Systemic interleukin (IL)-6 was determined in the plasma by ELISA. Results Pretreatment with remifentanil markedly reduced intestinal IRI (P < 0.001): In the ileum, we observed a more than 8-fold decrease in injured villi (4% vs 34% in saline-pretreated animals). In fact, the mucosa in the remifentanil group was as healthy as that of sham-operated animals. This protective effect was not as pronounced in the jejunum, but the percentage of damaged villi was still reduced considerably (18% vs 42%). There was up to 3-fold more tissue MDA after intestinal ischemia-reperfusion than after sham laparotomy, but this increase in lipid peroxidation was prevented by preconditioning with remifentanil (P < 0.05). The systemic inflammatory response triggered by intestinal IRI was significantly attenuated in mice pretreated with remifentanil (159 vs 805

Intratracheal Administration of Small Interfering RNA Targeting Fas Reduces Lung Ischemia-Reperfusion Injury.

PubMed

Del Sorbo, Lorenzo; Costamagna, Andrea; Muraca, Giuseppe; Rotondo, Giuseppe; Civiletti, Federica; Vizio, Barbara; Bosco, Ornella; Martin Conte, Erica L; Frati, Giacomo; Delsedime, Luisa; Lupia, Enrico; Fanelli, Vito; Ranieri, V Marco

2016-08-01

Lung ischemia-reperfusion injury is the main cause of primary graft dysfunction after lung transplantation and results in increased morbidity and mortality. Fas-mediated apoptosis is one of the pathologic mechanisms involved in the development of ischemia-reperfusion injury. We hypothesized that the inhibition of Fas gene expression in lungs by intratracheal administration of small interfering RNA could reduce lung ischemia-reperfusion injury in an ex vivo model reproducing the procedural sequence of lung transplantation. Prospective, randomized, controlled experimental study. University research laboratory. C57/BL6 mice weighing 28-30 g. Ischemia-reperfusion injury was induced in lungs isolated from mice, 48 hours after treatment with intratracheal small interfering RNA targeting Fas, control small interfering RNA, or vehicle. Isolated lungs were exposed to 6 hours of cold ischemia (4°C), followed by 2 hours of warm (37°C) reperfusion with a solution containing 10% of fresh whole blood and mechanical ventilation with constant low driving pressure. Fas gene expression was significantly silenced at the level of messenger RNA and protein after ischemia-reperfusion in lungs treated with small interfering RNA targeting Fas compared with lungs treated with control small interfering RNA or vehicle. Silencing of Fas gene expression resulted in reduced edema formation (bronchoalveolar lavage protein concentration and lung histology) and improvement in lung compliance. These effects were associated with a significant reduction of pulmonary cell apoptosis of lungs treated with small interfering RNA targeting Fas, which did not affect cytokine release and neutrophil infiltration. Fas expression silencing in the lung by small interfering RNA is effective against ischemia-reperfusion injury. This approach represents a potential innovative strategy of organ preservation before lung transplantation.

Platelets, diabetes and myocardial ischemia/reperfusion injury.

PubMed

Russo, Isabella; Penna, Claudia; Musso, Tiziana; Popara, Jasmin; Alloatti, Giuseppe; Cavalot, Franco; Pagliaro, Pasquale

2017-05-31

Mechanisms underlying the pathogenesis of ischemia/reperfusion injury are particularly complex, multifactorial and highly interconnected. A complex and entangled interaction is also emerging between platelet function, antiplatelet drugs, coronary diseases and ischemia/reperfusion injury, especially in diabetic conditions. Here we briefly summarize features of antiplatelet therapy in type 2 diabetes (T2DM). We also treat the influence of T2DM on ischemia/reperfusion injury and how anti-platelet therapies affect post-ischemic myocardial damage through pleiotropic properties not related to their anti-aggregating effects. miRNA-based signature associated with T2DM and its cardiovascular disease complications are also briefly considered. Influence of anti-platelet therapies and different effects of healthy and diabetic platelets on ischemia/reperfusion injury need to be further clarified in order to enhance patient benefits from antiplatelet therapy and revascularization. Here we provide insight on the difficulty to reduce the cardiovascular risk in diabetic patients and report novel information on the cardioprotective role of widely used anti-aggregant drugs.

Enhanced effect of gap junction uncouplers on macroscopic electrical properties of reperfused myocardium

PubMed Central

Rodriguez-Sinovas, Antonio; García-Dorado, David; Ruiz-Meana, Marisol; Soler-Soler, Jordi

2004-01-01

Transient inhibition of gap junction (GJ)-mediated communication with heptanol during myocardial reperfusion limits infarct size. However, inhibition of cell coupling in normal myocardium may be arrhythmogenic. The purpose of this study was to test the hypothesis that the consequences of GJ inhibition may be magnified in reperfused myocardium compared with normal tissue, thus allowing the inhibition of GJs in reperfused tissue while only minimally modifying overall macroscopic cell coupling in normal myocardium. Concentration–response curves were defined for the effects of heptanol, 18α-glycyrrhetinic acid, halothane, and palmitoleic acid on conduction velocity, tissue electrical impedance, developed tension and lactate dehydrogenase (LDH) release in normoxically perfused rat hearts (n = 17). Concentrations lacking significant effects on tissue impedance were added during the initial 15 min of reperfusion in hearts submitted to 60 min (n = 43) or 30 min (n = 35) of ischaemia. These concentrations markedly increased myocardial electrical impedance (resistivity and phase angle) in myocardium reperfused after either 30 or 60 min of ischaemia, and reduced reperfusion-induced LDH release after 1 h of ischaemia by 83.6, 57.9, 51.7 and 52.5% for heptanol, 18α-glycyrrhetinic acid, halothane and palmitoleic acid, respectively. LDH release was minimal in hearts submitted to 30 min of ischaemia, independently of group allocation. In conclusion, the present results strongly support the hypothesis that intercellular communication in postischaemic myocardium may be effectively reduced by concentrations of GJ inhibitors affecting only minimally overall electrical impedance in normal myocardium. Reduction of cell coupling during initial reperfusion was consistently associated with attenuated lethal reperfusion injury. PMID:15218064

Neuroprotective Mechanisms of Calycosin Against Focal Cerebral Ischemia and Reperfusion Injury in Rats.

PubMed

Wang, Yong; Ren, Qianyao; Zhang, Xing; Lu, Huiling; Chen, Jian

2018-01-01

Emerging evidence suggests that autophagy plays important roles in the pathophysiological processes of cerebral ischemia and reperfusion injury. Calycosin, an isoflavone phytoestrogen, possesses neuroprotective effects in cerebral ischemia and reperfusion in rats. Here, we investigated the neuroprotective effects of calycosin against ischemia and reperfusion injury, as well as related probable mechanisms behind autophagy pathways. A cerebral ischemic and reperfusion injury model was established by middle cerebral artery occlusion in male Sprague-Dawley rats. Neurological scores, infarct volumes, and brain water content were assessed after 24 h reperfusion following 2 h ischemia. Additionally, the expression of the autophagy-related protein p62 and NBR1 (neighbor of BRCA1 gene 1), as well as Bcl-2, and TNF-α in rat brain tissues was measured by RT-PCR, western blotting and immunohistochemical analyses. The results showed that calycosin pretreatment for 14 days markedly decreased infarct volume and brain edema, and ameliorated neurological scores in rats with focal cerebral ischemia and reperfusion. It was observed that levels of p62, NBR1 and Bcl-2 were greatly decreased, and levels of TNF-α significantly increased after ischemia and reperfusion injury. However, calycosin administration dramatically upregulated the expression of p62, NBR1 and Bcl-2, and downregulated the level of TNF-α. All data reveal that calycosin exerts a neuroprotective effect on cerebral ischemia and reperfusion injury, and the mechanisms maybe associated with its anti-autophagic, anti-apoptotic and anti-inflammatory action. © 2018 The Author(s). Published by S. Karger AG, Basel.

Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy.

PubMed

Xie, Min; Kong, Yongli; Tan, Wei; May, Herman; Battiprolu, Pavan K; Pedrozo, Zully; Wang, Zhao V; Morales, Cyndi; Luo, Xiang; Cho, Geoffrey; Jiang, Nan; Jessen, Michael E; Warner, John J; Lavandero, Sergio; Gillette, Thomas G; Turer, Aslan T; Hill, Joseph A

2014-03-11

Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury. Twenty-one rabbits were randomly assigned to 3 groups: (1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA's cardioprotective effects. The US Food and Drug Administration-approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.

Left ventricular unloading with intra-aortic counter pulsation prior to reperfusion reduces myocardial release of endothelin-1 and decreases infarction size in a porcine ischemia-reperfusion model.

PubMed

LeDoux, John F; Tamareille, Sophie; Felli, Patty R; Amirian, James; Smalling, Richard W

2008-10-01

We tested the hypothesis that unloading the left ventricle with intra-aortic balloon counter-pulsation just prior to reperfusion provides infarct salvage compared with left ventricular (LV) unloading postreperfusion or reperfusion alone. Previous reports demonstrated infarct salvage with complete LV unloading with an LVAD prior to reperfusion; however, partial LV unloading using intra-aortic balloon pumps (IABPs) has not been evaluated. Twenty-eight Yorkshire pigs were subjected to 1 hr of left anterior descending artery occlusion and 4 hr of reperfusion. An IABP was inserted and activated just prior to reperfusion (IABP-Pre), or 15 min after reperfusion (IABP-Post), or not at all (control). At baseline, the hemodynamic data were similar in the three groups. Myocardial infarct size expressed a percentage of zone at risk in control animals was 44.9% +/- 4.8%, IAPB-Pre group 20.9% +/- 5.1% (P < 0.05 compared to control), and IABP-Post group 33.2 +/- 6.1% (P = 0.16 vs. control group). There was a correlation between transcardiac endothelin-1 release at 15 min postreperfusion and infarct size (r = 0.59). LV unloading with an IABP prior to reperfusion reduces the extent of myocardial necrosis in hearts subjected to 1 hr of left anterior descending artery occlusion and 4 hr of reperfusion compared with either reperfusion alone or LV unloading after reperfusion. Inhibition of myocardial ET-1 release by LV unloading may be a significant mechanism of myocardial protection. These data suggest that in high-risk STEMI patients, IABP unloading prior to reperfusion might be more beneficial than IABP placement postreperfusion. 2008 Wiley-Liss, Inc.

Renoprotective effects of asialoerythropoietin in diabetic mice against ischaemia-reperfusion-induced acute kidney injury.

PubMed

Nakazawa, Jun; Isshiki, Keiji; Sugimoto, Toshiro; Araki, Shin-Ichi; Kume, Shinji; Yokomaku, Yukiyo; Chin-Kanasaki, Masami; Sakaguchi, Masayoshi; Koya, Daisuke; Haneda, Masakazu; Kashiwagi, Atsunori; Uzu, Takashi

2010-02-01

Diabetic patients are at higher risk of failure to recover after acute kidney injury, however, the mechanism and therapeutic strategies remain unclear. Erythropoietin is cytoprotective in a variety of non-haematopoietic cells. The aim of the present study was to clarify the mechanism of diabetes-related acceleration of renal damage after ischaemia-reperfusion injury and to examine the therapeutic potential of asialoerythropoietin, a non-haematopoietic erythropoietin derivative, against ischaemia-reperfusion-induced acute kidney injury in diabetic mice. C57BL/6J mice with and without streptozotocin-induced diabetes were subjected to 30 min unilateral renal ischaemia-reperfusion injury at 1 week after induction of diabetes. They were divided into four group: (i) non-diabetic plus ischaemia-reperfusion injury; (ii) non-diabetic plus ischaemia-reperfusion injury plus asialoerythropoietin (3000 IU/kg bodyweight); (iii) diabetic plus ischaemia-reperfusion injury; and (iv) diabetic plus ischemia-reperfusion injury plus asialoerythropoietin. Experiments were conducted at the indicated time periods after ischaemia-reperfusion injury. Ischaemia-reperfusion injury of diabetic kidney resulted in significantly low protein expression levels of bcl-2, an anti-apoptotic molecule, and bone morphogenetic protein-7 (BMP-7), an anti-fibrotic and pro-regenerative factor, compared with non-diabetic kidneys. Diabetic kidney subsequently showed severe damage including increased tubular cell apoptosis, tubulointerstitial fibrosis and decreased tubular proliferation, compared with non-diabetic kidney. Treatment with asialoerythropoietin induced bcl-2 and BMP-7 expression in diabetic kidney and decreased tubular cell apoptosis, tubulointerstitial fibrosis and accelerated tubular proliferation. Reduced induction bcl-2 and BMP-7 may play a role in the acceleration of renal damage after ischaemia-reperfusion injury in diabetic kidney. The renoprotective effects of asialoerythropoietin on acute

Rapamycin alleviates brain edema after focal cerebral ischemia reperfusion in rats.

PubMed

Guo, Wei; Feng, Guoying; Miao, Yanying; Liu, Guixiang; Xu, Chunsheng

2014-06-01

Brain edema is a major consequence of cerebral ischemia reperfusion. However, few effective therapeutic options are available for retarding the brain edema progression after cerebral ischemia. Recently, rapamycin has been shown to produce neuroprotective effects in rats after cerebral ischemia reperfusion. Whether rapamycin could alleviate this brain edema injury is still unclear. In this study, the rat stroke model was induced by a 1-h left transient middle cerebral artery occlusion using an intraluminal filament, followed by 48 h of reperfusion. The effects of rapamycin (250 μg/kg body weight, intraperitoneal; i.p.) on brain edema progression were evaluated. The results showed that rapamycin treatment significantly reduced the infarct volume, the water content of the brain tissue and the Evans blue extravasation through the blood-brain barrier (BBB). Rapamycin treatment could improve histological appearance of the brain tissue, increased the capillary lumen space and maintain the integrity of BBB. Rapamycin also inhibited matrix metalloproteinase 9 (MMP9) and aquaporin 4 (AQP4) expression. These data imply that rapamycin could improve brain edema progression after reperfusion injury through maintaining BBB integrity and inhibiting MMP9 and AQP4 expression. The data of this study provide a new possible approach for improving brain edema after cerebral ischemia reperfusion by administration of rapamycin.

Iodide Protects Heart Tissue from Reperfusion Injury

PubMed Central

Iwata, Akiko; Morrison, Michael L.; Roth, Mark B.

2014-01-01

Iodine is an elemental nutrient that is essential for mammals. Here we provide evidence for an acute therapeutic role for iodine in ischemia reperfusion injury. Infusion of the reduced form, iodide, but not the oxidized form iodate, reduces heart damage by as much as 75% when delivered intravenously following temporary loss of blood flow but prior to reperfusion of the heart in a mouse model of acute myocardial infarction. Normal thyroid function may be required because loss of thyroid activity abrogates the iodide benefit. Given the high degree of protection and the high degree of safety, iodide should be explored further as a therapy for reperfusion injury. PMID:25379708

Differential expression of Bcl-2 and Bax during gastric ischemia-reperfusion of rats

PubMed Central

Qiao, Wei-Li; Wang, Guang-Ming; Shi, Yue; Wu, Jin-Xia; Qi, You-Jian; Zhang, Jian-Fu; Sun, Hong; Yan, Chang-Dong

2011-01-01

AIM: To investigate expression of Bcl-2 and Bax in gastric ischemia-reperfusion (GI-R) and involvement of extracellular signal-regulated kinase (ERK) 1/2 activation. METHODS: The GI-R model was established by ligature of the celiac artery for 30 min and reperfusion in Sprague-Dawley rats. Rats were assigned to groups in accordance with their evaluation period: control, 0, 0.5, 1, 3, 6, 24, 48, and 72 h. Expression and distribution of Bcl-2 and Bax proteins were analyzed by immunohistochemistry and western blotting in gastric tissue samples after sacrifice. RESULTS: Compared with controls, the percentage of positive cells and protein levels of Bcl-2 decreased in the early phases of reperfusion, reached its minimum at 1 h (P < 0.05); it then increased, reaching its peak at 24 h of reperfusion (P < 0.05). The pattern of Bax expression was opposite to that of Bcl-2. Bax expression increased after reperfusion, with its peak at 1 h of reperfusion (P < 0.05), and then it decreased gradually to a minimum at 24 h after reperfusion (P < 0.05). On the other hand, inhibition of activation of ERK1/2 induced by PD98059, a specific upstream MEK inhibitor, had significant effects on Bcl-2 and Bax in GI-R. Compared with GI-R treatment only at 3 h of reperfusion, PD98059 reduced the number of Bcl-2 positive cells (0.58% of R3h group, P < 0.05) and Bcl-2 protein level (74% of R3h group, P < 0.05) but increased the number of Bax-positive cells (1.33-fold vs R3h group, P < 0.05) and Bax protein level (1.35-fold of R3h group, P < 0.05). CONCLUSION: These results indicated that the Bcl-2 and Bax played a pivotal role in the gastric mucosal I-R injury and repair by activation of ERK1/2. PMID:21483632

Cell Biology of Ischemia/Reperfusion Injury

PubMed Central

Kalogeris, Theodore; Baines, Christopher P.; Krenz, Maike; Korthuis, Ronald J.

2014-01-01

Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues. PMID:22878108

Protective effect of Shenfu injection preconditioning on lung ischemia-reperfusion injury

PubMed Central

Zhang, Hong; Wan, Zhanhai; Yan, Xiang; Wang, De-Gui; Leng, Yufang; Liu, Yongqiang; Zhang, Yan; Zhang, Haijun; Han, Xuena

2016-01-01

Lung ischemia-reperfusion injury remains a problem in thoracic surgery, as minimal progress has been made concerning its prevention and control. In the present study, the protective effects and the underlying mechanism of Shenfu injection preconditioning on a rat lung ischemia-reperfusion model was investigated. Shenfu injection is a well-known Chinese traditional medicine, which is composed of Red Radix Ginseng and Radix Aconitum carmichaelii, with ginseng saponin and aconitum alkaloids as the active ingredients. A total of 72 specific pathogen-free, healthy male Wistar rats were randomly divided into control, model and Shenfu injection (10 ml/kg injection prior to injury) groups and were assessed at the following points: Ischemia 45 min; reperfusion 60 min; and reperfusion 120 min. Blood collected from the aorta abdominalis was cryopreserved at −70°C for the analysis of malondialdehyde (MDA) and superoxide dismutase (SOD) activity. Lung tissues were divided into three equal sections in order to assess the wet-to-dry (W/D) lung ratio, tumor necrosis factor (TNF)-α expression levels, myeloperoxidase (MPO) activity, alveolar damage, total protein and hematoxylin and eosin staining. The results demonstrated that the lung W/D weight ratio, TNF-α expression levels and SOD activity in the Shenfu group were significantly lower at 120 min reperfusion (P<0.05), as compared with the model group. MPO and MDA activity significantly decreased following reperfusion at 60 and 120 min (P<0.05), as compared with the model group. In addition, the degree of alveolar damage in the Shenfu group was significantly decreased (P<0.05), as compared with the model group. In addition, compared with the model group, the degree of alveolar damage in the Shenfu group was significantly lower (P<0.05); however, no significant changes in total protein were observed. The extent of alveolar structural damage and the proportion of interstitial neutrophils and alveolar and interstitial red blood

Biological and histopathological investigations of moclobemide on injured ovarian tissue following induction of ischemia-reperfusion in rats.

PubMed

Ingec, Metin; Calik, Muhammet; Gundogdu, Cemal; Kurt, Ali; Yilmaz, Mehmet; Isaoglu, Unal; Salman, Suleyman; Akcay, Fatih; Suleyman, Halis

2012-04-01

The effects of moclobemide on damaged ovarian tissue induced by ischemia- reperfusion and damaged contralateral ovarian tissue were investigated in rats, biochemically and histologically. In this experimental study, 40 rats were equally divided into four groups: 10 mg/kg moclobemide, 20 mg/kg moclobemide, ischemia/reperfusion control, and intact control groups. A 2-2.5-cm-long vertical incision was made in the lower abdomen of each rat in order to reach the ovaries, after which a vascular clip was placed on the lower side of the right ovary of each animal in the two treatment groups and the ischemia-reperfusion control group, but not in the healthy (intact control) animal group. The purpose of this procedure was to create ischemia over the course of three hours, then the clips were unclamped to provide reperfusion for the next two hours. At the end of the two hours of reperfusion, all the animals were killed by high-dose anaesthesia and their ovaries were taken and subjected to histological and biochemical (malondialdehyde, nitric oxide, glutathione) studies. The obtained results showed that moclobemide suppressed nitric oxide and malondialdehyde production in the ischemia-reperfusion damage area, and prevented the decrease in endogenous antioxidant levels (glutathione) in the rat ovarian tissue. Moclobemide also prevented infiltration of leukocytes to the ovarian tissue. These results showed that moclobemide protected ovarian tissue against ischemiareperfusion injury. This study shows that moclobemide represses malondialdehyde and nitric oxide production in the rat ovarian tissue subjected to ischemia-reperfusion injury and keeps the endogenous antioxidant glutathione level from decreasing. Moclobemide also inhibits leukocytic migration into ovarian tissue following ischemia-reperfusion injury. From these results, it is suggested that moclobemide can be used in the treatment of ovarian ischemia-reperfusion injury.

[Protective effect of octreotide on liver warm ischemia reperfusion injury].

PubMed

Li, Jie-qun; Qi, Hai-zhi; He, Zhi-jun; Hu, Wei; Si, Zhong-zhou; Li, Yi-ning

2006-10-01

To explore the protective effect of octreotide on liver warm ischemia-reperfusion injury and its possible mechanism. Pringle's maneuver liver ischemia-reperfusion models were established. Forty eight male Sprague Daweley rats were randomly divided into a sham operation group (S group, n=16), an ischemia-reperfusion group (I/R group, n=16) and an octreotide preconditioning group (OPC group, n=16). ALT and AST in the serum were measured at 30 min after the ischemia and 120 min after the reperfusion. The histomorphological changes and ultrastructure of hepatocellular were observed by optic and transmission electronic microscope. Hepatic adenine nucleotide levels and energy changes (EC) were determined by high performance liquid chromatography (HPLC). (1) At 30 min after the ischemia and 120 min after the reperfusion, the levels of ALT and AST in the serum of OPC group was lower than those in I/R group, whereas the levels of ATP and EC in the hepatic tissue were higher than those in the I/R group (P<0.01 or P<0.05). Compared with the I/R group, the injury of hepatocellular histomorphology and ultrastructure in the OPC group was abated. (2) At 30, 60, and 120 min after the reperfusion, the levels of ATP and EC in the OPC groups were higher than those in the I/R group. During the ischemia, the levels of ATP and EC in the OPC group dropped more slowly than those in the I/R group, but ATP and EC in the OPC groups rose more quickly than those in the I/R group during the reperfusion. Octreotide precondition can improve the hepatocellular energy reserve, and protect the liver from warm ischemia-reperfusion injury. The protective of octreotide on warm ischemia-reperfusion injury may be related to its influence on endocrine secretion.

The effect of aloe vera on ischemia--Reperfusion injury of sciatic nerve in rats.

PubMed

Guven, Mustafa; Gölge, Umut Hatay; Aslan, Esra; Sehitoglu, Muserref Hilal; Aras, Adem Bozkurt; Akman, Tarik; Cosar, Murat

2016-04-01

Aloe vera is compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of aloe vera treatment in rats with experimental sciatic nerve ischemia/reperfusion injury. Twenty-eight male Wistar Albino rats were divided equally into 4 groups. Groups; Control group (no surgical procedure or medication), sciatic nerve ischemia/reperfusion group, sciatic nerve ischemia/reperfusion+aloe vera group and sciatic nerve ischemia/reperfusion+methylprednisolone group. Ischemia was performed by clamping the infrarenal abdominal aorta. 24 hours after ischemia, all animals were sacrificed. Sciatic nerve tissues were also examined histopathologically and biochemically. Ischemic fiber degeneration significantly decreased in the pre-treated with aloe vera and treated with methylprednisolone groups, especially in the pre-treated with aloe vera group, compared to the sciatic nerve ischemia/reperfusion group (p<0.05). A significant decrease in MDA, an increase in NRF1 level and SOD activity were observed in the groups which obtained from the AV and MP groups when compared to the sciatic nerve ischemia/reperfusion group. When all results were analysed it was seen that the aloe vera group was not statistically different compared to the MP group (p>0.05). Aloe vera is effective neuroprotective against sciatic nerve ischemia/reperfusion injury via antioxidant and anti-inflammatory properties. Also aloe vera was found to be as effective as MP. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion

PubMed Central

2013-01-01

Background Microglia cells continuously survey the healthy brain in a ramified morphology and, in response to injury, undergo progressive morphological and functional changes that encompass microglia activation. Although ideally positioned for immediate response to ischemic stroke (IS) and reperfusion, their progressive morphological transformation into activated cells has not been quantified. In addition, it is not well understood if diverse microglia morphologies correlate to diverse microglia functions. As such, the dichotomous nature of these cells continues to confound our understanding of microglia-mediated injury after IS and reperfusion. The purpose of this study was to quantitatively characterize the spatiotemporal pattern of microglia morphology during the evolution of cerebral injury after IS and reperfusion. Methods Male C57Bl/6 mice were subjected to focal cerebral ischemia and periods of reperfusion (0, 8 and 24 h). The microglia process length/cell and number of endpoints/cell was quantified from immunofluorescent confocal images of brain regions using a skeleton analysis method developed for this study. Live cell morphology and process activity were measured from movies acquired in acute brain slices from GFP-CX3CR1 transgenic mice after IS and 24-h reperfusion. Regional CD11b and iNOS expressions were measured from confocal images and Western blot, respectively, to assess microglia proinflammatory function. Results Quantitative analysis reveals a significant spatiotemporal relationship between microglia morphology and evolving cerebral injury in the ipsilateral hemisphere after IS and reperfusion. Microglia were both hyper- and de-ramified in striatal and cortical brain regions (respectively) after 60 min of focal cerebral ischemia. However, a de-ramified morphology was prominent when ischemia was coupled to reperfusion. Live microglia were de-ramified, and, in addition, process activity was severely blunted proximal to the necrotic core after IS

Digital image analysis of striated skeletal muscle tissue injury during reperfusion after induced ischemia

NASA Astrophysics Data System (ADS)

Rosero Salazar, Doris Haydee; Salazar Monsalve, Liliana

2015-01-01

Conditions such as surgical procedures or vascular diseases produce arterial ischemia and reperfusion injuries, which generate changes in peripheral tissues and organs, for instance, in striated skeletal muscle. To determine such changes, we conducted an experimental method in which 42 male Wistar rat were selected, to be undergone to tourniquet application on the right forelimb and left hind limb, to induce ischemia during one and three hours, followed by reperfusion periods starting at one hour and it was prolonged up to 32 days. Extensor carpi radialis longus and soleus respectively, were obtained to be processed for histochemical and morphometric analysis. By means of image processing and detection of regions of interest, variations of areas occupied by muscle fibers and intramuscular extracellular matrix (IM-ECM) throughout reperfusion were observed. In extensor carpi radialis longus, results shown reduction in the area occupied by muscle fibers; this change is significant between one hour and three hours ischemia followed by 16 hours, 48 hours and 32 days reperfusión (p˂0.005). To compare only periods of reperfusión that continued to three hours ischemia, were found significant differences, as well. For area occupied by IM-ECM, were identified increments in extensor carpi radialis longus by three hours ischemia and eight to 16 days reperfusion; in soleus, was observed difference by one hour ischemia with 42 hours reperfusion, and three hours ischemia followed by four days reperfusion (p˂0.005). Skeletal muscle develops adaptive changes in longer reperfusion, to deal with induced injury. Descriptions beyond 32 days reperfusion, can determine recovering normal pattern.

Increased E-selectin in hepatic ischemia-reperfusion injury mediates liver metastasis of pancreatic cancer

PubMed Central

YOSHIMOTO, KATSUHIRO; TAJIMA, HIDEHIRO; OHTA, TETSUO; OKAMOTO, KOICHI; SAKAI, SEISHO; KINOSHITA, JUN; FURUKAWA, HIROYUKI; MAKINO, ISAMU; HAYASHI, HIRONORI; NAKAMURA, KEISHI; OYAMA, KATSUNOBU; INOKUCHI, MASAFUMI; NAKAGAWARA, HISATOSHI; ITOH, HIROSHI; FUJITA, HIDETO; TAKAMURA, HIROYUKI; NINOMIYA, ITASU; KITAGAWA, HIROHISA; FUSHIDA, SACHIO; FUJIMURA, TAKASHI; WAKAYAMA, TOMOHIKO; ISEKI, SHOICHI; SHIMIZU, KOICHI

2012-01-01

Several recent studies have reported that selectins are produced during ischemia-reperfusion injury, and that selectin ligands play an important role in cell binding to the endothelium and in liver metastasis. Portal clamping during pancreaticoduodenectomy with vessel resection for pancreatic head cancer causes hepatic ischemia-reperfusion injury, which might promote liver metastasis. We investigated the liver colonization of pancreatic cancer cells under hepatic ischemia-reperfusion and examined the involvement of E-selectin and its ligands. A human pancreatic cancer cell line (Capan-1) was injected into the spleen of mice after hepatic ischemia-reperfusion (I/R group). In addition, to investigate the effect of an anti-E-selectin antibody on liver colonization in the IR group, mice received an intraperitoneal injection of the anti-E-selectin antibody following hepatic ischemia-reperfusion and tumor inoculation (IR+Ab group). Four weeks later, mice were sacrificed and the number of tumor nodules on the liver was compared to mice without hepatic ischemia-reperfusion (control group). The incidence of liver metastasis in the I/R group was significantly higher (16 of 20, 80%) than that in the control group (6 of 20, 30%) (P<0.01). Moreover, mice in the I/R group had significantly more tumor nodules compared to those in the control group (median, 9.9 vs. 2.7 nodules) (P<0.01). In the I/R+Ab group, only 2 of 5 (40%) mice developed liver metastases. RT-PCR and southern blotting of the liver extracts showed that the expression of IL-1 and E-selectin mRNA after hepatic ischemia-reperfusion was significantly higher than the basal levels. Hepatic ischemia-reperfusion increases liver metastases and E-selectin expression in pancreatic cancer. These results suggest that E-selectin produced due to hepatic ischemia-reperfusion is involved in liver metastasis. PMID:22766603

The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells.

PubMed

Koo, Tai Yeon; Lee, Jae-Ghi; Yan, Ji-Jing; Jang, Joon Young; Ju, Kyung Don; Han, Miyeun; Oh, Kook-Hwan; Ahn, Curie; Yang, Jaeseok

2017-08-01

Extracellular adenosine triphosphate (ATP) binds to purinergic receptors and, as a danger molecule, promotes inflammatory responses. Here we tested whether periodate-oxidized ATP (oATP), a P2X7 receptor (P2X7R) antagonist can attenuate renal ischemia-reperfusion injury and clarify the related cellular mechanisms. Treatment with oATP prior to ischemia-reperfusion injury decreased blood urea nitrogen, serum creatinine, the tubular injury score, and tubular epithelial cell apoptosis after injury. The infiltration of dendritic cells, neutrophils, macrophages, CD69 + CD4 + , and CD44 + CD4 + T cells was attenuated, but renal Foxp3 + CD4 + Treg infiltration was increased by oATP. The levels of IL-6 and CCL2 were reduced in the oATP group. Additionally, oATP treatment following injury improved renal function, decreased the infiltration of innate and adaptive effector cells, and increased the renal infiltration of Foxp3 + CD4 + Tregs. Post-ischemia-reperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemia-reperfusion injury in RAG-1 knockout mice; however, Treg depletion using PC61 abrogated the beneficial effects of oATP in wild-type mice. Furthermore, oATP treatment after transfer of Tregs from wild-type mice improved the beneficial effects of Tregs on ischemia-reperfusion injury, but treatment after transfer of Tregs from P2X7R knockout mice did not. Renal ischemia-reperfusion injury was also attenuated in P2X7R knockout mice. Experiments using bone marrow chimeras established that P2X7R expression on hematopoietic cells rather than non-hematopoietic cells, such as tubular epithelial cells, plays a major role in ischemia-reperfusion injury. Thus, oATP attenuated acute renal damage and facilitated renal recovery in ischemia-reperfusion injury by expansion of Tregs. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights

Oxidative Stress and Lung Ischemia-Reperfusion Injury

PubMed Central

Ferrari, Renata Salatti; Andrade, Cristiano Feijó

2015-01-01

Ischemia-reperfusion (IR) injury is directly related to the formation of reactive oxygen species (ROS), endothelial cell injury, increased vascular permeability, and the activation of neutrophils and platelets, cytokines, and the complement system. Several studies have confirmed the destructiveness of the toxic oxygen metabolites produced and their role in the pathophysiology of different processes, such as oxygen poisoning, inflammation, and ischemic injury. Due to the different degrees of tissue damage resulting from the process of ischemia and subsequent reperfusion, several studies in animal models have focused on the prevention of IR injury and methods of lung protection. Lung IR injury has clinical relevance in the setting of lung transplantation and cardiopulmonary bypass, for which the consequences of IR injury may be devastating in critically ill patients. PMID:26161240

Lipoic acid reduces ischemia-reperfusion injury in animal models.

PubMed

Freisleben, H J

2000-08-07

Hypoxia and reoxygenation were studied in rat hearts and ischemia and reperfusion in rat hindlimbs. Free radicals are known to be generated through these events and to propagate complications. In order to reduce hypoxic/ischemic and especially reoxygenation/reperfusion injury the (re)perfusion conditions were ameliorated including the treatment with antioxidants (lipoate or dihydrolipoate). In isolated working rat hearts cardiac and mitochondrial parameters are impaired during hypoxia and partially recover in reoxygenation. Dihydrolipoate, if added into the perfusion buffer at 0.3 microM concentration, keeps the pH higher (7. 15) during hypoxia as compared to controls (6.98). The compound accelerates the recovery of the aortic flow and stabilizes it during reoxygenation. With dihydrolipoate, ATPase activity is reduced, ATP synthesis is increased and phosphocreatine contents are higher than in controls. Creatine kinase activity is maintained during reoxygenation in the dihydrolipoate series. Isolated rat hindlimbs were stored for 4 h in a moist chamber at 18 degrees C. Controls were perfused for 30 min with a modified Krebs-Henseleit buffer at 60 mmHg followed by 30 min Krebs-Henseleit perfusion at 100 mmHg. The dihydrolipoate group contained 8.3 microM in the modified reperfusate (controlled reperfusion). With dihydrolipoate, recovery of the contractile function was 49% (vs. 34% in controls) and muscle flexibility was maintained whereas it decreased by 15% in the controls. Release of creatine kinase was significantly lower with dihydrolipoate treatment. Dihydrolipoate effectively reduces reoxygenation injury in isolated working rat hearts. Controlled reperfusion, including lipoate, prevents reperfusion syndrome after extended ischemia in exarticulated rat hindlimbs and in an in vivo pig hindlimbs model.

Organisation of reperfusion therapy for STEMI in a developing country

PubMed Central

Dharma, Surya; Andriantoro, Hananto; Dakota, Iwan; Purnawan, Ismi; Pratama, Vireza; Isnanijah, Herawati; Yamin, Muhammad; Bagus, Tjatur; Hartono, Benny; Ratnaningsih, Endang; Suling, Frits; Basalamah, M Abas

2015-01-01

Objective Routine evaluation of performance measures for the system of care for patients with ST-elevation myocardial infarction (STEMI) is needed to improve the STEMI network. We sought to evaluate the current status of reperfusion therapy for STEMI in the capital city of a developing country where a STEMI network was introduced in 2010. Methods Data were obtained from a local registry. A total of 28 812 patients admitted to the emergency department of a national cardiovascular hospital in three different periods (2007, 2010 and 2013) were retrospectively analysed; there were 2703 patients with STEMI. Results In 2013 compared with 2007, there was a major increase in the number of primary percutaneous coronary interventions (PCIs) (35% vs 24%, p<0.001), and the proportion of non-reperfused patients fell (62.8% vs 67.7%, p<0.001). An improvement in the overall STEMI mortality rate was also observed (7.5% vs 11.7%, p<0.001). Conclusions Implementation of a regional system of care for STEMI may improve utilisation of primary PCI. Future organisation of reperfusion therapy in a developing country such as Indonesia strongly calls for a strategy that focuses on prehospital care to minimise delay from the first medical contact to reperfusion therapy, and this may reduce the proportion of non-reperfused patients. These strategies are in concordance with guideline recommendations and may reduce or eliminate gaps in healthcare in developing countries, particularly the underutilisation of evidence-based therapies for patients with STEMI. Trial registration number NCT 02319473, Clinicaltrials.gov. PMID:26019883

Altering CO2 during reperfusion of ischemic cardiomyocytes modifies mitochondrial oxidant injury.

PubMed

Lavani, Romeen; Chang, Wei-Tien; Anderson, Travis; Shao, Zuo-Hui; Wojcik, Kimberly R; Li, Chang-Qing; Pietrowski, Robert; Beiser, David G; Idris, Ahamed H; Hamann, Kimm J; Becker, Lance B; Vanden Hoek, Terry L

2007-07-01

Acute changes in tissue CO2 and pH during reperfusion of the ischemic heart may affect ischemia/reperfusion injury. We tested whether gradual vs. acute decreases in CO2 after cardiomyocyte ischemia affect reperfusion oxidants and injury. Comparative laboratory investigation. Institutional laboratory. Embryonic chick cardiomyocytes. Microscope fields of approximately 500 chick cardiomyocytes were monitored throughout 1 hr of simulated ischemia (PO2 of 3-5 torr, PCO2 of 144 torr, pH 6.8), followed by 3 hrs of reperfusion (PO2 of 149 torr, PCO2 of 36 torr, pH 7.4), and compared with cells reperfused with relative hypercarbia (PCO2 of 71 torr, pH 6.8) or hypocarbia (PCO2 of 7 torr, pH 7.9). The measured outcomes included cell viability (via propidium iodide) and oxidant generation (reactive oxygen species via 2',7'-dichlorofluorescin oxidation and nitric oxide [NO] via 4,5-diaminofluorescein diacetate oxidation). Compared with normocarbic reperfusion, hypercarbia significantly reduced cell death from 54.8% +/- 4.0% to 26.3% +/- 2.8% (p < .001), significantly decreased reperfusion reactive oxygen species (p < .05), and increased NO at a later phase of reperfusion (p < .01). The NO synthase inhibitor N-nitro-L-arginine methyl ester (200 microM) reversed this oxidant attenuation (p < .05), NO increase (p < .05), and the cardioprotection conferred by hypercarbic reperfusion (increasing death to 54.3% +/- 6.0% [p < .05]). Conversely, hypocarbic reperfusion increased cell death to 80.4% +/- 4.5% (p < .01). It also increased reactive oxygen species by almost two-fold (p = .052), without affecting the NO level thereafter. Increased reactive oxygen species was attenuated by the mitochondrial complex III inhibitor stigmatellin (20 nM) when given at reperfusion (p < .05). Cell death also decreased from 85.9% +/- 4.5% to 52.2% +/- 6.5% (p < .01). The nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin (300 microM) had no effect on reperfusion reactive oxygen

Effect of taurine on ischemia-reperfusion injury.

PubMed

Schaffer, Stephen W; Jong, Chian Ju; Ito, Takashi; Azuma, Junichi

2014-01-01

Taurine is an abundant β-amino acid that regulates several events that dramatically influence the development of ischemia-reperfusion injury. One of these events is the extrusion of taurine and Na+ from the cell via the taurine/Na+ symport. The loss of Na+ during the ischemia-reperfusion insult limits the amount of available Na+ for Na+/Ca2+ exchange, an important process in the development of Ca2+ overload and the activation of the mitochondrial permeability transition, a key process in ischemia-reperfusion mediated cell death. Taurine also prevents excessive generation of reactive oxygen species by the respiratory chain, an event that also limits the activation of the MPT. Because taurine is an osmoregulator, changes in taurine concentration trigger "osmotic preconditioning," a process that activates an Akt-dependent cytoprotective signaling pathway that inhibits MPT pore formation. These effects of taurine have clinical implications, as experimental evidence reveals potential promise of taurine therapy in preventing cardiac damage during bypass surgery, heart transplantation and myocardial infarction. Moreover, severe loss of taurine from the heart during an ischemia-reperfusion insult may increase the risk of ventricular remodeling and development of heart failure.

Pretreatment with scutellaria baicalensis stem-leaf total flavonoid prevents cerebral ischemia-reperfusion injury

PubMed Central

Zhao, Shumin; Kong, Wei; Zhang, Shufeng; Chen, Meng; Zheng, Xiaoying; Kong, Xiangyu

2013-01-01

Pretreatment with scutellaria baicalensis stem-leaf total flavonoid has protective effects against ischemia and attenuates myocardial ischemia-reperfusion injury. In this study, rats were given scutellaria baicalensis stem-leaf total flavonoid intragastrically at 50, 100, and 200 mg/kg per day for 7 days before focal cerebral ischemia-reperfusion injury models were established using the suture method. We then determined the protective effects of scutellaria baicalensis stem-leaf total flavonoid pretreatment on focal cerebral ischemia-reperfusion injury. Results showed that neurological deficit scores increased, infarct volumes enlarged, apoptosis increased and Bcl-2 and Bax protein expression were upregulated at 24 hours after reperfusion. Pretreatment with scutellaria baicalensis stem-leaf total flavonoid at any dose lowered the neurological deficit scores, reduced the infarct volume, prevented apoptosis in hippocampal cells, attenuated neuronal and blood-brain barrier damage and upregulated Bcl-2 protein expression but inhibited Bax protein expression. Doses of 100 and 200 mg/kg were the most efficacious. Our findings indicate that pretreatment with scutellaria baicalensis stem-leaf total flavonoid at 100 and 200 mg/kg can improve the neurological functions and have preventive and protective roles after focal cerebral ischemia-reperfusion injury. PMID:25206639

Brief exposure to carbon monoxide preconditions cardiomyogenic cells against apoptosis in ischemia-reperfusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kondo-Nakamura, Mihoko; Shintani-Ishida, Kaori, E-mail: kaori@m.u-tokyo.ac.jp; Uemura, Koichi

We examined whether and how pretreatment with carbon monoxide (CO) prevents apoptosis of cardioblastic H9c2 cells in ischemia-reperfusion. Reperfusion (6 h) following brief ischemia (10 min) induced cytochrome c release, activation of caspase-9 and caspase-3, and apoptotic nuclear condensation. Brief CO pretreatment (10 min) or a caspase-9 inhibitor (Z-LEHD-FMK) attenuated these apoptotic changes. Ischemia-reperfusion increased phosphorylation of Akt at Ser472/473/474, and this was enhanced by CO pretreatment. A specific Akt inhibitor (API-2) blunted the anti-apoptotic effects of CO in reperfusion. In normoxic cells, CO enhanced O{sub 2}{sup -} generation, which was inhibited by a mitochondrial complex III inhibitor (antimycin A)more » but not by a NADH oxidase inhibitor (apocynin). The CO-enhanced Akt phosphorylation was suppressed by an O{sub 2}{sup -} scavenger (Tiron), catalase or a superoxide dismutase (SOD) inhibitor (DETC). These results suggest that CO pretreatment induces mitochondrial generation of O{sub 2}{sup -}, which is then converted by SOD to H{sub 2}O{sub 2}, and subsequent Akt activation by H{sub 2}O{sub 2} attenuates apoptosis in ischemia-reperfusion.« less

Protective effects of mangiferin on cerebral ischemia-reperfusion injury and its mechanisms.

PubMed

Yang, Zhang; Weian, Chen; Susu, Huang; Hanmin, Wang

2016-01-15

The aim of our study was to investigate the protective properties of mangiferin, a natural glucosyl xanthone found in both mango and papaya on the cerebral ischemia-reperfusion injury and the underlying mechanism. Wistar male rats were subjected to middle cerebral artery occlusion for 2h followed by 24h of reperfusion. Mangiferin (25, 50, and 100mg/kg, ig) or 0.5% carboxymethyl cellulose sodium was administered three times before ischemia and once at 2h after the onset of ischemia. Neurological score, infarct volume, and brain water content, some oxidative stress markers and inflammatory cytokines were evaluated after 24h of reperfusion. Treatment with mangiferin significantly ameliorated neurologic deficit, infarct volume and brain water content after cerebral ischemia reperfusion. Mangiferin also reduced the content of malondialdehyde (MDA), IL-1β and TNF-α, and up-regulated the activities of superoxide dismutase (SOD), glutathione (GSH) and IL-10 levels in the brain tissue of rats with the cerebral ischemia-reperfusion injury. Moreover, mangiferin up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream anti-oxidant protein heme oxygenase-1 (HO-1). The results indicate that mangiferin can play a certain protective role in the cerebral ischemia-reperfusion injury, and the protective effect of mangiferin may be related to the improvement on the antioxidant capacity of brain tissue and the inhibition of overproduction of inflammatory cytokines. The mechanisms are associated with enhancing the oxidant defense systems via the activation of Nrf2/HO-1 pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Activation of G protein‐coupled oestrogen receptor 1 at the onset of reperfusion protects the myocardium against ischemia/reperfusion injury by reducing mitochondrial dysfunction and mitophagy

PubMed Central

Feng, Yansheng; Madungwe, Ngonidzashe B; da Cruz Junho, Carolina Victoria

2017-01-01

Background and Purpose Recent evidence indicates that GPER (G protein‐coupled oestrogen receptor 1) mediates acute pre‐ischaemic oestrogen‐induced protection of the myocardium from ischaemia/reperfusion injury via a signalling cascade that includes PKC translocation, ERK1/2/ GSK‐3β phosphorylation and inhibition of the mitochondrial permeability transition pore (mPTP) opening. Here, we investigated the impact and mechanism involved in post‐ischaemic GPER activation in ischaemia/reperfusion injury. We determined whether GPER activation at the onset of reperfusion confers cardioprotective effects by protecting against mitochondrial impairment and mitophagy. Experimental Approach In vivo rat hearts were subjected to ischaemia followed by reperfusion with oestrogen (17β‐oestradiol, E2), E2 + G15, a GPER antagonist, or vehicle. Myocardial infarct size, the threshold for the opening of mPTP, mitophagy, mitochondrial membrane potential, ROS production, proteins ubiquitinated including cyclophilin D, and phosphorylation levels of ERK and GSK‐3β were measured. Results We found that post‐ischaemic E2 administration to both male and female ovariectomized‐rats reduced myocardial infarct size. Post‐ischaemic E2 administration preserved mitochondrial structural integrity and this was associated with a decrease in ROS production and increased mitochondrial membrane potential, as well as an increase in the mitochondrial Ca2+ load required to induce mPTP opening via activation of the MEK/ERK/GSK‐3β axis. Moreover, E2 reduced mitophagy via the PINK1/Parkin pathway involving LC3I, LC3II and p62 proteins. All these post‐ischaemic effects of E2 were abolished by G15 suggesting a GPER‐dependent mechanism. Conclusion These results indicate that post‐ischaemic GPER activation induces cardioprotective effects against ischaemia/reperfusion injury in males and females by protecting mitochondrial structural integrity and function and reducing mitophagy. PMID

Epigallocatechin-3-gallate protects against hepatic ischaemia-reperfusion injury by reducing oxidative stress and apoptotic cell death.

PubMed

Tak, Eunyoung; Park, Gil-Chun; Kim, Seok-Hwan; Jun, Dae Young; Lee, Jooyoung; Hwang, Shin; Song, Gi-Won; Lee, Sung-Gyu

2016-12-01

Objective To investigate the protective effects of epigallocatechin-3-gallate (EGCG), a major polyphenol source in green tea, against hepatic ischaemia-reperfusion injury in mice. Methods The partial hepatic ischaemia-reperfusion injury model was created by employing the hanging-weight method in C57BL/6 male mice. EGCG (50 mg/kg) was administered via an intraperitoneal injection 45 min before performing the reperfusion. A number of markers of inflammation, oxidative stress, apoptosis and liver injury were measured after the ischaemia-reperfusion injury had been induced. Results The treatment groups were: sham-operated (Sham, n = 10), hepatic ischaemia-reperfusion injury (IR, n = 10), and EGCG with ischaemia-reperfusion injury (EGCG-treated IR, n = 10). Hepatic ischaemia-reperfusion injury increased the levels of biochemical and histological markers of liver injury, increased the levels of malondialdehyde, reduced the glutathione/oxidized glutathione ratio, increased the levels of oxidative stress and lipid peroxidation markers, decreased B-cell lymphoma 2 levels, and increased the levels of Bax, cytochrome c, cleaved caspase-3, and cleaved caspase-9. Pretreatment with EGCG ameliorated all of these changes. Conclusion The antioxidant and antiapoptotic effects of EGCG protected against hepatic ischaemia-reperfusion injury in mice.

Epigallocatechin-3-gallate protects against hepatic ischaemia–reperfusion injury by reducing oxidative stress and apoptotic cell death

PubMed Central

Tak, Eunyoung; Park, Gil-Chun; Kim, Seok-Hwan; Jun, Dae Young; Lee, Jooyoung; Hwang, Shin; Lee, Sung-Gyu

2016-01-01

Objective To investigate the protective effects of epigallocatechin-3-gallate (EGCG), a major polyphenol source in green tea, against hepatic ischaemia–reperfusion injury in mice. Methods The partial hepatic ischaemia–reperfusion injury model was created by employing the hanging-weight method in C57BL/6 male mice. EGCG (50 mg/kg) was administered via an intraperitoneal injection 45 min before performing the reperfusion. A number of markers of inflammation, oxidative stress, apoptosis and liver injury were measured after the ischaemia–reperfusion injury had been induced. Results The treatment groups were: sham-operated (Sham, n = 10), hepatic ischaemia–reperfusion injury (IR, n = 10), and EGCG with ischaemia–reperfusion injury (EGCG-treated IR, n = 10). Hepatic ischaemia–reperfusion injury increased the levels of biochemical and histological markers of liver injury, increased the levels of malondialdehyde, reduced the glutathione/oxidized glutathione ratio, increased the levels of oxidative stress and lipid peroxidation markers, decreased B-cell lymphoma 2 levels, and increased the levels of Bax, cytochrome c, cleaved caspase-3, and cleaved caspase-9. Pretreatment with EGCG ameliorated all of these changes. Conclusion The antioxidant and antiapoptotic effects of EGCG protected against hepatic ischaemia–reperfusion injury in mice. PMID:27807255

Isoflurane produces sustained cardiac protection after ischemia-reperfusion injury in mice.

PubMed

Tsutsumi, Yasuo M; Patel, Hemal H; Lai, N Chin; Takahashi, Toshiyuki; Head, Brian P; Roth, David M

2006-03-01

Isoflurane reduces myocardial ischemia-reperfusion injury within hours to days of reperfusion. Whether isoflurane produces sustained cardiac protection has never been examined. The authors studied isoflurane-induced cardiac protection in the intact mouse after 2 h and 2 weeks of reperfusion and determined the dependence of this protection on adenosine triphosphate-dependent potassium channels and the relevance of this protection to myocardial function and apoptosis. Mice were randomly assigned to receive oxygen or isoflurane for 30 min with 15 min of washout. Some mice received mitochondrial (5-hydroxydecanoic acid) or sarcolemmal (HMR-1098) adenosine triphosphate-dependent potassium channel blockers with or without isoflurane. Mice were then subjected to a 30-min coronary artery occlusion followed by 2 h or 2 weeks of reperfusion. Infarct size was determined at 2 h and 2 weeks of reperfusion. Cardiac function and apoptosis were determined 2 weeks after reperfusion. Isoflurane did not change hemodynamics. Isoflurane reduced infarct size after reperfusion when compared with the control groups (27.7 +/- 6.3 vs. 41.7 +/- 6.4% at 2 h and 19.6 +/- 5.9 vs. 28.8 +/- 9.0% at 2 weeks). Previous administration of 5-hydroxydecanoic acid, but not HMR-1098, abolished isoflurane-induced cardiac protection. At 2 weeks, left ventricular end-diastolic diameter was decreased significantly and end-systolic pressure and maximum and minimum dP/dt were improved by isoflurane. Isoflurane-treated mice subjected to ischemia and 2 weeks of reperfusion showed less expression of proapoptotic genes, significantly decreased expression of cleaved caspase-3, and significantly decreased deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling-positive nuclei compared with the control group. Cardiac protection induced by isoflurane against necrotic and apoptotic cell death is associated with an acute memory period that is sustained and functionally relevant 2 weeks after

Neutrophil protein kinase Cδ as a mediator of stroke-reperfusion injury

PubMed Central

Chou, Wen-Hai; Choi, Doo-Sup; Zhang, Hong; Mu, Dezhi; McMahon, Tom; Kharazia, Viktor N.; Lowell, Clifford A.; Ferriero, Donna M.; Messing, Robert O.

2004-01-01

Thrombolysis is widely used to intervene in acute ischemic stroke, but reestablishment of circulation may paradoxically initiate a reperfusion injury. Here we describe studies with mice lacking protein kinase Cδ (PKCδ) showing that absence of this enzyme markedly reduces reperfusion injury following transient ischemia. This was associated with reduced infiltration of peripheral blood neutrophils into infarcted tissue and with impaired neutrophil adhesion, migration, respiratory burst, and degranulation in vitro. Total body irradiation followed by transplantation with bone marrow from PKCδ-null mice donors reduced infarct size and improved neurological outcome in WT mice, whereas marrow transplantation from WT donors increased infarction and worsened neurological scores in PKCδ-null mice. These results indicate an important role for neutrophil PKCδ in reperfusion injury and strongly suggest that PKCδ inhibitors could prove useful in the treatment of stroke. PMID:15232611

Rapamycin preconditioning attenuates transient focal cerebral ischemia/reperfusion injury in mice.

PubMed

Yin, Lele; Ye, Shasha; Chen, Zhen; Zeng, Yaoying

2012-12-01

Rapamycin, an mTOR inhibitor and immunosuppressive agent in clinic, has protective effects on traumatic brain injury and neurodegenerative diseases. But, its effects on transient focal ischemia/reperfusion disease are not very clear. In this study, we examined the effects of rapamycin preconditioning on mice treated with middle cerebral artery occlusion/reperfusion operation (MCAO/R). We found that the rapamycin preconditioning by intrahippocampal injection 20 hr before MCAO/R significantly improved the survival rate and longevity of mice. It also decreased the neurological deficit score, infracted areas and brain edema. In addition, rapamycin preconditioning decreased the production of NF-κB, TNF-α, and Bax, but not Bcl-2, an antiapoptotic protein in the ischemic area. From these results, we may conclude that rapamycin preconditioning attenuate transient focal cerebral ischemia/reperfusion injury and inhibits apoptosis induced by MCAO/R in mice.

Ilexsaponin A attenuates ischemia-reperfusion-induced myocardial injury through anti-apoptotic pathway.

PubMed

Zhang, Shuang-Wei; Liu, Yu; Wang, Fang; Qiang, Jiao; Liu, Pan; Zhang, Jun; Xu, Jin-Wen

2017-01-01

The protective effects of ilexsaponin A on ischemia-reperfusion-induced myocardial injury were investigated. Myocardial ischemia/reperfusion model was established in male Sprague-Dawley rats. Myocardial injury was evaluated by TTC staining and myocardial marker enzyme leakage. The in vitro protective potential of Ilexsaponin A was assessed on hypoxia/reoxygenation cellular model in neonatal rat cardiomyocytes. Cellular viability and apoptosis were evaluated by MTT and TUNEL assay. Caspase-3, cleaved caspase-3, bax, bcl-2, p-Akt and Akt protein expression levels were detected by western-blot. Ilexsaponin A treatment was able to attenuate the myocardial injury in ischemia/reperfusion model by reducing myocardial infarct size and lower the serum levels of LDH, AST and CK-MB. The in vitro study also showed that ilexsaponin A treatment could increase cellular viability and inhibit apoptosis in hypoxia/reoxygenation cardiomyocytes. Proapoptotic proteins including caspase-3, cleaved caspase-3 and bax were significantly reduced and anti-apoptotic protein bcl-2 was significantly increased by ilexsaponin A treatment in hypoxia/reoxygenation cardiomyocytes. Moreover, Ilexsaponin A treatment was able to increase the expression levels of p-Akt in hypoxia/reoxygenation cellular model and myocardial ischemia/reperfusion animal model. Coupled results from both in vivo and in vitro experiments indicate that Ilexsaponin A attenuates ischemia-reperfusion-induced myocardial injury through anti-apoptotic pathway.

Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway

PubMed Central

2011-01-01

Background Postconditioning (PostC) inhibits myocardial apoptosis after ischemia-reperfusion (I/R) injury. The JAK2-STAT3 pathway has anti-apoptotic effects and plays an essential role in the late protection of preconditioning. Our aim was to investigate the anti-apoptotic effect of PostC after prolonged reperfusion and the role of the JAK2-STAT3 pathway in the anti-apoptotic effect of PostC. Methods Wistar rats were subjected to 30 minutes ischemia and 2 or 24 hours (h) reperfusion, with or without PostC (three cycles of 10 seconds reperfusion and 10 seconds reocclusion at the onset of reperfusion). Separate groups of rats were treated with a JAK2 inhibitor (AG490) or a PI3K inhibitor (wortmannin) 5 minutes before PostC. Immunohistochemistry was used to analyze Bcl-2 protein levels after reperfusion. mRNA levels of Bcl-2 were detected by qRT-PCR. TTC staining was used to detect myocardial infarction size. Myocardial apoptosis was evaluated by TUNEL staining. Western-blot was used to detect p-STAT3 and p-Akt levels after reperfusion. Results There was more myocardial apoptosis at 24 h vs 2 h after reperfusion in all groups. PostC significantly reduced myocardial apoptosis and elevated Bcl-2 levels at both 2 and 24 hours after reperfusion. PostC increased p-STAT3 and p-Akt levels after reperfusion. Administration of AG490 reduced p-STAT3 and p-Akt levels and attenuated the anti-apoptotic effect of PostC. Wortmannin also reduced p-Akt levels and attenuated the anti-apoptotic effect of PostC but had no effect on p-STAT3 levels. AG490 abrogated the up-regulation of Bcl-2 by PostC. Conclusion PostC may reduce myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway. As a downstream target of JAK2 signaling, activation of PI3K/Akt pathway may be necessary in the protection of PostC. PMID:21810244

Inhibition of Angiotensin-II Production Increases Susceptibility to Acute Ischemia/Reperfusion Arrhythmia

PubMed Central

Taskin, Eylem; Tuncer, Kadir Ali; Guven, Celal; Kaya, Salih Tunc; Dursun, Nurcan

2016-01-01

Background Myocardial ischemia and reperfusion lead to impairment of electrolyte balance and, eventually, lethal arrhythmias. The aim of this study was to investigate the effects of pharmacological inhibition of angiotensin-II (Ang-II) production on heart tissue with ischemia-reperfusion damage, arrhythmia, and oxidative stress. Material/Methods Rats were divided into 4 groups: only ischemia/reperfusion (MI/R), captopril (CAP), aliskiren (AL), and CAP+AL. The drugs were given by gavage 30 min before anesthesia. Blood pressure and electrocardiography (ECG) were recorded during MI/R procedures. The heart tissue and plasma was kept so as to evaluate the total oxidant (TOS), antioxidant status (TAS), and creatine kinase-MB (CK-MB). Results Creatine kinase-MB was not different among the groups. Although TAS was not affected by inhibition of Ang-II production, TOS was significantly lower in the CAP and/or AL groups than in the MI/R group. Furthermore, oxidative stress index was significantly attenuated in the CAP and/or AL groups. Captopril significantly increased the duration of VT during ischemia; however, it did not have any effect on the incidence of arrhythmias. During reperfusion periods, aliskiren and its combinations with captopril significantly reduced the incidence of other types of arrhythmias. Captopril alone had no effect on the incidence of arrhythmias, but significantly increased arrhythmias score and durations of arrhythmias during reperfusion. MAP and heart rate did not show changes in any groups during ischemic and reperfusion periods. Conclusions Angiotensin-II production appears to be associated with elevated levels of reactive oxygen species, but Ang-II inhibitions increases arrhythmia, mainly by initiating ventricular ectopic beats. PMID:27889788

Retinal reperfusion in diabetic retinopathy following treatment with anti-VEGF intravitreal injections.

PubMed

Levin, Ariana M; Rusu, Irene; Orlin, Anton; Gupta, Mrinali P; Coombs, Peter; D'Amico, Donald J; Kiss, Szilárd

2017-01-01

The aim of this study is to report peripheral reperfusion of ischemic areas of the retina on ultra-widefield fluorescein angiography (UWFA) following anti-vascular endothelial growth factor (VEGF) intravitreal injections in patients treated for diabetic retinopathy. This study is a retrospective review of 16 eyes of 15 patients with diabetic retinopathy, who received anti-VEGF intravitreal injections and underwent pre- and postinjection UWFA. The main outcome measured was the presence of reperfusion in postinjection UWFA images in areas of the retina that demonstrated nonperfusion in preinjection images. Images were analyzed for reperfusion qualitatively and quantitatively by two graders. Twelve of 16 eyes (75%) or 11 of 15 patients (73.3%) demonstrated reperfusion following anti-VEGF injection. On UWFA, reperfusion was detected both within the field of 7-standard field (7SF) fluorescein angiography and in the periphery outside the 7SF. Four of 16 eyes or 4 of 15 patients did not demonstrate reperfusion, one of which had extensive scarring from prior panretinal photocoagulation. In patients with diabetic retinopathy, treatment with anti-VEGF agents can be associated with reperfusion of areas of nonperfusion, as demonstrated by UWFA.

Protective effect of chlorogenic acid on the focal cerebral ischemia reperfusion rat models.

PubMed

Miao, Mingsan; Cao, Lihua; Li, Ruiqi; Fang, Xiaoyan; Miao, Yanyan

2017-05-01

The aim of the study was to investigate the protective characteristic of chlorogenic acid, a natural glucosyl xanthone found in Lonicera Japonica on the cerebral ischemia reperfusion injury and the underlying mechanism. Focal cerebral ischemia reperfusion model was built by blocking the left middle cerebral artery in rats by using the suture-occluded method. Before operation, the corresponding drugs were given for each group once a day for 7 days. After 1 h of final administration, the model was built, after operation, reperfusion was conducted for 22 h, Before the reperfusion 10 min tail vein injection of large, medium and small dose of chlorogenic acid and then mortality was calculated, and Neurological deficit score (NDS) was conducted, and serum was collected to measure the NSE level; a 2 mm thick brain slice located at the intersection of optic nerves was collected for TTC staining, and the percentage of cerebral infarction area was calculated; brain homogenate was collected to measure the ICAM-1, VCAM-1, EPO and HIF-1α levels in brain tissue of cerebral ischemia reperfusion rat models; NGF was detected using immunohistochemical method; the morphological changes in brain tissue was observed with HE staining. All focal cerebral ischemia reperfusion rat models were duplicated successfully. Every chlorogenic acid group with different dosage can significantly reduce the mortality, NDS and cerebral infarction area of rats, and significantly increase the EPO, HIF-1α and NGF levels in brain tissue; significantly improve the pathological lesions of hippocampus and cortex in brain tissue. The results showed that chlorogenic acid could protect the focal cerebral ischemia reperfusion injury rat models by adjusting the inflammatory factor, hypoxia factor and nerve growth factor.

Dietary Fish Oil Blocks the Microcirculatory Manifestations of Ischemia- Reperfusion Injury in Striated Muscle in Hamsters

NASA Astrophysics Data System (ADS)

Lehr, Hans-Anton; Hubner, Christoph; Nolte, Dirk; Kohlschutter, Alfried; Messmer, Konrad

1991-08-01

Epidemiologic observations and experimental studies have demonstrated a protective effect of dietary fish oil on the clinical manifestations of ischemia-reperfusion injury. To investigate the underlying mechanisms, we used the dorsal skinfold chamber model for intravital fluorescence microscopy of the microcirculation in striated muscle of awake hamsters. In control hamsters (n = 7), reperfusion after a 4-hr pressure-induced ischemia to the muscle tissue elicited the adhesion of fluorescently stained leukocytes to the endothelium of postcapillary venules, capillary obstruction, and the breakdown of endothelial integrity. These microvascular manifestations of ischemia-reperfusion injury were significantly attenuated in animals (n = 7) when fed with a fish oil-enriched diet for 4 weeks prior to the experiments. In leukocyte total lipids, the fish oil diet resulted in a substantial displacement of arachidonic acid, the precursor of the potent adhesionpromoting leukotriene (LT) B_4, by fish oil-derived eicosapentaenoic acid, the precursor of biologically less potent LTB_5, emphasizing the mediator role of LTB_4 in ischemia-reperfusion injury. These results suggest that the preservation of microvascular perfusion by dietary fish oil contributes to its protective effects on the clinical manifestations of ischemia-reperfusion injury.

Mechanisms of load dependency of myocardial ischemia reperfusion injury

PubMed Central

Mozaffari, Mahmood S; Liu, Jun Yao; Abebe, Worku; Baban, Babak

2013-01-01

Coronary artery disease and associated ischemic heart disease are prevalent disorders worldwide. Further, systemic hypertension is common and markedly increases the risk for heart disease. A common denominator of systemic hypertension of various etiologies is increased myocardial load/mechanical stress. Thus, it is likely that high pressure/mechanical stress attenuates the contribution of cardioprotective but accentuates the contribution of cardiotoxic pathways thereby exacerbating the outcome of an ischemia reperfusion insult to the heart. Critical events which contribute to cardiomyocyte injury in the ischemic-reperfused heart include cellular calcium overload and generation of reactive oxygen/nitrogen species which, in turn, promote the opening of the mitochondrial permeability transition pore, an important event in cell death. Increasing evidence also indicates that the myocardium is capable of mounting a robust inflammatory response which contributes importantly to tissue injury. On the other hand, cardioprotective maneuvers of ischemic preconditioning and postconditioning have led to identification of complex web of signaling pathways (e.g., reperfusion injury salvage kinase) which ultimately converge on the mitochondria to exert cytoprotection. The present review is intended to briefly describe mechanisms of cardiac ischemia reperfusion injury followed by a discussion of our work focused on how pressure/mechanical stress modulates endogenous cardiotoxic and cardioprotective mechanisms to ultimately exacerbate ischemia reperfusion injury. PMID:24224132

Historical perspective on the pathology of myocardial ischemia/reperfusion injury.

PubMed

Jennings, Robert B

2013-08-02

A selective history of the pathophysiological, structural, and metabolic changes found during an episode of severe myocardial ischemia in the canine heart is presented. The changes that cause ischemic injury to become irreversible are discussed in detail because these changes are the target of any successful therapy designed to prevent ischemic cell death. Of these, the disruption of the sarcolemma, an injury the development of which is accelerated in vivo by the contraction of viable tissue elsewhere in the heart traumatizing the ischemic area, plus the changes in high-energy phosphate and the total adenine nucleotide pool are considered to be the critical events leading to the development of irreversibility. The discovery of preconditioning with ischemia is discussed, together with a brief description of postconditioning. Finally, reperfusion injury is discussed in a summary fashion. The evidence for the fact that myocytes are salvaged by reperfusion is presented, as is the evidence that myocytes become unsalvageable by reperfusion as the duration of ischemia increases. The concept that some of the myocytes that die after successful reperfusion with arterial blood actually are killed by changes initiated by reperfusion, so-called lethal reperfusion injury, is attractive in that prevention of this change would lead to greater salvage; however, the prevalence of this phenomenon in clinical practice remains to be determined.

Role of the plasma cascade systems in ischemia/reperfusion injury of bone.

PubMed

Zhang, Shengye; Wotzkow, Carlos; Bongoni, Anjan K; Shaw-Boden, Jane; Siegrist, Mark; Taddeo, Adriano; Blank, Fabian; Hofstetter, Willy; Rieben, Robert

2017-04-01

Ischemia/reperfusion (I/R) injury has been extensively studied in organs such as heart, brain, liver, kidney, and lung. As a vascularized organ, bone is known to be susceptible to I/R injury too, but the respective mechanisms are not well understood to date. We therefore hypothesized that, similar to other organs, plasma cascade-induced inflammation also plays a role in bone I/R injury. Reperfusion injury in rat tibia was induced by unilateral clamping of the femoral artery and additional use of a tourniquet, while keeping the femoral vein patent to prevent venous congestion. Rats were subjected to 4h ischemia and 24h reperfusion. Deposition of complement fragment C3b/c and fibrin as well as expression of tissue factor (TF), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and E-selectin was detected by immunohistochemistry. In plasma, the levels of high mobility group box1 (HMGB1) were measured by ELISA. The total level of complement in serum was assessed by the CH50 test. Our results show that deposition of C3b/c was significantly increased with respect to healthy controls in cortical bone as well as in marrow of reperfused limbs. C3b/c deposition was also increased in cortical bone, but not in bone marrow, of contralateral limbs. Deposition of fibrin, as well as expression of PAI-1, was significantly increased in bone after ischemia and reperfusion, whereas expression of tPA was reduced. These differences were most prominent in vessels of bone, both in marrow and cortical bone, and both in reperfused and contralateral limbs. However, PAI-1, was only increased in vessels of reperfused cortical bone and there were no significant changes in expression of E-selectin. With respect to solid bone tissue, a significant increase of C3b/c and fibrin deposition was shown in osteocytes, and for fibrin also in the bone matrix, in both contralateral and reperfused cortical bone compared with normal healthy controls. A slight expression of TF was

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

PubMed Central

Gaude, Edoardo; Aksentijević, Dunja; Sundier, Stephanie Y.; Robb, Ellen L.; Logan, Angela; Nadtochiy, Sergiy M.; Ord, Emily N. J.; Smith, Anthony C.; Eyassu, Filmon; Shirley, Rachel; Hu, Chou-Hui; Dare, Anna J.; James, Andrew M.; Rogatti, Sebastian; Hartley, Richard C.; Eaton, Simon; Costa, Ana S.H.; Brookes, Paul S.; Davidson, Sean M.; Duchen, Michael R.; Saeb-Parsy, Kourosh; Shattock, Michael J.; Robinson, Alan J.; Work, Lorraine M.; Frezza, Christian; Krieg, Thomas; Murphy, Michael P.

2014-01-01

Ischaemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death, and aberrant immune responses through generation of mitochondrial reactive oxygen species (ROS)1-5. Although mitochondrial ROS production in IR is established, it has generally been considered a non-specific response to reperfusion1,3. Here, we developed a comparative in vivo metabolomic analysis and unexpectedly identified widely conserved metabolic pathways responsible for mitochondrial ROS production during IR. We showed that selective accumulation of the citric acid cycle (CAC) intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase (SDH), which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. Upon reperfusion, the accumulated succinate is rapidly re-oxidised by SDH, driving extensive ROS generation by reverse electron transport (RET) at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo IR injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of IR injury. Furthermore, these findings reveal a novel pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation upon subsequent reperfusion is a potential therapeutic target to decrease IR injury in a range of pathologies. PMID:25383517

The effect of repeated diazepam administration on myocardial function in the ischemia-reperfused isolated rat heart.

PubMed

Shackebaei, Dareuosh; Kayhani, Bijan; Godini, Aliashraf; Pourshanazari, Aliasghar; Reshadat, Sohyla

2009-06-01

To evaluate whether repeated diazepam administration affects the heart in ischemia-reperfusion. This study was performed at the Medical Biology Research Center, Kermanshah, Iran, from March to September 2008. Four groups of rats were subjected to a daily injection of diazepam (group 1 [0.5 mg/kg for 21 days], group II [2.5 mg/kg for 5 days], and group III [5 mg/kg for 5 days] intraperitoneally), and saline solution (21 days) in the control groups. Isolated, perfused hearts were subjected to 40 minutes global ischemia, and 45 minutes reperfusion. The left ventricular developed pressure (LVDP), heart rate, and coronary flow were measured. Rate pressure product (RPP) was calculated. In reperfusion, released lactate dehydrogenase (LDH) enzyme in effluent was measured. It was observed that the recovery of the RPP and LVDP in reperfusion significantly decreased in the test group III (n=9) in comparison to the control (n=8). During the reperfusion period, the released LDH significantly increased in test group II (n=8) and group III in comparison with the control. The results show that repeated administration of diazepam (5 mg/kg for 5 days) reduced the cardiac performance in reperfusion, and significantly exacerbated the ischemia-reperfusion injury. It is probably mediated by the changing of cardiac susceptibility in ischemia due to repeated administration of diazepam.

Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK

PubMed Central

Filippone, Scott M.; Samidurai, Arun; Roh, Sean K.; Cain, Chad K.; He, Jun; Salloum, Fadi N.; Kukreja, Rakesh C.

2017-01-01

Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR) inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial infarct size through modulation of mTOR complexes. Adult C57 male mice were subjected to 30 min of myocardial ischemia followed by reperfusion for 1 hour/24 hours. Rapamycin (0.25 mg/kg) or DMSO (7.5%) was injected intracardially at the onset of reperfusion. Post-I/R survival (87%) and cardiac function (fractional shortening, FS: 28.63 ± 3.01%) were improved in Rapamycin-treated mice compared to DMSO (survival: 63%, FS: 17.4 ± 2.6%). Rapamycin caused significant reduction in myocardial infarct size (IS: 26.2 ± 2.2%) and apoptosis (2.87 ± 0.64%) as compared to DMSO-treated mice (IS: 47.0 ± 2.3%; apoptosis: 7.39 ± 0.81%). Rapamycin induced phosphorylation of AKT S473 (target of mTORC2) but abolished ribosomal protein S6 phosphorylation (target of mTORC1) after I/R. Rapamycin induced phosphorylation of ERK1/2 but inhibited p38 phosphorylation. Infarct-limiting effect of Rapamycin was abolished with ERK inhibitor, PD98059. Rapamycin also attenuated Bax and increased Bcl-2/Bax ratio. These results suggest that reperfusion therapy with Rapamycin protects the heart against I/R injury by selective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38. PMID:28373901

Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK.

PubMed

Filippone, Scott M; Samidurai, Arun; Roh, Sean K; Cain, Chad K; He, Jun; Salloum, Fadi N; Kukreja, Rakesh C; Das, Anindita

2017-01-01

Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR) inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial infarct size through modulation of mTOR complexes. Adult C57 male mice were subjected to 30 min of myocardial ischemia followed by reperfusion for 1 hour/24 hours. Rapamycin (0.25 mg/kg) or DMSO (7.5%) was injected intracardially at the onset of reperfusion. Post-I/R survival (87%) and cardiac function (fractional shortening, FS: 28.63 ± 3.01%) were improved in Rapamycin-treated mice compared to DMSO (survival: 63%, FS: 17.4 ± 2.6%). Rapamycin caused significant reduction in myocardial infarct size (IS: 26.2 ± 2.2%) and apoptosis (2.87 ± 0.64%) as compared to DMSO-treated mice (IS: 47.0 ± 2.3%; apoptosis: 7.39 ± 0.81%). Rapamycin induced phosphorylation of AKT S473 (target of mTORC2) but abolished ribosomal protein S6 phosphorylation (target of mTORC1) after I/R. Rapamycin induced phosphorylation of ERK1/2 but inhibited p38 phosphorylation. Infarct-limiting effect of Rapamycin was abolished with ERK inhibitor, PD98059. Rapamycin also attenuated Bax and increased Bcl-2/Bax ratio. These results suggest that reperfusion therapy with Rapamycin protects the heart against I/R injury by selective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38.

NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure.

PubMed

Roberts, Byron N; Christini, David J

2011-10-01

Reperfusion injury results from pathologies of cardiac myocyte physiology that develop when previously ischemic myocardium experiences a restoration of normal perfusion. Events in the development of reperfusion injury begin with the restoration of a proton gradient upon reperfusion, which then allows the sodium-proton exchanger (NHE) to increase flux, removing protons from the intracellular space while importing sodium. The resulting sodium overload drives increased reverse-mode sodium-calcium exchanger (NCX) activity, creating a secondary calcium overload that has pathologic consequences. One of the attempts to reduce reperfusion-related damage, NHE inhibition, has shown little clinical benefit, and only when NHE inhibitors are given prior to reperfusion. In an effort to further understand why NHE inhibitors have been largely unsuccessful, we employed a new mathematical cardiomyocyte model that we developed for the study of ischemia and reperfusion. Using this model, we simulated 20 minutes of ischemia and 10 minutes of reperfusion, while also simulating NHE inhibition by reducing NHE flux in our model by varying amounts and at different time points. In our simulations, when NHE inhibition is applied at the onset of reperfusion, increasing the degree of inhibition increases the peak sodium and calcium concentrations, as well as reducing intracellular pH recovery. When inhibition was instituted at earlier time points, some modest improvements were seen, largely due to reduced sodium concentrations prior to reperfusion. Analysis of all sodium flux pathways suggests that the sodium-potassium pump (NaK) plays the largest role in exacerbated sodium overload during reperfusion, and that reduced NaK flux is largely the result of impaired pH recovery. While NHE inhibition does indeed reduce sodium influx through that exchanger, the resulting prolongation of intracellular acidosis paradoxically increases sodium overload, largely mediated by impaired NaK function.

NHE Inhibition Does Not Improve Na+ or Ca2+ Overload During Reperfusion: Using Modeling to Illuminate the Mechanisms Underlying a Therapeutic Failure

PubMed Central

Roberts, Byron N.; Christini, David J.

2011-01-01

Reperfusion injury results from pathologies of cardiac myocyte physiology that develop when previously ischemic myocardium experiences a restoration of normal perfusion. Events in the development of reperfusion injury begin with the restoration of a proton gradient upon reperfusion, which then allows the sodium-proton exchanger (NHE) to increase flux, removing protons from the intracellular space while importing sodium. The resulting sodium overload drives increased reverse-mode sodium-calcium exchanger (NCX) activity, creating a secondary calcium overload that has pathologic consequences. One of the attempts to reduce reperfusion-related damage, NHE inhibition, has shown little clinical benefit, and only when NHE inhibitors are given prior to reperfusion. In an effort to further understand why NHE inhibitors have been largely unsuccessful, we employed a new mathematical cardiomyocyte model that we developed for the study of ischemia and reperfusion. Using this model, we simulated 20 minutes of ischemia and 10 minutes of reperfusion, while also simulating NHE inhibition by reducing NHE flux in our model by varying amounts and at different time points. In our simulations, when NHE inhibition is applied at the onset of reperfusion, increasing the degree of inhibition increases the peak sodium and calcium concentrations, as well as reducing intracellular pH recovery. When inhibition was instituted at earlier time points, some modest improvements were seen, largely due to reduced sodium concentrations prior to reperfusion. Analysis of all sodium flux pathways suggests that the sodium-potassium pump (NaK) plays the largest role in exacerbated sodium overload during reperfusion, and that reduced NaK flux is largely the result of impaired pH recovery. While NHE inhibition does indeed reduce sodium influx through that exchanger, the resulting prolongation of intracellular acidosis paradoxically increases sodium overload, largely mediated by impaired NaK function. PMID

Mathematical Modeling of Ischemia-Reperfusion Injury and Postconditioning Therapy.

PubMed

Fong, D; Cummings, L J

2017-11-01

Reperfusion (restoration of blood flow) after a period of ischemia (interruption of blood flow) can paradoxically place tissues at risk of further injury: so-called ischemia-reperfusion injury or IR injury. Recent studies have shown that postconditioning (intermittent periods of further ischemia applied during reperfusion) can reduce IR injury. We develop a mathematical model to describe the reperfusion and postconditioning process following an ischemic insult, treating the blood vessel as a two-dimensional channel, lined with a monolayer of endothelial cells that interact (respiration and mechanotransduction) with the blood flow. We investigate how postconditioning affects the total cell density within the endothelial layer, by varying the frequency of the pulsatile flow and the oxygen concentration at the inflow boundary. We find that, in the scenarios we consider, the pulsatile flow should be of high frequency to minimize cellular damage, while oxygen concentration at the inflow boundary should be held constant, or subject to only low-frequency variations, to maximize cell proliferation.

Nigella sativa relieves the deleterious effects of ischemia reperfusion injury on liver

PubMed Central

Yildiz, Fahrettin; Coban, Sacit; Terzi, Alpaslan; Ates, Mustafa; Aksoy, Nurten; Cakir, Hale; Ocak, Ali Riza; Bitiren, Muharrem

2008-01-01

AIM: To determine whether Nigella sativa prevents hepatic ischemia-reperfusion injury to the liver. METHODS: Thirty rats were divided into three groups as sham (Group 1), control (Group 2), and Nigella sativa (NS) treatment group (Group 3). All rats underwent hepatic ischemia for 45 min followed by 60 min period of reperfusion. Rats were intraperitoneally infused with only 0.9% saline solution in group 2. Rats in group 3 received NS (0.2 mL/kg) intraperitoneally, before ischemia and before reperfusion. Blood samples and liver tissues were harvested from the rats, and then the rats were sacrificed. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were determined. Total antioxidant capacity (TAC), catalase (CAT), total oxidative status (TOS), oxidative stress index (OSI) and myeloperoxidase (MPO) in hepatic tissue were measured. Also liver tissue histopathology was evaluated by light microscopy. RESULTS: The levels of liver enzymes in group 3 were significantly lower than those in the group 2. TAC in liver tissue was significantly higher in group 3 than in group 2. TOS, OSI and MPO in hepatic tissue were significantly lower in group 3 than the group 2. Histological tissue damage was milder in the NS treatment group than that in the control group. CONCLUSION: Our results suggest that Nigella sativa treatment protects the rat liver against to hepatic ischemia-reperfusion injury. PMID:18777598

Bicarbonate Increases Ischemia-Reperfusion Damage by Inhibiting Mitophagy

PubMed Central

Kowaltowski, Alicia J.; Gottlieb, Roberta A.

2016-01-01

During an ischemic event, bicarbonate and CO2 concentration increase as a consequence of O2 consumption and lack of blood flow. This event is important as bicarbonate/CO2 is determinant for several redox and enzymatic reactions, in addition to pH regulation. Until now, most work done on the role of bicarbonate in ischemia-reperfusion injury focused on pH changes; although reperfusion solutions have a fixed pH, cardiac resuscitation protocols commonly employ bicarbonate to correct the profound acidosis associated with respiratory arrest. However, we previously showed that bicarbonate can increase tissue damage and protein oxidative damage independent of pH. Here we show the molecular basis of bicarbonate-induced reperfusion damage: the presence of bicarbonate selectively impairs mitophagy, with no detectable effect on autophagy, proteasome activity, reactive oxygen species production or protein oxidation. We also show that inhibition of autophagy reproduces the effects of bicarbonate in reperfusion injury, providing additional evidence in support of this mechanism. This phenomenon is especially important because bicarbonate is widely used in resuscitation protocols after cardiac arrest, and while effective as a buffer, may also contribute to myocardial injury. PMID:27973540

Bicarbonate Increases Ischemia-Reperfusion Damage by Inhibiting Mitophagy.

PubMed

Queliconi, Bruno B; Kowaltowski, Alicia J; Gottlieb, Roberta A

2016-01-01

During an ischemic event, bicarbonate and CO2 concentration increase as a consequence of O2 consumption and lack of blood flow. This event is important as bicarbonate/CO2 is determinant for several redox and enzymatic reactions, in addition to pH regulation. Until now, most work done on the role of bicarbonate in ischemia-reperfusion injury focused on pH changes; although reperfusion solutions have a fixed pH, cardiac resuscitation protocols commonly employ bicarbonate to correct the profound acidosis associated with respiratory arrest. However, we previously showed that bicarbonate can increase tissue damage and protein oxidative damage independent of pH. Here we show the molecular basis of bicarbonate-induced reperfusion damage: the presence of bicarbonate selectively impairs mitophagy, with no detectable effect on autophagy, proteasome activity, reactive oxygen species production or protein oxidation. We also show that inhibition of autophagy reproduces the effects of bicarbonate in reperfusion injury, providing additional evidence in support of this mechanism. This phenomenon is especially important because bicarbonate is widely used in resuscitation protocols after cardiac arrest, and while effective as a buffer, may also contribute to myocardial injury.

The possible protective effects of dipyridamole on ischemic reperfusion injury of priapism

PubMed Central

Karaguzel, Ersagun; Bayraktar, Cemil; Kutlu, Omer; Yulug, Esin; Mentese, Ahmet; Okatan, Ali Ertan; Colak, Fatih; Ozer, Serap; O.Kazaz, Ilke

2016-01-01

ABSTRACT Purpose To investigate the protective effects against ischemia reperfusion injury of dipyridamole in a model of induced priapism in rats. Materials and Methods Twenty-four male Sprague-Dawley rats were divided into four groups, control, P/R, P/R+DMSO and P/R+D. 3ml blood specimens were collected from vena cava inferior in order to determine serum MDA, IMA, TAS, TOS and OSI values, and penile tissue was taken for histopathological examination in control group. Priapism was induced in P/R group. After 1h, priapism was concluded and 30 min reperfusion was performed. In P/R+DMSO group 1ml/kg DMSO was administered intraperitoneally 30 min before reperfusion, while in P/R+D group 10mg/kg dipyridamole was administered intraperitoneally 30 min before reperfusion. Blood and penis specimens were collected after the end of 30 min reperfusion period. Sinusoidal area (µm2), tears in tunica albuginea and injury parameters in sinusoidal endothelium of penis were investigated. Results Histopathological examination revealed no significant changes in term of sinusoidal area. A decrease in tears was observed in P/R+D group compared to P/R group (p<0.05). Endothelial injury decreased in P/R+D group compared to P/R group (p>0.05). There were no significant differences in MDA and IMA values between groups. A significant increase in TOS and OSI values was observed in P/R+D group compared to P/R group. A significant decrease in TAS levels was observed in P/R+D group compared to the P/R group. Conclusions The administration of dipyridamole before reperfusion in ischemic priapism model has a potential protective effect against histopathological injury of the penis. PMID:27136481

Reperfusion injury and reactive oxygen species: The evolution of a concept☆

PubMed Central

Granger, D. Neil; Kvietys, Peter R.

2015-01-01

Reperfusion injury, the paradoxical tissue response that is manifested by blood flow-deprived and oxygen-starved organs following the restoration of blood flow and tissue oxygenation, has been a focus of basic and clinical research for over 4-decades. While a variety of molecular mechanisms have been proposed to explain this phenomenon, excess production of reactive oxygen species (ROS) continues to receive much attention as a critical factor in the genesis of reperfusion injury. As a consequence, considerable effort has been devoted to identifying the dominant cellular and enzymatic sources of excess ROS production following ischemia-reperfusion (I/R). Of the potential ROS sources described to date, xanthine oxidase, NADPH oxidase (Nox), mitochondria, and uncoupled nitric oxide synthase have gained a status as the most likely contributors to reperfusion-induced oxidative stress and represent priority targets for therapeutic intervention against reperfusion-induced organ dysfunction and tissue damage. Although all four enzymatic sources are present in most tissues and are likely to play some role in reperfusion injury, priority and emphasis has been given to specific ROS sources that are enriched in certain tissues, such as xanthine oxidase in the gastrointestinal tract and mitochondria in the metabolically active heart and brain. The possibility that multiple ROS sources contribute to reperfusion injury in most tissues is supported by evidence demonstrating that redox-signaling enables ROS produced by one enzymatic source (e.g., Nox) to activate and enhance ROS production by a second source (e.g., mitochondria). This review provides a synopsis of the evidence implicating ROS in reperfusion injury, the clinical implications of this phenomenon, and summarizes current understanding of the four most frequently invoked enzymatic sources of ROS production in post-ischemic tissue. PMID:26484802

Protective Effects of Ultramicronized Palmitoylethanolamide (PEA-um) in Myocardial Ischaemia and Reperfusion Injury in VIVO.

PubMed

Di Paola, Rosanna; Cordaro, Marika; Crupi, Rosalia; Siracusa, Rosalba; Campolo, Michela; Bruschetta, Giuseppe; Fusco, Roberta; Pugliatti, Pietro; Esposito, Emanuela; Cuzzocrea, Salvatore

2016-08-01

Myocardial infarction is the leading cause of death, occurs after prolonged ischemia of the coronary arteries. Restore blood flow is the first intervention help against heart attack. However, reperfusion of the arteries leads to ischemia/reperfusion injury (I/R). The fatty acid amide palmitoylethanolamide (PEA) is an endogenous compound widely present in living organisms, with analgesic and anti-inflammatory properties. The present study evaluated the effect of ultramicronized palmitoylethanolamide (PEA-um) treatment on the inflammatory process associated with myocardial I/R. Myocardial ischemia reperfusion injury was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 2 h of reperfusion. PEA-um, was administered (10 mg/kg) 15 min after ischemia and 1 h after reperfusion. In this study, we demonstrated that PEA-um treatment reduces myocardial tissue injury, neutrophil infiltration, adhesion molecules (ICAM-1, P-selectin) expression, proinflammatory cytokines (TNF-α, IL-1β) production, nitrotyrosine and PAR formation, nuclear factor kB expression, and apoptosis (Fas-L, Bcl-2) activation. In addition to study whether the protective effect of PEA-um on myocardial ischemia reperfusion injury is also related to the activation of PPAR-α, in a separate set of experiments it has been performed myocardial I/R in PPARα mice. Genetic ablation of peroxisome proliferator activated receptor (PPAR)-α in PPAR-αKO mice exacerbated Myocardial ischemia reperfusion injury when compared with PPAR-αWT mice. PEA-um induced cardioprotection in PPAR-α wild-type mice, but the same effect cannot be observed in PPAR-αKO mice. Our results have clearly shown a modulation of the inflammatory process, associated with myocardial ischemia reperfusion injury, following administration of PEA-um.

Characterization of Microparticles after Hepatic Ischemia-Reperfusion Injury

PubMed Central

Freeman, Christopher M.; Quillin, Ralph C.; Wilson, Gregory C.; Nojima, Hiroyuki; Johnson, Bobby L.; Sutton, Jeffrey M.; Schuster, Rebecca M.; Blanchard, John; Edwards, Michael J.; Caldwell, Charles C.; Lentsch, Alex B.

2014-01-01

Background Hepatic ischemia-reperfusion (I/R) is a well-studied model of liver injury and has demonstrated a biphasic injury followed by recovery and regeneration. Microparticles (MPs) are a developing field of study and these small membrane bound vesicles have been shown to have effector function in other physiologic and pathologic states. This study was designed to quantify the levels of MPs from various cell origins–platelets, neutrophils, and endolethial cells–following hepatic ischemia-reperfusion injury. Methods A murine model was used with mice undergoing 90 minutes of partial hepatic ischemia followed by various times of reperfusion. Following reperfusion, plasma samples were taken and MPs of various cell origins were labeled and levels were measured using flow cytometry. Additionally, cell specific MPs were further assessed by Annexin V, which stains for the presence of phosphatidylserine, a cell surface marker linked to apoptosis. Statistical analysis was performed using one-way analysis of variance with subsequent Student-Newman-Keuls test with data presented as the mean and standard error of the mean. Results MPs from varying sources show an increase in circulating levels following hepatic I/R injury. However, the timing of the appearance of different MP subtypes differs for each cell type. Platelet and neutrophil-derived MP levels demonstrated an acute elevation following injury whereas endothelial-derived MP levels demonstrated a delayed elevation. Conclusion This is the first study to characterize circulating levels of cell-specific MPs after hepatic I/R injury and suggests that MPs derived from platelets and neutrophils serve as markers of inflammatory injury and may be active participants in this process. In contrast, MPs derived from endothelial cells increase after the injury response during the reparative phase and may be important in angiogenesis that occurs in the regenerating liver. PMID:24879335

Blockade of Hsp20 Phosphorylation Exacerbates Cardiac Ischemia/Reperfusion Injury by Suppressed Autophagy and Increased Cell Death

PubMed Central

Qian, Jiang; Ren, Xiaoping; Wang, Xiaohong; Zhang, Pengyuan; Jones, W. Keith; Molkentin, Jeffery D.; Fan, Guo-Chang; Kranias, Evangelia G.

2009-01-01

Rationale The levels of a small heat shock protein 20 (Hsp20) and its phosphorylation are increased upon ischemic insults, and overexpression of Hsp20 protects the heart against ischemia/reperfusion injury. However, the mechanism underlying cardioprotection of Hsp20 and especially the role of its phosphorylation in regulating ischemia/reperfusion-induced autophagy, apoptosis and necrosis remain to be clarified. Objective Herein we generated a cardiac-specific overexpression model, carrying non-phosphorylatable Hsp20, where serine 16 was substituted with alanine (Hsp20S16A). By subjecting this model to ischemia/reperfusion, we addressed whether: 1) the cardioprotective effects of Hsp20 are associated with serine 16 phosphorylation; 2) blockade of Hsp20 phosphorylation influences the balance between autophagy and cell death; and 3) the aggregation pattern of Hsp20 is altered by its phosphorylation. Methods and Results Our results demonstrated that Hsp20S16A hearts were more sensitive to ischemia/reperfusion injury, evidenced by lower recovery of contractile function and increased necrosis and apoptosis, compared with non-transgenic (TG) hearts. Interestingly, autophagy was activated in non-TG hearts, but significantly inhibited in Hsp20S16A hearts following ischemia/reperfusion. Accordingly, pre-treatment of Hsp20S16A hearts with rapamycin, an activator of autophagy, resulted in improvement of functional recovery, compared with saline-treated Hsp20S16A hearts. Furthermore, upon ischemia/reperfusion, the oligomerization pattern of Hsp20 appeared to shift to higher aggregates in Hsp20S16A hearts. Conclusion Collectively, these data indicate that blockade of Ser16-Hsp20 phosphorylation attenuates the cardioprotective effects of Hsp20 against ischemia/reperfusion injury, which may be due to suppressed autophagy and increased cell death. Therefore, phosphorylation of Hsp20 at serine 16 may represent a potential therapeutic target in ischemic heart disease. PMID:19850943

Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury

PubMed Central

Wang, Yanzhe; He, Zhiyi; Deng, Shumin

2016-01-01

Background Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance. Methods The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed. Results UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect. Conclusion UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the

Neuroprotection of ebselen against ischemia/reperfusion injury involves GABA shunt enzymes.

PubMed

Seo, Jeong Yeol; Lee, Choong Hyun; Cho, Jun Hwi; Choi, Jung Hoon; Yoo, Ki-Yeon; Kim, Dae Won; Park, Ok Kyu; Li, Hua; Choi, Soo Young; Hwang, In Koo; Won, Moo-Ho

2009-10-15

Seleno-organic compound, ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), is a substrate with radical-scavenging activity. In this study, we observed the neuroprotective effects of ebselen against ischemic damage and on GABA shunt enzymes such as glutamic acid decarboxylase 67 (GAD67), GABA transaminse (GABA-T) and succinic semialdehyde dehydrogenase (SSADH) in the hippocampal CA1 region after 5 min of transient forebrain ischemia in gerbils. For this, vehicle (physiological saline) or ebselen was administered 30 min before or after ischemia/reperfusion and sacrificed 4 days after ischemia/reperfusion. The administration of ebselen significantly reduced the neuronal death in the CA1 region induced by ischemia/reperfusion. In addition, treatment with ebselen markedly elevated GAD67, GABA-T and SSADH immunoreactivity and their protein levels compared to that in the vehicle-treated group, respectively. These results suggest that ebselen protects neurons from ischemic damage via control of the expressions of GABA shunt enzymes to enter the TCA cycle.

Cardioprotective properties of Crataegus oxycantha extract against ischemia-reperfusion injury

PubMed Central

Swaminathan, Jayachandran Kesavan; Khan, Mahmood; Mohan, Iyappu K; Selvendiran, Karuppaiyah; Devaraj, S. Niranjali; Rivera, Brian K.; Kuppusamy, Periannan

2010-01-01

The aim of the study was to investigate the cardioprotective effect and mechanism of Crataegus oxycantha (COC) extract, a well-known natural antioxidant-based cardiotonic, against ischemia/reperfusion (I/R) injury. Electron paramagnetic resonance studies showed that COC extract was capable of scavenging superoxide, hydroxyl, and peroxyl radicals, in vitro. The cardioprotective efficacy of the extract was studied in a crystalloid perfused heart model of I/R injury. Hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. During reperfusion, COC extract was infused at a dose rate of 1 mg/ml/min for 10 min. Hearts treated with COC extract showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase and lactate dehydrogenase activities. The expressions of xanthine oxidase and NADPH oxidase were significantly reduced in the treated group. A significant upregulation of the anti-apoptotic proteins Bcl-2 and Hsp70 with simultaneous downregulation of the pro-apoptotic proteins cytochrome c and cleaved caspase-3 was observed. The molecular signaling cascade including phospho-Akt (ser-473) and HIF-1α that lead to the activation or suppression of apoptotic pathway also showed a significant protective role in the treatment group. No significant change in phospho-p38 levels was observed. The results suggested that the COC extract may reduce the oxidative stress in the reperfused myocardium, and play a significant role in the inhibition of apoptotic pathways leading to cardioprotection. PMID:20171068

Pre-Conditioning with CDP-Choline Attenuates Oxidative Stress-Induced Cardiac Myocyte Death in a Hypoxia/Reperfusion Model

PubMed Central

González-Pacheco, Héctor; Méndez-Domínguez, Aurelio; Hernández, Salomón; López-Marure, Rebeca; Vazquez-Mellado, Maria J.; Aguilar, Cecilia; Rocha-Zavaleta, Leticia

2014-01-01

Background. CDP-choline is a key intermediate in the biosynthesis of phosphatidylcholine, which is an essential component of cellular membranes, and a cell signalling mediator. CDP-choline has been used for the treatment of cerebral ischaemia, showing beneficial effects. However, its potential benefit for the treatment of myocardial ischaemia has not been explored yet. Aim. In the present work, we aimed to evaluate the potential use of CDP-choline as a cardioprotector in an in vitro model of ischaemia/reperfusion injury. Methods. Neonatal rat cardiac myocytes were isolated and subjected to hypoxia/reperfusion using the coverslip hypoxia model. To evaluate the effect of CDP-choline on oxidative stress-induced reperfusion injury, the cells were incubated with H2O2 during reperfusion. The effect of CDP-choline pre- and postconditioning was evaluated using the cell viability MTT assay, and the proportion of apoptotic and necrotic cells was analyzed using the Annexin V determination by flow cytometry. Results. Pre- and postconditioning with 50 mg/mL of CDP-choline induced a significant reduction of cells undergoing apoptosis after hypoxia/reperfusion. Preconditioning with CDP-choline attenuated postreperfusion cell death induced by oxidative stress. Conclusion. CDP-choline administration reduces cell apoptosis induced by oxidative stress after hypoxia/reperfusion of cardiac myocytes. Thus, it has a potential as cardioprotector in ischaemia/reperfusion-injured cardiomyocytes. PMID:24578622

Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps.

PubMed

Jansen, Marcel P B; Emal, Diba; Teske, Gwendoline J D; Dessing, Mark C; Florquin, Sandrine; Roelofs, Joris J T H

2017-02-01

Acute kidney injury is often the result of ischemia reperfusion injury, which leads to activation of coagulation and inflammation, resulting in necrosis of renal tubular epithelial cells. Platelets play a central role in coagulation and inflammatory processes, and it has been shown that platelet activation exacerbates acute kidney injury. However, the mechanism of platelet activation during ischemia reperfusion injury and how platelet activation leads to tissue injury are largely unknown. Here we found that renal ischemia reperfusion injury in mice leads to increased platelet activation in immediate proximity of necrotic cell casts. Furthermore, platelet inhibition by clopidogrel decreased cell necrosis and inflammation, indicating a link between platelet activation and renal tissue damage. Necrotic tubular epithelial cells were found to release extracellular DNA, which, in turn, activated platelets, leading to platelet-granulocyte interaction and formation of neutrophil extracellular traps ex vivo. Renal ischemia reperfusion injury resulted in increased DNA-platelet and DNA-platelet-granulocyte colocalization in tissue and elevated levels of circulating extracellular DNA and platelet factor 4 in mice. After renal ischemia reperfusion injury, neutrophil extracellular traps were formed within renal tissue, which decreased when mice were treated with the platelet inhibitor clopidogrel. Thus, during renal ischemia reperfusion injury, necrotic cell-derived DNA leads to platelet activation, platelet-granulocyte interaction, and subsequent neutrophil extracellular trap formation, leading to renal inflammation and further increase in tissue injury. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Protective effect of preconditioning and adenosine pretreatment in experimental skeletal muscle reperfusion injury.

PubMed

Papanastasiou, S; Estdale, S E; Homer-Vanniasinkam, S; Mathie, R T

1999-07-01

Prolonged ischaemia followed by reperfusion (I/R) of skeletal muscle results in significant tissue injury. Ischaemic preconditioning (IPC), achieved by repeated brief periods of I/R before prolonged ischaemia or adenosine pretreatment, can prevent I/R injury in cardiac muscle. The aim of this study was to ascertain in a rodent model if damage to skeletal muscle due to global hindlimb tourniquet-induced I/R could be similarly attenuated. Anaesthetized rats were randomized (n = 6-10 per group) to five groups: sham-operated controls; I/R (4 h of ischaemia, 2 h of reperfusion); IPC (three cycles of 10 min of ischaemia/10 min of reperfusion) alone; IPC immediately preceding I/R; or adenosine 1000 microg/kg immediately before I/R. At the end of reperfusion, biopsies were taken from the left gastrocnemius muscle for measurement of myeloperoxidase (MPO) and reduced glutathione (GSH). Before ischaemia and at the end of reperfusion, blood samples were taken for measurement of nitric oxide metabolites, tumour necrosis factor (TNF) alpha and macrophage inflammatory protein (MIP) 2. IPC before I/R resulted in lower levels of MPO (P < 0.001) and TNF-alpha (P = 0.004), and higher levels of GSH (P < 0.001) and nitric oxide metabolites (P = 0.002) than I/R alone. Adenosine had effects comparable to IPC pretreatment (P < 0.001 for MPO, P = 0.002 for GSH, P = 0.02 for nitric oxide metabolites and P = 0.001 for TNF-alpha). There was no difference in the blood pressure or the MIP-2 concentration among the groups. IPC or pretreatment with adenosine ameliorates the I/R injury of skeletal muscle.

Loss of ErbB2-PI3K/Akt signaling prevents zinc pyrithione-induced cardioprotection during ischemia/reperfusion.

PubMed

Thokala, Sandhya; Inapurapu, Santhipriya; Bodiga, Vijaya Lakshmi; Vemuri, Praveen Kumar; Bodiga, Sreedhar

2017-04-01

The purpose of this study was to determine if zinc homeostasis is affected during ischemia/reperfusion, if so, whether zinc pyrithione limits myocardial cell death and improves hemodynamics when administered as an adjunct to reperfusion and if ErbB receptor tyrosine kinases that are important for the long-term structural integrity of the heart are indispensable for reperfusion salvage. Isolated perfused rat hearts were subjected to 35min of global ischemia and reperfused for 120min to determine the relative intracellular zinc levels by TSQ staining. The hearts were reperfused in the presence of incremental concentrations of zinc pyrithione for the first 10min during reperfusion. Silencing or blockade of ErbB2 using a monoclonal antibody, ErbB2 kinase inhibition and PI3kinase inhibition was used to study their critical role in zinc pyrithione-induced cardioprotection. We found that there was a profound decrease in intracellular zinc after ischemia/reperfusion resulting in increased apoptosis, caspase-3 activation, and infarct size. A dose-dependent reduction of infarct size with zinc pyrithione in the range of 5-20μmol/l (optimal protection was seen at 10μmol/l with infarct size of 16±2% vs. I/R vehicle, 33±2%, p<0.01). Increased TUNEL staining and caspase-3 activity observed after ischemia/reperfusion were attenuated by zinc pyrithione administration during the reperfusion. Moreover, this protection was sensitive to silencing and blockade of ErbB2, inhibition of ErbB2 kinase activity or PI3-kinase activity. Western blot analysis revealed that zinc pyrithione resulted in decreased caspase-3 activation, rapid stabilization of ErbB2/ErbB1 heterodimers, and increased activation of PI3K/Akt signaling cascade. Zinc pyrithione attenuates lethal perfusion-induced injury in a manner that is reliant on ErbB2/PI3K/Akt activity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Incremental balloon deflation following complete resuscitative endovascular balloon occlusion of the aorta results in steep inflection of flow and rapid reperfusion in a large animal model of hemorrhagic shock.

PubMed

Davidson, Anders J; Russo, Rachel M; Ferencz, Sarah-Ashley E; Cannon, Jeremy W; Rasmussen, Todd E; Neff, Lucas P; Johnson, M Austin; Williams, Timothy K

2017-07-01

To avoid potential cardiovascular collapse after resuscitative endovascular balloon occlusion of the aorta (REBOA), current guidelines recommend methodically deflating the balloon for 5 minutes to gradually reperfuse distal tissue beds. However, anecdotal evidence suggests that this approach may still result in unpredictable aortic flow rates and hemodynamic instability. We sought to characterize aortic flow dynamics following REBOA as the balloon is deflated in accordance with current practice guidelines. Eight Yorkshire-cross swine were splenectomized, instrumented, and subjected to rapid 25% total blood volume hemorrhage. After 30 minutes of shock, animals received 60 minutes of Zone 1 REBOA with a low-profile REBOA catheter. During subsequent resuscitation with shed blood, the aortic occlusion balloon was gradually deflated in stepwise fashion at the rate of 0.5 mL every 30 seconds until completely deflated. Aortic flow rate and proximal mean arterial pressure (MAP) were measured continuously over the period of balloon deflation. Graded balloon deflation resulted in variable initial return of aortic flow (median, 78 seconds; interquartile range [IQR], 68-105 seconds). A rapid increase in aortic flow during a single-balloon deflation step was observed in all animals (median, 819 mL/min; IQR, 664-1241 mL/min) and corresponded with an immediate decrease in proximal MAP (median, 30 mm Hg; IQR, 14.5-37 mm Hg). Total balloon volume and time to return of flow demonstrated no correlation (r = 0.016). This study is the first to characterize aortic flow during balloon deflation following REBOA. A steep inflection point occurs during balloon deflation that results in an abrupt increase in aortic flow and a concomitant decrease in MAP. Furthermore, the onset of distal aortic flow was inconsistent across study animals and did not correlate with initial balloon volume or relative deflation volume. Future studies to define the factors that affect aortic flow during balloon

Protective effects of hydrogen enriched saline on liver ischemia reperfusion injury by reducing oxidative stress and HMGB1 release

PubMed Central

2014-01-01

Background The nuclear protein high-mobility group box 1 (HMGB1) is a key trigger for the inflammatory reaction during liver ischemia reperfusion injury (IRI). Hydrogen treatment was recently associated with down-regulation of the expression of HMGB1 and pro-inflammatory cytokines during sepsis and myocardial IRI, but it is not known whether hydrogen has an effect on HMGB1 in liver IRI. Methods A rat model of 60 minutes 70% partial liver ischemia reperfusion injury was used. Hydrogen enriched saline (2.5, 5 or 10 ml/kg) was injected intraperitoneally 10 minutes before hepatic reperfusion. Liver injury was assessed by serum alanine aminotransferase (ALT) enzyme levels and histological changes. We also measured malondialdehyde (MDA), hydroxynonenal (HNE) and 8-hydroxy-guanosine (8-OH-G) levels as markers of the peroxidation injury induced by reactive oxygen species (ROS). In addition, pro-inflammatory cytokines including TNF-α and IL-6, and high mobility group box B1 protein (HMGB1) were measured as markers of post ischemia-reperfusion inflammation. Results Hydrogen enriched saline treatment significantly attenuated the severity of liver injury induced by ischemia-reperfusion. The treatment group showed reduced serum ALT activity and markers of lipid peroxidation and post ischemia reperfusion histological changes were reduced. Hydrogen enriched saline treatment inhibited HMGB1 expression and release, reflecting a reduced local and systemic inflammatory response to hepatic ischemia reperfusion. Conclusion These results suggest that, in our model, hydrogen enriched saline treatment is protective against liver ischemia-reperfusion injury. This effect may be mediated by both the anti-oxidative and anti-inflammatory effects of the solution. PMID:24410860

Transduction of anti-cell death protein FNK protects isolated rat hearts from myocardial infarction induced by ischemia/reperfusion.

PubMed

Arakawa, Masayuki; Yasutake, Masahiro; Miyamoto, Masaaki; Takano, Teruo; Asoh, Sadamitsu; Ohta, Shigeo

2007-05-08

Artificial anti-cell death protein FNK, a Bcl-x(L) derivative with three amino acid-substitutions (Y22F, Q26N, and R165K) has enhanced anti-apoptotic and anti-necrotic activity and facilitates cell survival in many species and cell types. The objectives of this study were (i) to investigate whether the protein conjugated with a protein transduction domain (PTD-FNK) reduces myocardial infarct size and improves post-ischemic cardiac function in ischemic/reperfused rat hearts, and (ii) to understand the mechanism(s) by which PTD-FNK exerts a protective effect. Isolated rat hearts were subjected to 35-min global ischemia, followed by 120-min reperfusion using the Langendorff methods. PTD-FNK (a total of 30 microl) was injected intramuscularly into the anterior wall of the left ventricle either at 1 min after induction of global ischemia (group A) or at 30 min after induction of global ischemia (at 5 min before reperfusion) (group B). In group A, infarct size was significantly reduced from 47.8+/-6.8% in the control to 30.4+/-5.2, 28.7+/-3.8, and 30.4+/-6.8% with PTD-FNK at 5, 50, and 500 nmol/l, respectively (p<0.05). Temporal recovery of left ventricular developed pressure at 60 min and 120 min after reperfusion was significantly better in PTD-FNK (50 and 500 nmol/l)-treated groups than in the control (p<0.05). In contrast, PTD-FNK treatment had no effect on group B. Western blot analysis showed that PTD-FNK markedly inhibited procaspase-3 cleavage (activation of caspase-3) and reduced the number of nuclei stained by a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphoshate nick-end labeling (TUNEL) assay. These findings suggest that PTD-FNK reduces the volume of myocardial infarction with corresponding functional recovery, at least in part, through the suppression of myocardial apoptosis following ischemia/reperfusion.

Protective effect of agmatine on ischemia/reperfusion-induced renal injury in rats.

PubMed

Sugiura, Takahiro; Tsutsui, Hidenobu; Takaoka, Masanori; Kobuchi, Shuhei; Hayashi, Kentaro; Fujii, Toshihide; Matsumura, Yasuo

2008-03-01

Enhanced renal sympathetic nerve activity (RSNA) during ischemic period and the renal venous norepinephrine (NE) overflow after reperfusion play important roles in the development of ischemic/reperfusion (I/R)-induced acute renal failure (ARF) in rats. This study evaluated whether agmatine, which is known to reduce sympathetic nerve activity and NE overflow by electrical stimulation, would prevent the I/R-induced renal dysfunction. Ischemic ARF was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion 2 weeks after the contralateral nephrectomy. Intravenous (IV) injection of agmatine (100 and 300 micromol/kg) to ischemic ARF rats dose-dependently suppressed the enhanced RSNA and attenuated the I/R-induced renal dysfunction and histological damage. Intracerebroventricular (ICV) injection of agmatine (600 nmol/kg) to ischemic ARF rats suppressed the enhanced RSNA during the ischemic period and attenuated the I/R-induced renal injury. Furthermore, both IV and ICV injection of agmatine significantly suppressed the renal venous NE overflow after the reperfusion. These results indicate that agmatine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppression of the enhanced RSNA during ischemic period and NE overflow from renal sympathetic nerve endings.

Hemorheological changes in ischemia-reperfusion: an overview on our experimental surgical data.

PubMed

Nemeth, Norbert; Furka, Istvan; Miko, Iren

2014-01-01

Blood vessel occlusions of various origin, depending on the duration and extension, result in tissue damage, causing ischemic or ischemia-reperfusion injuries. Necessary surgical clamping of vessels in vascular-, gastrointestinal or parenchymal organ surgery, flap preparation-transplantation in reconstructive surgery, as well as traumatological vascular occlusions, all present special aspects. Ischemia and reperfusion have effects on hemorheological state by numerous ways: besides the local metabolic and micro-environmental changes, by hemodynamic alterations, free-radical and inflammatory pathways, acute phase reactions and coagulation changes. These processes may be harmful for red blood cells, impairing their deformability and influencing their aggregation behavior. However, there are still many unsolved or non-completely answered questions on relation of hemorheology and ischemia-reperfusion. How do various organ (liver, kidney, small intestine) or limb ischemic-reperfusionic processes of different duration and temperature affect the hemorheological factors? What is the expected magnitude and dynamics of these alterations? Where is the border of irreversibility? How can hemorheological investigations be applied to experimental models using laboratory animals in respect of inter-species differences? This paper gives a summary on some of our research data on organ/tissue ischemia-reperfusion, hemorheology and microcirculation, related to surgical research and experimental microsurgery.

Relaxin protects against myocardial injury caused by ischemia and reperfusion in rat heart.

PubMed Central

Bani, D.; Masini, E.; Bello, M. G.; Bigazzi, M.; Sacchi, T. B.

1998-01-01

Myocardial injury caused by ischemia and reperfusion comes from multiple pathogenic events, including endothelial damage, neutrophil extravasation into tissue, platelet and mast cell activation, and peroxidation of cell membrane lipids, which are followed by myocardial cell alterations resulting eventually in cell necrosis. The current study was designed to test the possible cardioprotective effect of the hormone relaxin, which has been found to cause coronary vessel dilation and to inhibit platelet and mast cell activation. Ischemia (for 30 minutes) was induced in rat hearts in vivo by ligature of the left anterior descending coronary artery; reperfusion (for 60 minutes or less if the rats died before this predetermined time) was induced by removal of the ligature. Relaxin (100 ng) was given intravenously 30 minutes before ischemia. The results obtained showed that relaxin strongly reduces 1) the extension of the myocardial areas affected by ischemia-reperfusion-induced damage, 2) ventricular arrhythmias, 3) mortality, 4) myocardial neutrophil number, 5) myeloperoxidase activity, a marker of neutrophil accumulation, 6) production of malonyldialdehyde, an end product of lipid peroxidation, 7) mast cell granule release, 8) calcium overload, and 9) morphological signs of myocardial cell injury. This study shows that relaxin can be regarded as an agent with a marked cardioprotective action against ischemia-reperfusion-induced myocardial injury. Images Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 PMID:9588905

Effects of defibrotide, a novel oligodeoxyribonucleotide, on ischaemia and reperfusion injury of the rat liver.

PubMed

Kim, Kwang Joon; Shin, Yong Kyoo; Song, Jin Ho; Oh, Byung Kwon; Choi, Myung Sup; Sohn, Uy Dong

2002-02-01

1. The purpose of this study was to investigate the protective effects of defibrotide, a single-stranded polydeoxyribonucleotide, on ischaemia-reperfusion injury to the liver using a rat model. 2. Ischaemia of the left and median lobes was created by total inflow occlusion for 30 min followed by 60 min of reperfusion. Hepatic injury was assessed by the release of liver enzymes (alanine transferase, ALT and lactic dehydrogenase, LDH). Hepatic oxidant stress was measured by superoxide production, lipid peroxidation and nitrite/nitrate formation. Leukocyte-endothelium interaction and Kupffer cell mobilization were quantified by measuring hepatic myeloperoxidase (MPO), polymorphonuclear leukocyte adherence to superior mesenteric artery (SMA) and immunostaining of Kupffer cell. 3. Defibrotide treatment resulted in a significant inhibition of postreperfusion superoxide generation, lipid peroxidation, serum ALT activity, serum LDH activity, MPO activity, serum nitrite/nitrate level, leukocyte adherence to SMA, and Kupffer cell mobilization, indicating a significant attenuation of hepatic dysfunction. 4. A significant correlation existed between liver ischaemia/reperfusion and hepatic injury, suggesting that liver ischaemia/reperfusion injury is mediated predominantly by generation of oxygen free radicals and mobilization of Kupffer cells. 5. We conclude that defibrotide significantly protects the liver against liver ischaemia/reperfusion injury by interfering with Kupffer cell mobilization and formation of oxygen free radicals. This study provides strong evidence that defibrotide has important beneficial effects on acute inflammatory tissue injury such as that occurring in the reperfusion of the ischaemic liver.

Renoprotective Effect of Humic Acid on Renal Ischemia-Reperfusion Injury: An Experimental Study in Rats.

PubMed

Akbas, Alpaslan; Silan, Coskun; Gulpinar, Murat Tolga; Sancak, Eyup Burak; Ozkanli, Sidika Seyma; Cakir, Dilek Ulker

2015-12-01

Humic acid is an antioxidant molecule used in agriculture and livestock breeding, as well as in medicine. Our aim was to investigate the potential renoprotective effects of humic acid in a renal ischemia reperfusion model. Twenty-one rats were randomly divided into three equal groups. Intraperitoneal serum or humic acid was injected at 1, 12, and 24 h. Non-ischemic group I was evaluated as sham. The left renal artery was clamped in serum (group II) and intraperitoneal humic acid (group III) to subject to left renal ischemic reperfusion procedure. Ischemia and reperfusion time was 60 min for each. Total antioxidant status, total oxidative status, oxidative stress index, and ischemia-modified albumin levels were analyzed biochemically from the serum samples. Kidneys were evaluated histopatologically and immunohistochemically. Biochemical results showed that total oxidative status, ischemia-modified albumin, and oxidative stress index levels were significantly decreased, but total antioxidant status was increased in the humic acid group (III) compared with the ischemia group (II) On histopathological examination, renal tubular dilatation, tubular cell damage and necrosis, dilatation of Bowman's capsule, hyaline casts, and tubular cell spillage were decreased in the humic acid group (III) compared with the ischemia group (II). Immunohistochemical results showed that apoptosis was deteriorated in group III. Renal ischemia reperfusion injury was attenuated by humic acid administration. These observations indicate that humic acid may have a potential therapeutic effect on renal ischemia reperfusion injury by preventing oxidative stress.

Effect of endovascular reperfusion in relation to site of arterial occlusion.

PubMed

Lemmens, Robin; Hamilton, Scott A; Liebeskind, David S; Tomsick, Tom A; Demchuk, Andrew M; Nogueira, Raul G; Marks, Michael P; Jahan, Reza; Gralla, Jan; Yoo, Albert J; Yeatts, Sharon D; Palesch, Yuko Y; Saver, Jeffrey L; Pereira, Vitor M; Broderick, Joseph P; Albers, Gregory W; Lansberg, Maarten G

2016-02-23

To assess whether the association between reperfusion and improved clinical outcomes after stroke differs depending on the site of the arterial occlusive lesion (AOL). We pooled data from Solitaire With the Intention for Thrombectomy (SWIFT), Solitaire FR Thrombectomy for Acute Revascularisation (STAR), Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2), and Interventional Management of Stroke Trial (IMS III) to compare the strength of the associations between reperfusion and clinical outcomes in patients with internal carotid artery (ICA), proximal middle cerebral artery (MCA) (M1), and distal MCA (M2/3/4) occlusions. Among 710 included patients, the site of the AOL was the ICA in 161, the proximal MCA in 389, and the distal MCA in 160 patients (M2 = 131, M3 = 23, and M4 = 6). Reperfusion was associated with an increase in the rate of good functional outcome (modified Rankin Scale [mRS] score 0-2) in patients with ICA (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.7-7.2) and proximal MCA occlusions (OR 6.2, 95% CI 3.8-10.2), but not in patients with distal MCA occlusions (OR 1.4, 95% CI 0.8-2.6). Among patients with M2 occlusions, a subset of the distal MCA cohort, reperfusion was associated with excellent functional outcome (mRS 0-1; OR 2.2, 95% CI 1.0-4.7). The association between endovascular reperfusion and better clinical outcomes is more profound in patients with ICA and proximal MCA occlusions compared to patients with distal MCA occlusions. Because there are limited data from randomized controlled trials on the effect of endovascular therapy in patients with distal MCA occlusions, these results underscore the need for inclusion of this subgroup in future endovascular therapy trials. © 2016 American Academy of Neurology.

Ischemia/reperfusion-induced injury of forebrain mitochondria and protection by ascorbate.

PubMed

Sciamanna, M A; Lee, C P

1993-09-01

Complete, reversible forebrain ischemia was induced with a seven-vessel occlusion rat model. Previous studies of ischemic (M. A. Sciamanna, J. Zinkel, A. Y. Fabi, and C. P. Lee, 1992, Biochim. Biophys. Acta 1134, 223-232) rat brain mitochondria (RBM) showed that ischemia of 30 min caused an approximately 60% decrease in State 3 respiratory rates with both succinate and NAD-linked substrates and also in energy-linked Ca2+ transport. No significant change was seen in the State 4 rates. The inhibition of respiration could be prevented by EGTA or ruthenium red. In this paper it is shown that reperfusion (5 h) following ischemia (30 min) further impaired RBM respiratory activities (succinate and NAD-linked substrates). The presence of EGTA or ruthenium red in the assay medium did not protect against ischemia/reperfusion-induced injury. The effects of ascorbate, an oxygen radical scavenger, were studied. RBM isolated from ascorbate-treated animals (0.8 mg ascorbate/kg body weight) after ischemia (30 min) alone showed only a slight increase in State 3 (approximately 25%) and a decrease in State 4 (approximately 20%) activities with succinate, when compared to untreated 30-min ischemic animals, whereas, with glutamate+malate little or no effect was seen. The respiratory activities of RBM from ascorbate-treated, ischemic/reperfused (30 min/5 h) rats were restored to approximately 65% of controls levels. Ascorbate protection was dose-dependent with maximum protection at 0.8 mg ascorbate/kg body weight of rat. The k of succinate oxidase-supported Ca2+ uptake also returned to 62% of control values. Protection by ascorbate was most effective when administered prior to the onset of ischemia and provided partial protection when administered after the onset of reperfusion. These results suggest that ischemia-induced injury is primarily mediated by disruption of cellular Ca2+ homeostasis, and reperfusion-induced injury by peroxidative events.

The effects of epidural bupivacaine on ischemia/reperfusion-induced liver injury.

PubMed

Sarikus, Z; Bedirli, N; Yilmaz, G; Bagriacik, U; Bozkirli, F

2016-01-01

Several animal studies showed beneficial effects of thoracic epidural anesthesia (TEA) in hippocampal, mesenteric and myocardial IR injury (2-4). In this study, we investigated the effects of epidural bupivacaine on hepatic ischemia reperfusion injury in a rat model. Eighteen rats were randomly divided into three groups each containing 6 animals. The rats in Group C had sham laparotomy. The rats in the Group S were subjected to liver IR through laparotomy and 20 mcg/kg/h 0.9% NaCl was administered to these rats via an epidural catheter. The rats in the Group B were subjected to liver IR and were given 20 mcg/kg/h bupivacaine via an epidural catheter. Liver tissue was harvested for MDA analysis, apoptosis and histopathological examination after 60 minutes of ischemia followed by 360 minutes of reperfusion. Blood samples were also collected for TNF-α, IL-1β, AST and ALT analysis. The AST and ALT levels were higher in ischemia and reperfusion group, which received only normal saline via the thoracic epidural catheter, compared to the sham group. In the ischemia reperfusion group, which received bupivacaine via the epidural catheter, IL-1 levels were significantly higher than in the other groups. TNF-α levels were higher in the Groups S and B compared to the sham group. Bupivacaine administration induced apoptosis in all animals. These results showed that thoracic epidural bupivacaine was not a suitable agent for preventing inflammatory response and lipid peroxidation in experimental hepatic IR injury in rats. Moreover, epidural bupivacaine triggered apoptosis in hepatocytes. Further research is needed as there are no studies in literature investigate the effects of epidural bupivacaine on hepatic ischemia reperfusion injury (Tab. 3, Fig. 3, Ref. 34).

Dietary broccoli sprouts protect against myocardial oxidative damage and cell death during ischemia-reperfusion.

PubMed

Akhlaghi, Masoumeh; Bandy, Brian

2010-09-01

Cruciferous vegetables are known for antioxidant and anti-carcinogenic effects. In the current study we asked whether dietary broccoli sprouts can protect the heart from ischemia-reperfusion. Rats were fed either control diet (sham and control groups) or a diet mixed with 2% dried broccoli sprouts for 10 days. After 10 days the isolated hearts were subjected to ischemia for 20 min and reperfusion for 2 h, and evaluated for cell death, oxidative damage, and Nrf2-regulated phase 2 enzyme activities. Broccoli sprouts feeding inhibited markers of necrosis (lactate dehydrogenase release) and apoptosis (caspase-3 activity) by 78-86%, and decreased indices of oxidative stress (thiobarbituric acid reactive substances and aconitase inactivation) by 82-116%. While broccoli sprouts increased total glutathione and activities of the phase 2 enzymes glutamate cysteine ligase and quinone reductase in liver, they did not affect these in ischemic-reperfused heart. While the mechanism is not clear, the results show that a relatively short dietary treatment with broccoli sprouts can strongly protect the heart against oxidative stress and cell death caused by ischemia-reperfusion.

Effect of trapidil in myocardial ischemia-reperfusion injury in rabbit.

PubMed

Liu, Mingjie; Sun, Qi; Wang, Qiang; Wang, Xiuying; Lin, Peng; Yang, Ming; Yan, Yuanyuan

2014-01-01

To evaluate the cardioprotective effects of trapidil on myocardial ischemia-reperfusion injury (MIRI) in rabbits. Rabbits were subjected to 40 min of myocardial ischemia followed by 120 min of reperfusion. Blood for superoxide dismutase (SOD) and malondialdehyde (MDA) were estimated. At the end of reperfusion, the rabbits were sacrificed and the hearts were isolated for histological examination. An apoptotic index (AI) was determined using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling (TUNEL) method. The expression of apoptosis-related proteins Bax and Bcl-2 was analyzed using immunohistochemistry. Statistical analyses were performed by one-way analysis of variance (ANOVA), P < 0.05 considered statistically significant. Trapidil caused a significant (P < 0.05) increase in SOD activity, as decreased MDA levels and significantly (P < 0.05) reduced the expression of Bax as compared with the ischemia-reperfusion (IR) control group. Trapidil may attenuate the myocardial damage produced by IR injury and offer potential cardioprotective action.

Temporal relationship of serum markers and tissue damage during acute intestinal ischemia/reperfusion

PubMed Central

la Garza, Francisco Javier Guzmán-de; Ibarra-Hernández, Juan Manuel; Cordero-Pérez, Paula; Villegas-Quintero, Pablo; Villarreal-Ovalle, Claudia Ivette; Torres-González, Liliana; Oliva-Sosa, Norma Edith; Alarcón-Galván, Gabriela; Fernández-Garza, Nancy Esthela; Muñoz-Espinosa, Linda Elsa; Cámara-Lemarroy, Carlos Rodrigo; Carrillo-Arriaga, José Gerardo

2013-01-01

OBJECTIVE: It is essential to identify a serological marker of injury in order to study the pathophysiology of intestinal ischemia reperfusion. In this work, we studied the evolution of several serological markers after intestinal ischemia reperfusion injury in rats. The markers of non-specific cell damage were aspartate aminotransferase, alanine aminotransaminase, and lactic dehydrogenase, the markers of inflammation were tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta, and the markers of intestinal mucosal damage were intestinal fatty acid binding protein and D-lactate. We used Chiús classification to grade the histopathological damage. METHODS: We studied 35 Wistar rats divided into groups according to reperfusion time. The superior mesenteric artery was clamped for 30 minutes, and blood and biopsies were collected at 1, 3, 6, 12, 24, and 48 hours after reperfusion. We plotted the mean ± standard deviation and compared the baseline and maximum values for each marker using Student's t-test. RESULTS: The maximum values of interleukin-1 beta and lactic dehydrogenase were present before the maximal histopathological damage. The maximum tumor necrosis factor alpha and D-lactate expressions coincided with histopathological damage. Alanine aminotransaminase and aspartate aminotransferase had a maximum expression level that increased following the histopathological damage. The maximum expressions of interluken-6 and intestinal fatty acid binding protein were not significantly different from the Sham treated group. CONCLUSION: For the evaluation of injury secondary to acute intestinal ischemia reperfusion with a 30 minute ischemia period, we recommend performing histopathological grading, quantification of D-lactate, which is synthesized by intestinal bacteria and is considered an indicator of mucosal injury, and quantification of tumor necrosis factor alpha as indicators of acute inflammation three hours after reperfusion. PMID:23917671

Aripiprazole prevents renal ischemia/reperfusion injury in rats, probably through nitric oxide involvement.

PubMed

Gholampour, Hanieh; Moezi, Leila; Shafaroodi, Hamed

2017-10-15

Renal ischemia/reperfusion (I/R) injury is strongly related to morbidity and mortality. Oxidative stress, inflammation, and apoptosis play key roles in renal dysfunction following renal I/R. Aripiprazole is an atypical antipsychotic which used for the treatment of schizophrenia and bipolar disorder. Recent studies have reported aripiprazole as displaying certain anti-inflammatory effects. Regarding the underlying mechanisms of renal ischemia-reperfusion, therefore, nephroprotective effects might be predicted to be seen with aripiprazole. I/R injury was induced by bilateral clamping of the renal pedicles (45min) followed by reperfusion (24h). The mechanism of aripiprazole-mediated nephroprotection was explored by a combined use of aripiprazole and L-NAME (non-selective nitric oxide synthase inhibitor). Animals were given aripiprazole (2.5, 5, 10 and 20mg/kg) intraperitoneally, 30min before ischemia. L-NAME was administered before the aripiprazole injection. Serum creatinine and blood urea nitrogen were assessed after 24h of reperfusion. Serum levels of malondialdehyde (MDA), TNF-α and IL-1β were measured for rats treated with aripiprazole. The extent of necrosis was measured by the stereology method. Ischemia/reperfusion caused significant renal dysfunction and marked renal injury. Aripiprazole reduced creatinine and blood urea nitrogen. Serum levels of MDA, IL-1β and TNF-α were significantly lower in the aripiprazole group. Aripiprazole treatment also decreased the volume of kidney necrosis. The administration of L-NAME reversed the renoprotective effect of aripiprazole on BUN and creatinine, but enhanced the anti-necrotic effect of aripiprazole. The results show that a single dose of aripiprazole significantly improved renal function following ischemia/reperfusion injury - probably through the involvement of nitric oxide. Copyright © 2017 Elsevier B.V. All rights reserved.

Cardioprotective properties of Crataegus oxycantha extract against ischemia-reperfusion injury.

PubMed

Swaminathan, J K; Khan, M; Mohan, I K; Selvendiran, K; Niranjali Devaraj, S; Rivera, B K; Kuppusamy, P

2010-08-01

The aim of the study was to investigate the cardioprotective effect and mechanism of Crataegus oxycantha (COC) extract, a well-known natural antioxidant-based cardiotonic, against ischemia/reperfusion (I/R) injury. Electron paramagnetic resonance studies showed that COC extract was capable of scavenging superoxide, hydroxyl, and peroxyl radicals, in vitro. The cardioprotective efficacy of the extract was studied in a crystalloid perfused heart model of I/R injury. Hearts were subjected to 30min of global ischemia followed by 45min of reperfusion. During reperfusion, COC extract was infused at a dose rate of 1mg/ml/min for 10min. Hearts treated with COC extract showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase and lactate dehydrogenase activities. The expressions of xanthine oxidase and NADPH oxidase were significantly reduced in the treated group. A significant upregulation of the anti-apoptotic proteins Bcl-2 and Hsp70 with simultaneous downregulation of the pro-apoptotic proteins cytochrome c and cleaved caspase-3 was observed. The molecular signaling cascade including phospho-Akt (ser-473) and HIF-1alpha that lead to the activation or suppression of apoptotic pathway also showed a significant protective role in the treatment group. No significant change in phospho-p38 levels was observed. The results suggested that the COC extract may reduce the oxidative stress in the reperfused myocardium, and play a significant role in the inhibition of apoptotic pathways leading to cardioprotection. 2010 Elsevier GmbH. All rights reserved.

Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor {kappa}B p65 activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xue, Xia; Center for New Drugs Evaluation, Shandong University, Jinan 250012; Qu, Xian-Jun

Research highlights: {yields} Permanent NF-{kappa}B p65 activation contributes to the infarction after ischemia-reperfusion injury in rats. {yields} Baicalin can markedly inhibit the nuclear NF-{kappa}B p65 expression and m RNA levels after ischemia-reperfusion injury in rats. {yields} Baicalin decreased the cerebral infarction area via inhibiting the activation of nuclear NF-{kappa}B p65. -- Abstract: Baicalin is a flavonoid compound purified from plant Scutellaria baicalensis Georgi. We aimed to evaluate the neuroprotective effects of baicalin against cerebral ischemic reperfusion injury. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. Baicalin at dosesmore » of 50, 100 and 200 mg/kg was intravenously injected after ischemia onset. Twenty-four hours after reperfusion, the neurological deficit was scored and infarct volume was measured. Hematoxylin and eosin (HE) staining was performed to analyze the histopathological changes of cortex and hippocampus neurons. We examined the levels of NF-{kappa}B p65 in ischemic cortexes by Western blot analysis and RT-PCR assay. The results showed that the neurological deficit scores were significantly decreased from 2.0 {+-} 0.7 to 1.2 {+-} 0.4 and the volume of infarction was reduced by 25% after baicalin injection. Histopathological examination showed that the increase of neurons with pycnotic shape and condensed nuclear in cortex and hippocampus were not observed in baicalin treated animals. Further examination showed that NF-{kappa}B p65 in cortex was increased after ischemia reperfusion injury, indicating the molecular mechanism of ischemia reperfusion injury. The level of NF-{kappa}B p65 was decreased by 73% after baicalin treatment. These results suggest that baicalin might be useful as a potential neuroprotective agent in stroke therapy. The neuroprotective effects of baicalin may relate to inhibition of NF-{kappa}B p65.« less

Action of iloprost and PGE1 on global ischemic and reperfused myocardium: a 31P-NMR-study.

PubMed

Pissarek, M; Gründer, W; Keller, T; Goos, H; Mest, H J; Krause, E G

1988-01-01

The influence of iloprost, PGE1 and of the combined application of iloprost and PGE1 on high energy phosphate contents was investigated in isolated rat hearts perfused aerob at 37 degrees C in Langendorff mode. Changes in creatine phosphate, ATP and inorganic phosphate were registered during 20 minutes of global ischemia and 56 minutes of reperfusion with 31P-NMR-spectroscopic methods starting drug application prior to ischemia simultaneously with onset of heart perfusion. Most effective in preservation of high energy phosphates was the combined application of PGE1 and iloprost resulting in a creatine phosphate/inorganic phosphate ratio of 103.2 +/- 30.9% of pre-ischemia values compared to 52.5 +/- 6.1% in control group without drug application 0-5 minutes after onset of reperfusion, 148.8 +/- 24.8% vs 78.8 +/- 15.2% at 6-11 minutes of reperfusion and 116.6 +/- 16% vs 68.9 +/- 12.7% at 12-17 minutes of reperfusion. The same trend was observed employing ATP/inorganic phosphate ratio. The improved energy state in reperfused hearts following application of PGE1 and iloprost in combination is presumed to be supported by a reduction of the loss of high energy phosphates (HEP) during global ischemia and by a cytoprotective effect of iloprost immediately after starting reperfusion.

Platelet P2Y₁₂ blockers confer direct postconditioning-like protection in reperfused rabbit hearts.

PubMed

Yang, Xi-Ming; Liu, Yanping; Cui, Lin; Yang, Xiulan; Liu, Yongge; Tandon, Narendra; Kambayashi, Junichi; Downey, James M; Cohen, Michael V

2013-05-01

Blockade of platelet activation during primary percutaneous intervention for acute myocardial infarction is standard care to minimize stent thrombosis. To determine whether antiplatelet agents offer any direct cardioprotective effect, we tested whether they could modify infarction in a rabbit model of ischemia/reperfusion caused by reversible ligation of a coronary artery. The P2Y₁₂ (adenosine diphosphate) receptor blocker cangrelor administered shortly before reperfusion in rabbits undergoing 30-minute regional ischemia/3-hour reperfusion reduced infarction from 38% of ischemic zone in control hearts to only 19%. Protection was dose dependent and correlated with the degree of inhibition of platelet aggregation. Protection was comparable to that seen with ischemic postconditioning (IPOC). Cangrelor protection, but not its inhibition of platelet aggregation, was abolished by the same signaling inhibitors that block protection from IPOC suggesting protection resulted from protective signaling rather than anticoagulation. As with IPOC, protection was lost when cangrelor administration was delayed until 10 minutes after reperfusion and no added protection was seen when cangrelor and IPOC were combined. These findings suggest both IPOC and cangrelor may protect by the same mechanism. No protection was seen when cangrelor was used in crystalloid-perfused isolated hearts indicating some component in whole blood is required for protection. Clopidogrel had a very slow onset of action requiring 2 days of treatment before platelets were inhibited, and only then the hearts were protected. Signaling inhibitors given just prior to reperfusion blocked clopidogrel's protection. Neither aspirin nor heparin was protective. Clopidogrel and cangrelor protected rabbit hearts against infarction. The mechanism appears to involve signal transduction during reperfusion rather than inhibition of intravascular coagulation. We hypothesize that both drugs protect by activating IPOC

The Comparison of the Outcomes between Primary PCI, Fibrinolysis, and No Reperfusion in Patients ≥ 75 Years Old with ST-Segment Elevation Myocardial Infarction: Results from the Chinese Acute Myocardial Infarction (CAMI) Registry.

PubMed

Peiyuan, He; Jingang, Yang; Haiyan, Xu; Xiaojin, Gao; Ying, Xian; Yuan, Wu; Wei, Li; Yang, Wang; Xinran, Tang; Ruohua, Yan; Chen, Jin; Lei, Song; Xuan, Zhang; Rui, Fu; Yunqing, Ye; Qiuting, Dong; Hui, Sun; Xinxin, Yan; Runlin, Gao; Yuejin, Yang

2016-01-01

Only a few randomized trials have analyzed the clinical outcomes of elderly ST-segment elevation myocardial infarction (STEMI) patients (≥ 75 years old). Therefore, the best reperfusion strategy has not been well established. An observational study focused on clinical outcomes was performed in this population. Based on the national registry on STEMI patients, the in-hospital outcomes of elderly patients with different reperfusion strategies were compared. The primary endpoint was defined as death. Secondary endpoints included recurrent myocardial infarction, ischemia driven revascularization, myocardial infarction related complications, and major bleeding. Multivariable regression analysis was performed to adjust for the baseline disparities between the groups. Patients who had primary percutaneous coronary intervention (PCI) or fibrinolysis were relatively younger. They came to hospital earlier, and had lower risk of death compared with patients who had no reperfusion. The guideline recommended medications were more frequently used in patients with primary PCI during the hospitalization and at discharge. The rates of death were 7.7%, 15.0%, and 19.9% respectively, with primary PCI, fibrinolysis, and no reperfusion (P < 0.001). Patients having primary PCI also had lower rates of heart failure, mechanical complications, and cardiac arrest compared with fibrinolysis and no reperfusion (P < 0.05). The rates of hemorrhage stroke (0.3%, 0.6%, and 0.1%) and other major bleeding (3.0%, 5.0%, and 3.1%) were similar in the primary PCI, fibrinolysis, and no reperfusion group (P > 0.05). In the multivariable regression analysis, primary PCI outweighs no reperfusion in predicting the in-hospital death in patients ≥ 75 years old. However, fibrinolysis does not. Early reperfusion, especially primary PCI was safe and effective with absolute reduction of mortality compared with no reperfusion. However, certain randomized trials were encouraged to support the conclusion.

Maintenance of cAMP in non-heart-beating donor lungs reduces ischemia-reperfusion injury.

PubMed

Hoffmann, S C; Bleiweis, M S; Jones, D R; Paik, H C; Ciriaco, P; Egan, T M

2001-06-01

Studies suggest that pulmonary vascular ischemia-reperfusion injury (IRI) can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, assessed by capillary filtration coeficient (Kfc), in lungs retrieved from non-heart-beating donors (NHBDs) and reperfused with the addition of the beta(2)-adrenergic receptor agonist isoproterenol (iso), and rolipram (roli), a phosphodiesterase (type IV) inhibitor. Using an in situ isolated perfused lung model, lungs were retrieved from NHBD rats at varying intervals after death and either ventilated with O(2) or not ventilated. The lungs were reperfused with Earle's solution with or without a combination of iso (10 microM) and roli (2 microM). Kfc, lung viability, and pulmonary hemodynamics were measured. Lung tissue levels of adenine nucleotides and cAMP were measured by HPLC. Combined iso and roli (iso/roli) reperfusion decreased Kfc significantly (p < 0.05) compared with non-iso/roli-reperfused groups after 2 h of postmortem ischemia. Total adenine nucleotide (TAN) levels correlated with Kfc in non-iso/roli-reperfused (r = 0.89) and iso/roli-reperfused (r = 0.97) lungs. cAMP levels correlated with Kfc (r = 0.93) in iso/roli-reperfused lungs. Pharmacologic augmentation of tissue TAN and cAMP levels might ameliorate the increased capillary permeability observed in lungs retrieved from NHBDs.

Ischemia and reperfusion injury in renal transplantation: hemodynamic and immunological paradigms

PubMed Central

Requião-Moura, Lúcio Roberto; Durão, Marcelino de Souza; de Matos, Ana Cristina Carvalho; Pacheco-Silva, Alvaro

2015-01-01

Ischemia and reperfusion injury is an inevitable event in renal transplantation. The most important consequences are delayed graft function, longer length of stay, higher hospital costs, high risk of acute rejection, and negative impact of long-term follow-up. Currently, many factors are involved in their pathophysiology and could be classified into two different paradigms for education purposes: hemodynamic and immune. The hemodynamic paradigm is described as the reduction of oxygen delivery due to blood flow interruption, involving many hormone systems, and oxygen-free radicals produced after reperfusion. The immune paradigm has been recently described and involves immune system cells, especially T cells, with a central role in this injury. According to these concepts, new strategies to prevent ischemia and reperfusion injury have been studied, particularly the more physiological forms of storing the kidney, such as the pump machine and the use of antilymphocyte antibody therapy before reperfusion. Pump machine perfusion reduces delayed graft function prevalence and length of stay at hospital, and increases long-term graft survival. The use of antilymphocyte antibody therapy before reperfusion, such as Thymoglobulin™, can reduce the prevalence of delayed graft function and chronic graft dysfunction. PMID:25993079

miR-21 Contributes to Xenon-conferred Amelioration of Renal Ischemia–Reperfusion Injury in Mice

PubMed Central

Jia, Ping; Teng, Jie; Zou, Jianzhou; Fang, Yi; Zhang, Xiaoyan; Bosnjak, Zeljko J.; Liang, Mingyu; Ding, Xiaoqiang

2015-01-01

Background MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Methods Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Results Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti–miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti–miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1α and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1α. Conclusions These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning. PMID:23681145

Pharmacologic Effects of Cannabidiol on Acute Reperfused Myocardial Infarction in Rabbits: Evaluated With 3.0T Cardiac Magnetic Resonance Imaging and Histopathology.

PubMed

Feng, Yuanbo; Chen, Feng; Yin, Ting; Xia, Qian; Liu, Yewei; Huang, Gang; Zhang, Jian; Oyen, Raymond; Ni, Yicheng

2015-10-01

Cannabidiol (CBD) has anti-inflammatory effects. We explored its therapeutic effects on cardiac ischemia-reperfusion injury with an experimental imaging platform. Reperfused acute myocardial infarction (AMI) was induced in rabbits with a 90-minute coronary artery occlusion followed by 24-hour reperfusion. Before reperfusion, rabbits received 2 intravenous doses of 100 μg/kg CBD (n = 10) or vehicle (control, n = 10). Evans blue was intravenously injected for later detection of the AMI core. Cardiac magnetic resonance imaging was performed to evaluate cardiac morphology and function. After euthanasia, blood troponin I (cTnI) was assessed, and the heart was excised and infused with multifunctional red iodized oil dye. The heart was sliced for digital radiography to quantify the perfusion density rate, area at risk (AAR), and myocardial salvage index, followed by histomorphologic staining. Compared with controls, CBD treatment improved systolic wall thickening (P < 0.05), significantly increased blood flow in the AAR (P < 0.05), significantly decreased microvascular obstruction (P < 0.05), increased the perfusion density rate by 1.7-fold, lowered the AMI core/AAR ratio (P < 0.05), and increased the myocardial salvage index (P < 0.05). These improvements were associated with reductions in serum cTnI, cardiac leukocyte infiltration, and myocellular apoptosis (P < 0.05). Thus, CBD therapy reduced AMI size and facilitated restoration of left ventricular function. We demonstrated that this experimental platform has potential theragnostic utility.

Neuroprotective effect of antioxidants on ischaemia and reperfusion-induced cerebral injury.

PubMed

Gupta, Ram; Singh, Manjeet; Sharma, Ajay

2003-08-01

The present study is designed to investigate the effect of dietary flavanoid rutin, micronutrient selenium and garlic oil on ischaemia and reperfusion-induced cerebral injury. Global cerebral ischaemia was induced by occluding right and left common carotid arteries for 10min followed by reperfusion for 24h. Cerebral infarct size was estimated using triphenyltetrazolium chloride staining. Elevated plus maze was employed to estimate short-term memory. Degree of motor incoordination was evaluated using inclined beam-walking test and lateral push test. Mitochondrial thiobarbituric acid reactive substances (TBARS) assay was employed as an index of oxidative stress. Global cerebral ischaemia followed by reperfusion produced a significant impairment in short-term memory and motor coordination and produced a notable increase in mitochondrial TBARS. Administration of rutin and garlic oil before global cerebral ischaemia markedly reduced cerebral infarct size and attenuated impairment in short-term memory and motor coordination. Administration of sodium selenite either before or after global cerebral ischaemia markedly reduced cerebral infarct size and attenuated impairment in short-term memory and motor coordination. The protective effect of rutin, sodium selenite and garlic oil was accompanied by a marked decrease in mitochondrial TBARS. On the basis of these results, it may be suggested that rutin and garlic oil administrated before cerebral ischaemia may scavenge reactive oxygen species and consequently attenuate global cerebral ischaemia and reperfusion-induced cerebral injury. Sodium selenite administrated before and after cerebral ischaemia may be neuroprotective due to its antioxidant effect.

Iloprost ameliorates post-ischemic lung reperfusion injury and maintains an appropriate pulmonary ET-1 balance.

PubMed

Kawashima, Masahiro; Nakamura, Takayuki; Schneider, Sven; Vollmar, Brigitte; Lausberg, Henning F; Bauer, Michael; Menger, Michael D; Schäfers, Hans-Joachim

2003-07-01

Ischemia-reperfusion (I/R) injury of the lung involves increased pulmonary vascular resistance. Prostaglandins are thought to have a beneficial effect in lung transplantation, but their mechanism in I/R injury is unknown. We investigated whether iloprost, a stable prostacyclin analogue, prevents I/R-associated pulmonary vascular dysfunction and whether it affects endothelin-1 (ET-1) balance. In an isolated blood-perfusion model, we subjected lungs of Lewis rats to 45 minutes of ischemia at 37 degrees C and randomly allocated the lungs to 3 groups (n = 6 each): iloprost (33.3 nmol/liter) added to the perfusate before ischemia and reperfusion (ILO+IR), iloprost (33.3 nmol/liter) given only before reperfusion (ILO+R), and controls without iloprost treatment (ILO-). Reperfusion induced marked pulmonary edema in non-treated controls (ILO-), which was attenuated in ILO+R lungs and completely prevented in ILO+IR lungs. At 60 minutes reperfusion, arterial oxygen tension was significantly greater in both ILO+R and ILO+IR lungs compared with ILO- controls. Mean pulmonary artery pressure and pulmonary vascular resistance were slightly decreased in the ILO+R and significantly decreased in the ILO+IR group compared with the ILO- controls. Plasma levels of big ET-1, measured in both afferent and efferent blood, showed that I/R results in increased pulmonary venous levels of big ET-1. Interestingly, the increased venoarterial ET-1 gradient in ILO- lungs decreased significantly in the ILO+IR group. We demonstrated in an isolated lung perfusion model that iloprost ameliorates post-ischemic lung reperfusion injury and maintains an appropriate pulmonary ET-1 balance.

[Decreasing reperfusion damage with N-acetylcysteine in experimental pancreas transplantion].

PubMed

Mayer, H; Thies, J; Schmidt, J; Gebhard, M M; Herfarth, C; Klar, E

1998-01-01

In this study we investigated the effect of donor and recipient conditioning with N-acetylcysteine on the ischemia/reperfusion injury after experimental pancreas-transplantation. We performed standardized pancreaticoduodenal transplantation in male lewis rats. The pancreas was perfused with UW-solution, harvested and conserved at 4 degrees C. Cold ischemia time was 1.5 hours and 16 hours respectively. The microcirculation in the transplanted organ was quantified by means of intravital microscopy 1.5 hours after implantation and reperfusion in the recipient. After 16 hours of cold ischemia we found a significant reduction in capillary erythrocyte velocity and a significantly enhanced leucocyte/endothelium interaction. The treatment with N-acetylcysteine resulted in a significant improvement of these microcirculatory disorders after prolonged cold ischemia.

Analysis of temporal dynamics in imagery during acute limb ischemia and reperfusion

NASA Astrophysics Data System (ADS)

Irvine, John M.; Regan, John; Spain, Tammy A.; Caruso, Joseph D.; Rodriquez, Maricela; Luthra, Rajiv; Forsberg, Jonathon; Crane, Nicole J.; Elster, Eric

2014-03-01

Ischemia and reperfusion injuries present major challenges for both military and civilian medicine. Improved methods for assessing the effects and predicting outcome could guide treatment decisions. Specific issues related to ischemia and reperfusion injury can include complications arising from tourniquet use, such as microvascular leakage in the limb, loss of muscle strength and systemic failures leading to hypotension and cardiac failure. Better methods for assessing the viability of limbs/tissues during ischemia and reducing complications arising from reperfusion are critical to improving clinical outcomes for at-risk patients. The purpose of this research is to develop and assess possible prediction models of outcome for acute limb ischemia using a pre-clinical model. Our model relies only on non-invasive imaging data acquired from an animal study. Outcome is measured by pathology and functional scores. We explore color, texture, and temporal features derived from both color and thermal motion imagery acquired during ischemia and reperfusion. The imagery features form the explanatory variables in a model for predicting outcome. Comparing model performance to outcome prediction based on direct observation of blood chemistry, blood gas, urinalysis, and physiological measurements provides a reference standard. Initial results show excellent performance for the imagery-base model, compared to predictions based direct measurements. This paper will present the models and supporting analysis, followed by recommendations for future investigations.

Conditioning the heart to prevent myocardial reperfusion injury during PPCI

PubMed Central

2012-01-01

For patients presenting with a ST-segment elevation myocardial infarction (STEMI), early myocardial reperfusion by primary percutaneous coronary intervention (PPCI) remains the most effective treatment strategy for limiting myocardial infarct size, preserving left ventricular systolic function, and preventing the onset of heart failure. Recent advances in PCI technology to improve myocardial reperfusion and the introduction of novel anti-platelet and anti-thrombotic agents to maintain the patency of the infarct-related coronary artery continue to optimize PPCI procedure. However, despite these improvements, STEMI patients still experience significant major adverse cardiovascular events. One major contributing factor has been the inability to protect the heart against the lethal myocardial reperfusion injury, which accompanies PPCI. Past attempts to translate cardioprotective strategies, discovered in experimental studies to prevent lethal myocardial reperfusion injury, into the clinical setting of PPCI have been disappointing. However, a number of recent proof-of-concept clinical studies suggest that the heart can be ‘conditioned’ to protect itself against lethal myocardial reperfusion injury, as evidenced by a reduction in myocardial infarct size. This can be achieved using either mechanical (such as ischaemic postconditioning, remote ischaemic preconditioning, therapeutic hypothermia, or hyperoxaemia) or pharmacological (such as cyclosporin-A, natriuretic peptide, exenatide) ‘conditioning’ strategies as adjuncts to PPCI. Furthermore, recent developments in cardiac magnetic resonance (CMR) imaging can provide a non-invasive imaging strategy for assessing the efficacy of these novel adjunctive therapies to PPCI in terms of key surrogate clinical endpoints such as myocardial infarct size, myocardial salvage, left ventricular ejection fraction, and the presence of microvascular obstruction or intramyocardial haemorrhage. In this article, we review the

Garlicin attenuates reperfusion no-reflow in a catheter-based porcine model of acute myocardial infarction.

PubMed

Peng, Yang; Jiahui, Li; Aili, Li; Yong, Wang; Zaixiang, Shi; Yuannan, Ke; Xianlun, Li

2012-08-01

To evaluate whether garlicin can attenuate reperfusion no-reflow in a catheter-based porcine model of acute myocardial infarction (AMI). Twenty-two swine were used: six in a sham-operation group, and eight each in the control and garlicin groups. The distal part of the left anterior descending coronary artery (LAD) in the latter two groups was occluded by a dilated balloon for 2 hr, then reperfused for 3 hr. Garlicin (1.88mg/kg) was injected just before reperfusion until reperfusion for 1 hr in the garlicin group. Hemodynamic data were examined before AMI, 2 hr after occlusion, and 3 hr after reperfusion. Myocardial contrast echocardiography (MCE) and pathological staining were performed to evaluate the myocardial no-reflow area (NRA). Serum proinflammatory cytokines and endothelin (ET)-1 were examined by radioimmunoassay. Left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP) significantly improved in the garlicin group after reperfusion compared with the control group and also 2hr after AMI (p<0.05 for both). MCE and pathological staining both showed garlicin attenuated reperfusion NRA after AMI (p<0.05, p<0.01). Garlicin not only decreased serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α after reperfusion (p<0.05 for both), but also ET-1 level (p<0.01). Garlicin attenuated reperfusion no-reflow in our catheter-based porcrine model of AMI, possibly through decreasing serum proinflammatory cytokines and ET-1.

Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia.

PubMed

Chi, O Z; Barsoum, S; Vega-Cotto, N M; Jacinto, E; Liu, X; Mellender, S J; Weiss, H R

2016-03-01

Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1h and reperfusion for 2h with and without rapamycin (20mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C(14)-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5±0.8% control vs. 21.5±0.9% rapamycin). We also found that ischemia-reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia-reperfusion. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

The Relative Influences of Phosphometabolites and pH on Action Potential Morphology during Myocardial Reperfusion: A Simulation Study

PubMed Central

Roberts, Byron N.; Christini, David J.

2012-01-01

Myocardial ischemia-reperfusion (IR) injury represents a constellation of pathological processes that occur when ischemic myocardium experiences a restoration of perfusion. Reentrant arrhythmias, which represent a particularly lethal manifestation of IR injury, can result when ischemic tissue exhibits decreased excitability and/or changes of action potential duration (APD), conditions that precipitate unidirectional conduction block. Many of the cellular components that are involved with IR injury are modulated by pH and/or phosphometabolites such as ATP and phosphocreatine (PCr), all of which can be manipulated in vivo and potentially in the clinical setting. Using a mathematical model of the cardiomyocyte that we previously developed to study ischemia and reperfusion, we performed a series of simulations with the aim of determining whether pH- or phosphometabolite-related processes play a more significant role in generating changes in excitability and action potential morphology that are associated with the development of reentry. In our simulations, persistent shortening of APD, action potential amplitude (APA), and depolarization of the resting membrane potential were more severe when ATP and PCr availability were suppressed during reperfusion than when extracellular pH recovery was inhibited. Reduced phosphometabolite availability and pH recovery affected multiple ion channels and exchangers. Some of these effects were the result of direct modulation by phosphometabolites and/or acidosis, while others resulted from elevated sodium and calcium loads during reperfusion. In addition, increasing ATP and PCr availability during reperfusion was more beneficial in terms of increasing APD and APA than was increasing the amount of pH recovery. Together, these results suggest that therapies directed at increasing ATP and/or PCr availability during reperfusion may be more beneficial than perturbing pH recovery with regard to mitigating action potential changes that

Glycine aggravates ischemia reperfusion-induced acute kidney injury through N-Methyl-D-Aspartate receptor activation in rats.

PubMed

Arora, Shiyana; Kaur, Tajpreet; Kaur, Anudeep; Singh, Amrit Pal

2014-08-01

The present study was designed to investigate the role of glycine in ischemia reperfusion-induced acute kidney injury (AKI) in rats. The AKI was induced in rats by occluding renal pedicles for 40 min followed by reperfusion for 24 h. The AKI was assessed by measuring creatinine clearance, blood urea nitrogen, plasma uric acid, potassium, fractional excretion of sodium, and microproteinuria. The oxidative stress in renal tissues was assessed by quantification of myeloperoxidase activity, thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. Glycine (100, 200, and 400 mg/kg, i.p.) was administered to rats 30 min before subjecting to AKI. The glycinergic receptor blocker, strychnine (0.75 mg/kg i.p.), and glycine-binding site blocker at N-methyl-D-aspartate (NMDA) receptor, kynurenic acid (300 and 600 mg/kg i.p.), were used in the present study. The ischemia reperfusion induced AKI as witnessed by significant change in plasma, urinary, and tissue parameters employed in the present study. Glycine treatment increased ischemia reperfusion-induced AKI. The treatment with strychnine did not show any protection, whereas kynurenic acid ameliorated renal ischemia reperfusion-induced AKI. The results obtained in present study suggest that glycine increases ischemia reperfusion-induced renal damage through NMDA receptor agonism rather than strychnine-sensitive glycinergic receptors. Hence, it is concluded that glycine aggravates ischemia reperfusion-induced AKI. In addition, the activation of strychnine-insensitive glycine-binding site of NMDA receptors is responsible for its renal-damaging effect rather than strychnine-sensitive glycinergic receptors.

Ischaemia–reperfusion injury in liver transplantation—from bench to bedside

PubMed Central

Zhai, Yuan; Petrowsky, Henrik; Hong, Johnny C.; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.

2013-01-01

Ischaemia–reperfusion injury (IRI) in the liver, a major complication of haemorrhagic shock, resection and transplantation, is a dynamic process that involves the two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury. This Review highlights the latest mechanistic insights into innate–adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia–reperfusion, discusses progress in large animal experiments and examines efforts to minimize liver IRI in patients who have received a liver transplant. The interlinked signalling pathways in multiple hepatic cell types, the IRI kinetics and positive versus negative regulatory loops at the innate–adaptive immune interface are discussed. The current gaps in our knowledge and the pathophysiology aspects of IRI in which basic and translational research is still required are stressed. An improved appreciation of cellular immune events that trigger and sustain local inflammatory responses, which are ultimately responsible for organ injury, is fundamental to developing innovative strategies for treating patients who have received a liver transplant and developed ischaemia–reperfusion inflammation and organ dysfunction. PMID:23229329

Glucose oxidation positively regulates glucose uptake and improves cardiac function recovery after myocardial reperfusion.

PubMed

Li, Tingting; Xu, Jie; Qin, Xinghua; Hou, Zuoxu; Guo, Yongzheng; Liu, Zhenhua; Wu, Jianjiang; Zheng, Hong; Zhang, Xing; Gao, Feng

2017-11-01

Myocardial reperfusion decreases glucose oxidation and uncouples glucose oxidation from glycolysis. Therapies that increase glucose oxidation lessen myocardial ischemia-reperfusion (I/R) injury. However, the regulation of glucose uptake during reperfusion remains poorly understood. We found that glucose uptake was remarkably diminished in the myocardium following reperfusion in Sprague-Dawley rats as detected by 18 F-labeled and fluorescent-labeled glucose analogs, even though GLUT1 was upregulated by threefold and GLUT4 translocation remained unchanged compared with those of sham-treated rats. The decreased glucose uptake was accompanied by suppressed glucose oxidation. Interestingly, stimulating glucose oxidation by inhibition of pyruvate dehydrogenase kinase 4 (PDK4), a rate-limiting enzyme for glucose oxidation, increased glucose uptake and alleviated I/R injury. In vitro data in neonatal myocytes showed that PDK4 overexpression decreased glucose uptake, whereas its knockdown increased glucose uptake, suggesting that PDK4 has a role in regulating glucose uptake. Moreover, inhibition of PDK4 increased myocardial glucose uptake with concomitant enhancement of cardiac insulin sensitivity following myocardial I/R. These results showed that the suppressed glucose oxidation mediated by PDK4 contributes to the reduced glucose uptake in the myocardium following reperfusion, and enhancement of glucose uptake exerts cardioprotection. The findings suggest that stimulating glucose oxidation via PDK4 could be an efficient approach to improve recovery from myocardial I/R injury. Copyright © 2017 the American Physiological Society.

[Effects of combined use of total alkaloids of Uncaria rhynchophylla and Coryadlis ambailis migo on cerebral ischemia-reperfusion injury in rats].

PubMed

Hu, Xue-yong; Sun, An-sheng; Sui, Yu-xia

2007-11-01

To study the effects of combined use of total alkaloids (TA) of Uncaria rhynchophylla (UR) and Coryadlis ambailis migo (CAM) on cerebral ischemia/reperfusion injury in rats. Rat model of middle cerebral artery ischemia/reperfusion was established, the changes of neurological state was scored before and after treatment with the two kinds of TA, single or combined, and the changes of cerebral infarcted volume, cerebral water content, activities of NOS and SOD and content of MDA in rats' brain were estimated as well. After being treated with the combination of both TA, the average neurological score, cerebral infracted volume, cerebral water content, activity of NOS and content of MDA in the model rats significantly decreased, and the activity of SOD was significantly increased (all P < 0.05). The effect of combined use of the two TA was higher than that of use TA of UR or CAM alone (P <0.05). Moreover, the central nervous system inhibitory effect induced by combined TA was significantly weaker than that of UR. Combined use of TA of UR and CAM may facilitate the protection against cerebral ischemia/reperfusion damage, the action mechanism might be relevant to reducing the lipid peroxidation injury of brain cells through inhibiting the NOS activity and increasing the SOD activity.

Role of sirtuins in ischemia-reperfusion injury.

PubMed

Pantazi, Eirini; Zaouali, Mohamed Amine; Bejaoui, Mohamed; Folch-Puy, Emma; Ben Abdennebi, Hassen; Roselló-Catafau, Joan

2013-01-01

Ischemia-reperfusion injury (IRI) remains an unresolved and complicated situation in clinical practice, especially in the case of organ transplantation. Several factors contribute to its complexity; the depletion of energy during ischemia and the induction of oxidative stress during reperfusion initiate a cascade of pathways that lead to cell death and finally to severe organ injury. Recently, the sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylases has gained increasing attention from researchers, due to their involvement in the modulation of a wide variety of cellular functions. There are seven mammalian sirtuins and, among them, the nuclear/cytoplasmic sirtuin 1 (SIRT1) and the mitochondrial sirtuin 3 (SIRT3) are ubiquitously expressed in many tissue types. Sirtuins are known to play major roles in protecting against cellular stress and in controlling metabolic pathways, which are key processes during IRI. In this review, we mainly focus on SIRT1 and SIRT3 and examine their role in modulating pathways against energy depletion during ischemia and their involvement in oxidative stress, apoptosis, microcirculatory stress and inflammation during reperfusion. We present evidence of the beneficial effects of sirtuins against IRI and emphasize the importance of developing new strategies by enhancing their action.

Methylene Blue Attenuates Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats

PubMed Central

Wang, Liangrong; Chen, Baihui; Lin, Bi; Ye, Yuzhu; Bao, Caiying; Zhao, Xiyue; Jin, Lida

2018-01-01

Objective This study was aimed to investigate the protective effect of methylene blue against lung injury induced by reperfusion of ischemic hindlimb in a rat model. Methods Twenty-four healthy adult male Sprague-Dawley rats were equally randomized into three groups: sham (SM) group, ischemia reperfusion (IR) group, and methylene blue (MB) group. Rats in both IR and MB groups were subjected to 4 h of ischemia by clamping the left femoral artery and then followed by 4 h of reperfusion. Treatment with 1% methylene blue (50 mg/kg) was administrated intraperitoneally at 10 min prior to reperfusion in the MB group. After 4 h of reperfusion, malondialdehyde (MDA) level, myeloperoxidase (MPO), and superoxide dismutase (SOD) activities in lung tissue were detected; inflammatory cytokines, including IL-1β and IL-6, were measured in bronchoalveolar lavage fluid (BALF); correspondingly, the morphological changes and water content in both gastrocnemius muscle and lung samples were evaluated. Results Hindlimb IR caused remarkable morphological abnormalities and edema in both muscle and lung tissues. SOD activity was decreased, both the MPO activity and MDA level in lung tissue, as well as IL-1β and IL-6 levels in BALF, were increased in the IR group (p < 0.05). Compared with the IR group, SOD activity was increased, whereas MPO activity and MDA level in lung tissue and IL-1β and IL-6 levels in BALF were decreased in the MB group (p < 0.05). Also, the histological damage and edema in both lung and muscle tissues were significantly attenuated by the treatment of methylene blue. Conclusion Methylene blue attenuates lung injury induced by hindlimb IR in rats, at least in part, by inhibiting oxidative stress. PMID:29713238

Protective Effects of Hydrocortisone, Vitamin C and E Alone or in Combination against Renal Ischemia-Reperfusion Injury in Rat.

PubMed

Azari, Omid; Kheirandish, Reza; Azizi, Shahrzad; Farajli Abbasi, Mohammad; Ghahramani Gareh Chaman, Shahin; Bidi, Masoud

2015-01-01

Renal ischemia reperfusion injury may occur in a variety of clinical situations, following a transient drop in total or regional blood flow to the kidney. This study was performed to investigate the protective effects of different antioxidants such as vitamin C, vitamin E, hydrocortisone and combination of these agents against experimental renal ischemia-reperfusion injury. Thirty male rats were divided into six groups. Group Sham, Group I/R: (45 min of ischemia followed by 1h of reperfusion), Group I/R+Vit C: (50 mg/kg Vit C, IV, immediately after reperfusion), Group I/R+Vit E: (20 mg/kg Vit E, IM, 15 min before reperfusion), Group I/R+Hydrocortisone: (50 mg/kg, IV, immediately after reperfusion), and Group Combination: Ischemia-reperfusion plus combination of Vit C, E and hydrocortisone. After the experiments, the left kidney was removed and the tissues were processed for histopathological examination. Severe injuries such as necrosis of tubules, atrophy of glomerulus, and hemorrhage were observed in group I/R. Histological scores indicating tissue injury significantly decreased in all treatment groups compared to the group I/R. The renal tissue in group treatment was preserved in comparison with the group I/R. Comparison between the treatment groups showed that group combination was more effective and group vit E was less effective in protecting of renal tissue against I/R injuries. The results demonstrated simultaneous administration of combination of Vit C, E and hydrocortisone before reperfusion of blood flow to the ischemic tissue could show a synergy against deleterious effects of I/R injuries in kidney.

miR-21 contributes to xenon-conferred amelioration of renal ischemia-reperfusion injury in mice.

PubMed

Jia, Ping; Teng, Jie; Zou, Jianzhou; Fang, Yi; Zhang, Xiaoyan; Bosnjak, Zeljko J; Liang, Mingyu; Ding, Xiaoqiang

2013-09-01

MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti-miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti-miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1α and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1α. These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning.

Effects of ischemic preconditioning and iloprost on myocardial ischemia-reperfusion damage in rats.

PubMed

Ay, Yasin; Kara, Ibrahim; Aydin, Cemalettin; Ay, Nuray Kahraman; Teker, Melike Elif; Senol, Serkan; Inan, Bekir; Basel, Halil; Uysal, Omer; Zeybek, Rahmi

2013-01-01

This study investigates the effects of cardiac ischemic preconditioning and iloprost on reperfusion damage in rats with myocardial ischemia/reperfusion. 38 male Wistar Albino rats used in this study were divided into 5 groups. The control group (Group 1) (n=6), ischemia/reperfusion (IR) group (Group 2) (n=8), cardiac ischemic preconditioning (CIP) group (Group 3) (n=8), iloprost (ILO) group (Group 4) (n=8), and cardiac ischemic preconditioning + iloprost (CIP+ILO) group (Group 5) (n=8). Pre-ischemia, 15 minutes post-ischemia, 45 minutes post-reperfusion, mean blood pressure (MBP), and heart rates (HR) were recorded. The rate-pressure product (RPP) was calculated. Post-reperfusion plasma creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin (cTn) vlaues, and infarct size/area at risk (IS/AAR) were calculated from myocardial tissue samples. Arrhythmia and ST segment elevations were evaluated during the ischemia and reperfusion stages. Although the MBP, HR, RPP values, biochemical parameters of CK-MB and LDH levels, IS/AAR rates, ST segment elevation values were found to be similar in CIP and CIP+ILO groups and the IR and ILO groups (p>0.05), CIP-containing group values had a positively meaningful difference (p<0.05) compared with the IR and ILO group. While mild-moderate findings of damage were observed in Group 3 and Group 5, severely findings of damage were releaved in Group 2 and Group 4. The arrhythmia score of the ILO group was meaningfully lower (F: 41.4, p<0.001) than the IR group. We can conclude that the effects of myocardial reperfusion damage can be reduced by cardiac ischemic preconditioning, intravenous iloprost reduced the incidence of ventricular arrhythmia associated with reperfusion, and its use with CIP caused no additional changes.

Cerebral ischemia and reperfusion increases the heterogeneity of local oxygen supply/consumption balance.

PubMed

Weiss, Harvey R; Grayson, Jeremy; Liu, Xia; Barsoum, Sylviana; Shah, Harsh; Chi, Oak Z

2013-09-01

After cerebral vessel blockage, local blood flow and O2 consumption becomes lower and oxygen extraction increases. With reperfusion, blood flow is partially restored. We examined the effects of ischemia-reperfusion on the heterogeneity of local venous oxygen saturation in rats in order to determine the pattern of microregional O2 supply/consumption balance in reperfusion. The middle cerebral artery was blocked for 1 hour using the internal carotid approach in 1 group (n=9) and was then reperfused for 2 hours in another group (n=9) of isoflurane-anesthetized rats. Regional cerebral blood flow was determined using a C(14)-iodoantipyrine autoradiographic technique. Regional small vessel arterial and venous oxygen saturations were determined microspectrophotometrically. After 1 hour of ischemia, local cerebral blood flow (92±10 versus 50±10 mL/min per 100 g) and O2 consumption (4.5±0.6 versus 2.7±0.5 mL O2/min per 100 g) decreased compared with the contralateral cortex. Oxygen extraction increased (4.7±0.2 versus 5.4±0.3 mL O2/100 mL) and the variation in small vein (20-60 μm) O2 saturation as determined by its coefficient of variation (=100×SD/mean) increased (5.5 versus 10.5). With 2 hours of reperfusion, the blood flow decrement was reduced and O2 consumption returned to the value in the contralateral cortex. Oxygen extraction remained elevated in the ischemic-reperfused area and the coefficient of variation of small vein O2 saturation increased further (17.3). These data indicated continued reduction of O2 supply/consumption balance with reperfusion. They also demonstrated many small regions of low oxygenation within the reperfused cortical region.

The Akt/GSK-3β pathway mediates flurbiprofen-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rats.

PubMed

Sun, Baozhu; Chen, Lin; Wei, Xinbing; Xiang, Yanxiao; Liu, Xiaoqian; Zhang, Xiumei

2011-06-17

Apoptosis is one of the major mechanisms of cell death during cerebral ischemia and reperfusion injury. Flurbiprofen has been shown to reduce cerebral ischemia/reperfusion injury in both focal and global cerebral ischemia models, but the mechanism remains unclear. This study aimed to investigate the potential association between the neuroprotective effect of flurbiprofen and the apoptosis inhibiting signaling pathways, in particularly the Akt/GSK-3β pathway. A focal cerebral ischemia rat model was subjected to middle cerebral artery occlusion (MCAO) for 120 min and then treated with flurbiprofen at the onset of reperfusion. The infarct volume and the neurological deficit scores were evaluated at 24h after reperfusion. Cell apoptosis, apoptosis-related proteins and the levels of p-Akt and p-GSK-3β in ischemic penumbra were measured using TUNEL and western blot. The results showed that administration of flurbiprofen at the doses of 5 and 10mg/kg significantly attenuated brain ischemia/reperfusion injury, as shown by a reduction in the infarct volume, neurological deficit scores and cell apoptosis. Moreover, flurbiprofen not only inhibited the expression of Bax protein and p-GSK-3β, but also increased the expression of Bcl-2 protein, the ratio of Bcl-2/Bax as well as the P-Akt level. Taken together, these results suggest that flurbiprofen protects the brain from ischemia/reperfusion injury by reducing apoptosis and this neuroprotective effect may be partly due to the activation of Akt/GSK-3β signaling pathway. Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

Cardioprotective effects of grape seed proanthocyanidin against ischemic reperfusion injury.

PubMed

Sato, M; Maulik, G; Ray, P S; Bagchi, D; Das, D K

1999-06-01

There is increasing evidence to indicate cardioprotective effects of red wine consumption. Such cardioprotective properties of wine have been attributed to certain polyphenolic constituents of grapes. The purpose of this investigation was to examine whether proanthocyanidins derived from grape seeds possess cardioprotective properties. Rats were randomly divided into two groups: grape-seed proanthocyanidin was administered orally to one group of rats (100 mg/kg/day) for 3 weeks while the other group served as control. After 3 weeks, rats were killed, hearts excised, mounted on the perfusion apparatus and perfused with Krebs-Henseleit bicarbonate (KHB) buffer. After stabilization hearts were perfused in the working mode for baseline measurements of contractile functions. Hearts were then subjected to 30 min of global ischemia followed by 2 h of reperfusion. Coronary perfusates were collected to monitor malonaldehyde formation, a presumptive marker for oxidative stress development. At the end of each experiment, the heart was processed for infarct size determination. Peroxyl radical scavenging activity of proanthocyanidin was determined by examining its ability to remove peroxyl radical generated by 2,2'-azobis (2-amidinopropane) dihydrochloride while hydroxyl radical scavenging activity was tested with its ability to reduce 7-OH.-coumarin-3-carboxylic acid. The results of our study demonstrated that proanthocyanidin-fed animals were resistant to myocardial ischemia reperfusion injury as evidenced by improved recovery of post-ischemic contractile functions. The proanthocyanidin-fed group revealed reduced extent of myocardial infarction compared to the control group. Fluorimetric study demonstrated the antioxidant property of proanthocyanidin as judged by its ability to directly scavenge peroxyl radicals. Taken together, the results of this study showed that grape seed-proanthocyanidins possess a cardioprotective effect against ischemia reperfusion injury. Such

[Effects of flunarizine and vitamin C on hemodynamics in rat heart subjected to ischemia-reperfusion].

PubMed

Xian, Y; Lan, T; Wang, Y

1998-09-01

Langendorff perfusion isolated rat heart was subjected to total global ischemia (coronary flow rate is equal to zero) for 10 minutes and reperfusion for 15 minutes. The heart rate (HR), left ventricular developed pressure (LVDP), coronary flow rate (CFR), electrocardiogram (ECG) and the effects of calcium antagonist-flunarizine (FNZ) and/or oxygen free radical scavenger--vitamine C on the above parameters were observed. The results showed that FNZ dilated coronary vessel (P < 0.01) and had a slight negative chronotropic effect, but it had no effect on LVP. Vitamine C did not affect HR, LVP and CFR. The recovery of the product of HR and LVDP-Rate Pressure Product (RPP) in the FNZ + Vit. C group, Vit. C group and FNZ group was significantly higher than that in the control group (P < 0.05) at ten minutes reperfusion. All the results suggest that FNZ and Vit. C may improve the recovery of heart function after reperfusion.

Comparing short versus standard-length balloon for intra-aortic counterpulsation: results from a porcine model of myocardial ischaemia-reperfusion.

PubMed

Gelsomino, Sandro; Lozekoot, Pieter W J; Lorusso, Roberto; de Jong, Monique M J; Parise, Orlando; Matteucci, Francesco; Lucà, Fabiana; La Meir, Mark; Gensini, Gian Franco; Maessen, Jos G

2016-05-01

We compare a short and a standard-size balloon with same filling volumes to verify the differences in terms of visceral flow, coronary circulation and haemodynamic performance during aortic counterpulsation in an animal model of myocardial ischaemia-reperfusion injury. Eighteen healthy pigs underwent 120-min ligation of the left anterior descending coronary artery followed by 6 h of reperfusion, and they were randomly assigned to have intra-aortic balloon counterpulsation (IABP) with a 40-ml short-balloon (n = 6) or a 40-ml standard-length balloon (n = 6), or to undergo no IABP implantation (controls, n = 6). Haemodynamics and visceral and coronary flows were measured at baseline (t0), at 2 h of ischaemia (t1) and every hour thereafter until 6 h of reperfusion (from tR1 to tR6), respectively. Mesenteric flows increased significantly at tR1 only in the short-balloon group (P < 0.001) and it was constantly higher than in the standard-balloon group regardless of mean arterial pressure, systemic vascular resistance and cardiac output (CO; all, P < 0.001). Renal blood flows were significantly increased during IABP treatment with values constantly and significantly higher in short balloons at any following experimental step (all, P < 0.05). IABP improved CO and coronary blood flow, and reduced afterload, myocardial resistances and myocardial oxygen consumption without differences between the short and the standard-length balloon (all, P > 0.05). The short balloon prevents visceral ischaemia and, compared with the standard-size balloon, it does not lose IABP beneficial cardiac and coronary-related effects. Further studies are warranted to confirm our findings. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Ischemia-reperfusion injury in rat fatty liver: role of nutritional status.

PubMed

Caraceni, P; Nardo, B; Domenicali, M; Turi, P; Vici, M; Simoncini, M; De Maria, N; Trevisani, F; Van Thiel, D H; Derenzini, M; Cavallari, A; Bernardi, M

1999-04-01

Fatty livers are more sensitive to the deleterious effects of ischemia-reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia-reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P <.01). Accordingly, fasting and fatty degeneration had a synergistic effect in exacerbating liver injury. Mitochondrial damage was a predominant feature of ultrastructural hepatocyte injury in fasted fatty livers. Glucose supplementation partially prevented the fasting-induced depletion of glycogen and improved the 7-day rat survival to 45%. These data indicate that rat fatty livers exposed to normothermic ischemia-reperfusion injury are much more sensitive to fasting than histologically normal livers. Because glucose supplementation improves both the hepatic glycogen stores and the rat survival, a nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers.

Reperfusion therapy of myocardial infarction in Mexico: A challenge for modern cardiology.

PubMed

Martínez-Sánchez, Carlos; Arias-Mendoza, Alexandra; González-Pacheco, Héctor; Araiza-Garaygordobil, Diego; Marroquín-Donday, Luis Alfonso; Padilla-Ibarra, Jorge; Sierra-Fernández, Carlos; Altamirano-Castillo, Alfredo; Álvarez-Sangabriel, Amada; Azar-Manzur, Francisco Javier; Briseño-de la Cruz, José Luis; Mendoza-García, Salvador; Piña-Reyna, Yigal; Martínez-Ríos, Marco Antonio

Mexico has been positioned as the country with the highest mortality attributed to myocardial infarction among the members of the Organization for Economic Cooperation and Development. This rate responds to multiple factors, including a low rate of reperfusion therapy and the absence of a coordinated system of care. Primary angioplasty is the reperfusion method recommended by the guidelines, but requires multiple conditions that are not reached at all times. Early pharmacological reperfusion of the culprit coronary artery and early coronary angiography (pharmacoinvasive strategy) can be the solution to the logistical problem that primary angioplasty rises. Several studies have demonstrated pharmacoinvasive strategy as effective and safe as primary angioplasty ST-elevation myocardial infarction, which is postulated as the choice to follow in communities where access to PPCI is limited. The Mexico City Government together with the National Institute of Cardiology have developed a pharmaco-invasive reperfusion treatment program to ensure effective and timely reperfusion in STEMI. The model comprises a network of care at all three levels of health, including a system for early pharmacological reperfusion in primary care centers, a digital telemedicine system, an inter-hospital transport network to ensure primary angioplasty or early percutaneous coronary intervention after fibrinolysis and a training program with certification of the health care personal. This program intends to reduce morbidity and mortality associated with myocardial infarction. Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. All rights reserved.

Prolonged Ischemia Triggers Necrotic Depletion of Tissue Resident Macrophages to Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury

PubMed Central

Yue, Shi; Zhou, Haoming; Wang, Xuehao; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.; Zhai, Yuan

2017-01-01

Although mechanisms of immune activation against liver ischemia reperfusion injury (IRI) have been studied extensively, questions regarding liver resident macrophages, i.e., Kupffer cells, remain controversial. Recent progress in the biology of tissue resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver resident vs. infiltrating macrophages by fluorescence-activated cell sorting (FACS) and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages (iMØ), but also necrotic depletion of KCs. Inhibition of Receptor Interacting Protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induce depletion, resulting in the reduction of iMØ infiltration, suppression of pro-inflammatory immune activation and protection of livers from IRI. The depletion of KCs by clodronate-liposomes abrogated these effects of Nec-1s. Additionally, liver reconstitutions with KCs post-ischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, i.e., RIP-1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI. PMID:28289160

Selective heart rate reduction with ivabradine slows ischaemia-induced electrophysiological changes and reduces ischaemia–reperfusion-induced ventricular arrhythmias

PubMed Central

Ng, Fu Siong; Shadi, Iqbal T.; Peters, Nicholas S.; Lyon, Alexander R.

2013-01-01

Heart rates during ischaemia and reperfusion are possible determinants of reperfusion arrhythmias. We used ivabradine, a selective If current inhibitor, to assess the effects of heart rate reduction (HRR) during ischaemia–reperfusion on reperfusion ventricular arrhythmias and assessed potential anti-arrhythmic mechanisms by optical mapping. Five groups of rat hearts were subjected to regional ischaemia by left anterior descending artery occlusion for 8 min followed by 10 min of reperfusion: (1) Control n = 10; (2) 1 μM of ivabradine perfusion n = 10; (3) 1 μM of ivabradine + 5 Hz atrial pacing throughout ischaemia–reperfusion n = 5; (4) 1 μM of ivabradine + 5 Hz pacing only at reperfusion; (5) 100 μM of ivabradine was used as a 1 ml bolus upon reperfusion. For optical mapping, 10 hearts (ivabradine n = 5; 5 Hz pacing n = 5) were subjected to global ischaemia whilst transmembrane voltage transients were recorded. Epicardial activation was mapped, and the rate of development of ischaemia-induced electrophysiological changes was assessed. HRR observed in the ivabradine group during both ischaemia (195 ± 11 bpm vs. control 272 ± 14 bpm, p < 0.05) and at reperfusion (168 ± 13 bpm vs. 276 ± 14 bpm, p < 0.05) was associated with reduced reperfusion ventricular fibrillation (VF) incidence (20% vs. 90%, p < 0.05). Pacing throughout ischaemia–reperfusion abolished the protective effects of ivabradine (100% VF), whereas pacing at reperfusion only partially attenuated this effect (40% VF). Ivabradine, given as a bolus at reperfusion, did not significantly affect VF incidence (80% VF). Optical mapping experiments showed a delay to ischaemia-induced conduction slowing (time to 50% conduction slowing: 10.2 ± 1.3 min vs. 5.1 ± 0.7 min, p < 0.05) and to loss of electrical excitability in ivabradine-perfused hearts (27.7 ± 4.3 min vs. 14.5 ± 0.6 min, p < 0.05). Ivabradine administered throughout ischaemia

Immunomodulation by splenectomy or by FTY720 protects the heart against ischemia reperfusion injury.

PubMed

Goltz, D; Huss, S; Ramadori, E; Büttner, R; Diehl, L; Meyer, R

2015-11-01

The pathogenesis of myocardial ischemia-reperfusion injury (MI/R) involves an inflammatory response in the myocardium undergoing reperfusion. Modulation of this response by splenectomy constitutes an option to protect the heart from MI/R. To mimic the effect of splenectomy in a pharmacological approach, the sphingosine-1-phosphate agonist FTY720 was applied at the onset of reperfusion. In a closed chest model of MI/R, infarct size was assessed by triphenyltetrazolium chloride staining after 1 h of ischemia and 24 h of reperfusion, and by Masson trichrome staining 21 days after reperfusion in splenectomised mice, mice post-conditioned with FTY720 IP (1 mg/kg), and controls. In addition, hemodynamic parameters were recorded after 24 h and 21 days by catheterization. Infarct size, and immune cell invasion of phagocytic monocytes investigated by FACS after 24 h of reperfusion were significantly reduced by both splenectomy, and FTY720 treatment. Evaluation after 21 days of reperfusion revealed that FTY720 treated animals had an improved hemodynamic outcome compared to placebo treated as well as splenectomised animals. FTY720 treatment reduced cell injury as effectively as splenectomy by lowering the number of phagocytic monocytes invading the myocardium and ameliorated hemodynamic outcome within the first 21 days. © 2015 Wiley Publishing Asia Pty Ltd.

The role of glycogen synthase kinase 3 beta in brain injury induced by myocardial ischemia/reperfusion injury in a rat model of diabetes mellitus.

PubMed

Zhao, Bo; Gao, Wen-Wei; Liu, Ya-Jing; Jiang, Meng; Liu, Lian; Yuan, Quan; Hou, Jia-Bao; Xia, Zhong-Yuan

2017-10-01

Myocardial ischemia/reperfusion injury can lead to severe brain injury. Glycogen synthase kinase 3 beta is known to be involved in myo-cardial ischemia/reperfusion injury and diabetes mellitus. However, the precise role of glycogen synthase kinase 3 beta in myocardial ischemia/reperfusion injury-induced brain injury is unclear. In this study, we observed the effects of glycogen synthase kinase 3 beta on brain injury induced by myocardial ischemia/reperfusion injury in diabetic rats. Rat models of diabetes mellitus were generated via intraperitoneal injection of streptozotocin. Models of myocardial ischemia/reperfusion injury were generated by occluding the anterior descending branch of the left coronary artery. Post-conditioning comprised three cycles of ischemia/reperfusion. Immunohistochemical staining and western blot assays demonstrated that after 48 hours of reperfusion, the structure of the brain was seriously damaged in the experimental rats compared with normal controls. Expression of Bax, interleukin-6, interleukin-8, terminal deoxynucleotidyl transferase dUTP nick end labeling, and cleaved caspase-3 in the brain was significantly increased, while expression of Bcl-2, interleukin-10, and phospho-glycogen synthase kinase 3 beta was decreased. Diabetes mellitus can aggravate inflammatory reactions and apoptosis. Ischemic post-conditioning with glycogen synthase kinase 3 beta inhibitor lithium chloride can effectively reverse these changes. Our results showed that myocardial ischemic post-conditioning attenuated myocardial ischemia/reperfusion injury-induced brain injury by activating glyco-gen synthase kinase 3 beta. According to these results, glycogen synthase kinase 3 beta appears to be an important factor in brain injury induced by myocardial ischemia/reperfusion injury.

Down-regulation of NOX4 by betulinic acid protects against cerebral ischemia-reperfusion in mice.

PubMed

Lu, Pei; Zhang, Chen-Chen; Zhang, Xiao-Min; Li, Hui-Ge; Luo, Ai-Lin; Tian, Yu-Ke; Xu, Hui

2017-10-01

acid reduced infarct volume and ameliorated the neurological deficit in this stroke mouse model. Our results suggest that betulinic acid protects against cerebral ischemia/reperfusion injury in mice and the down-regulation of NOX4 may represent a mechanism contributing to this effect.

Vascular responsiveness measured by tissue oxygen saturation reperfusion slope is sensitive to different occlusion durations and training status.

PubMed

McLay, Kaitlin M; Gilbertson, James E; Pogliaghi, Silvia; Paterson, Donald H; Murias, Juan M

2016-10-01

reperfusion slope at 30 s was smaller than for all longer occlusion durations (P < 0.05), and 1 min occlusion resulted in a reperfusion slope that was less steep than following 2 and 3 min (P < 0.05), albeit not different from 5 min (P > 0.05). The present study demonstrated that the reperfusion rate of StO2 is sensitive to different occlusion durations, and that changes in the reperfusion rate in response to a variety of ischaemic challenges can be used to detect differences in vascular responsiveness between trained and untrained groups. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

ERK phosphorylation plays an important role in the protection afforded by hypothermia against renal ischemia-reperfusion injury.

PubMed

Choi, Dae Eun; Jeong, Jin Young; Choi, Hyunsu; Chang, Yoon Kyung; Ahn, Moon Sang; Ham, Young Rok; Na, Ki Ryang; Lee, Kang Wook

2017-02-01

Although hypothermia attenuates the renal injury induced by ischemia-reperfusion, the detailed molecular pathway(s) involved remains unknown. ERK phosphorylation is known to protect against ischemia-reperfusion injury. Also, it has been reported that hypothermia may induce ERK phosphorylation in the heart and brain. We evaluated the role played by ERK in hypothermic protection against renal ischemia-reperfusion injury. C57Bl/6 mice were divided into the following groups: sham-operated (cold, 32°C) vs normal temperature (37°C); ischemia-reperfusion mice (32°C vs 37°C); and PD98059- or vehicle-treated ischemia-reperfusion mice (32°C). Kidneys were harvested 10 and 27 minutes after induction of renal ischemia and 24 hours after ischemia-reperfusion injury. Functional and molecular markers of kidney injury were evaluated. To explore the molecular mechanism involved the expression levels of renal HIF-1 and associated proteins were evaluated. The blood urea nitrogen (BUN) and serum creatinine (s-Cr) levels and the histologic renal injury scores were significantly lower in 32°C ischemia-reperfusion than 37°C ischemia-reperfusion kidneys (all P values < .05). The expression levels of Bax and caspase-3 and the extent of TUNEL and 8-OHdG cell positivity decreased, whereas the renal Bcl-2 level increased, in 32°C ischemia-reperfusion compared to 37°C ischemia-reperfusion mice. The extent of renal ERK phosphorylation was significantly higher in ischemia-reperfusion than sham-operated kidneys. Also, ERK phosphorylation was significantly increased in the kidneys of 32°C compared to 37°C ischemia-reperfusion mice. PD98059 treatment of 32°C ischemia-reperfusion mice significantly decreased the renal HIF-1 level (P < .05) and increased the BUN, s-Cr, renal Bax, and caspase-3 expression levels; the tissue injury score; and the proportions of TUNEL- and 8-OHdG-positive cells. PD98059 also increased the renal Bcl-2 level in such mice. Hypothermia attenuates the renal

Liver transplantation in man: morphometric analysis of the parenchymal alterations following cold ischaemia and warm ischaemia/reperfusion

PubMed Central

VIZZOTTO, LAURA; VERTEMATI, MAURIZIO; DEGNA, CARLO TOMMASINI; ASENI, PAOLO

2001-01-01

Ischaemia and reperfusion phases represent critical events during liver transplantation. The purpose of this study was to describe morphological alterations of both vascular and parenchymal compartments after ischaemia and reperfusion and to evaluate the possible relationship between morphometric parameters and biochemical/clinical data. Three needle biopsies were drawn from 20 patients who underwent orthotopic liver transplantation. The first biopsy was taken before flushing with preservation solution, and the second and the third to evaluate respectively the effects of cold ischaemia and of warm ischaemia/reperfusion. Biopsies were examined by an image analyser and morphometric parameters related to the liver parenchyma were evaluated. At the second biopsy we observed a decrease of the endothelium volume fraction while the same parameter referred to the sinusoidal lumen achieved a peak value. The hepatocytes showed a lower surface parenchymal/vascular sides ratio. This parameter was reversed at the end of the reperfusion phase; furthermore the third biopsy revealed endothelial swelling and a decreased volume fraction of the sinusoidal lumen. The results quantify the damage to the sinusoidal bed which, as already known, is one of the main targets of cold ischaemia; warm ischaemia and reperfusion accentuate endothelial damage. The end of transplantation is characterised by damage chiefly to parenchymal cells. Hepatocytes show a rearrangement of their surface sides, probably related to the alterations of the sinusoidal bed. In addition, the fluctuations of morphometric parameters during ischaemia/reperfusion correlate positively with biochemical data and clinical course of the patients. PMID:11430699

4-Phenylbutyrate protects rat skin flaps against ischemia-reperfusion injury and apoptosis by inhibiting endoplasmic reticulum stress

PubMed Central

YUE, ZHEN-SHUANG; ZENG, LIN-RU; QUAN, REN-FU; TANG, YANG-HUA; ZHENG, WEN-JIE; QU, GANG; XU, CAN-DA; ZHU, FANG-BING; HUANG, ZHONG-MING

2016-01-01

4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid, which has been demonstrated to regulate endoplasmic reticulum (ER) stress. ER stress-induced cell apoptosis has an important role in skin flap ischemia; however, a pharmacological approach for treating ischemia-induced ER dysfunction has yet to be reported. In the present study, the effects of 4-PBA-induced ER stress inhibition on ischemia-reperfusion injury were investigated in the skin flap of rats, and transcriptional regulation was examined. 4-PBA attenuated ischemia-reperfusion injury and inhibited cell apoptosis in the skin flap. Furthermore, 4-PBA reversed the increased expression levels of two ER stress markers: CCAAT/enhancer-binding protein-homologous protein and glucose-regulated protein 78. These results suggested that 4-PBA was able to protect rat skin flaps against ischemia-reperfusion injury and apoptosis by inhibiting ER stress marker expression and ER stress-mediated apoptosis. The beneficial effects of 4-PBA may prove useful in the treatment of skin flap ischemia-reperfusion injury. PMID:26648447

Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Haiyan; Department of Pharmacology, Tianjin Medical University, Tianjin 300070; Huh, Jin

Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2 h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured. Morphinemore » reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. - Highlights: • Morphine induced mito-Src phosphorylation and reduced infarct size in rat hearts. • Morphine failed to reduce I/R-induced LDH release in Src-silencing HL-1 cells. • Morphine prevented mitochondria damage caused by I/R through Src. • Morphine

The Effect of Botulinum Toxin A on Ischemia-Reperfusion Injury in a Rat Model

PubMed Central

2017-01-01

Introduction While studies using various materials to overcome ischemia-reperfusion (IR) injury are becoming increasingly common, studies on the effects of botulinum toxin A (BoTA) on IR injury in musculocutaneous flaps are still limited. The purpose of this study was to examine our hypotheses that BoTA provide protection of musculocutaneous flap from ischemia-reperfusion injury. Method Five days after pretreatment injection (BoTA versus normal saline), a right superior musculocutaneous flap (6 × 1.5 cm in size) was made. Ischemia was created by a tourniquet strictly wrapping the pedicle containing skin and muscle for 8 h. After ischemia, the tourniquet was cut, and the musculocutaneous flap was reperfused. Results The overall survival percentage of flap after 8 h of pedicle clamping followed by reperfusion was 87.32 ± 3.67% in the control group versus 95.64 ± 3.25% in the BoTA group (p < 0.001). The BoTA group had higher expression of CD34, HIF-1α, VEGF, and NF-kB comparing to control group in qRT-PCR analysis. Conclusions In this study, we found that local BoTA preconditioning yielded significant protection against IR injury in a rat musculocutaneous flap model. PMID:28589130

Inhibition of cerebral ischemia/reperfusion injury-induced apoptosis: nicotiflorin and JAK2/STAT3 pathway.

PubMed

Hu, Guang-Qiang; Du, Xi; Li, Yong-Jie; Gao, Xiao-Qing; Chen, Bi-Qiong; Yu, Lu

2017-01-01

Nicotiflorin is a flavonoid extracted from Carthamus tinctorius. Previous studies have shown its cerebral protective effect, but the mechanism is undefined. In this study, we aimed to determine whether nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis through the JAK2/STAT3 pathway. The cerebral ischemia/reperfusion injury model was established by middle cerebral artery occlusion/reperfusion. Nicotiflorin (10 mg/kg) was administered by tail vein injection. Cell apoptosis in the ischemic cerebral cortex was examined by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Bcl-2 and Bax expression levels in ischemic cerebral cortex were examined by immunohistochemial staining. Additionally, p-JAK2, p-STAT3, Bcl-2, Bax, and caspase-3 levels in ischemic cerebral cortex were examined by western blot assay. Nicotiflorin altered the shape and structure of injured neurons, decreased the number of apoptotic cells, down-regulates expression of p-JAK2, p-STAT3, caspase-3, and Bax, decreased Bax immunoredactivity, and increased Bcl-2 protein expression and immunoreactivity. These results suggest that nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis via the JAK2/STAT3 pathway.

The effect of butorphanol postconditioning on myocardial ischaemia reperfusion injury in rats

PubMed Central

Wu, Yun; Wan, Jing; Zhen, Wen-Zhon; Chen, Liu-Fang; Zhan, Jia; Ke, Jian-Juan; Zhang,, Zong-Ze; Wang, Yan-Lin

2014-01-01

OBJECTIVES Butorphanol tartrate is a synthetic opioid partial agonist analgesic. Butorphanol targets the heart, mainly via κ-opioid receptor (κ-OR) activation. The purpose of this study was to determine the effect and mechanism underlying butorphanol postconditioning (B-Post) on myocardial ischaemia reperfusion injury in rats. METHODS Seventy-five male Sprague–Dawley rats were randomly divided into five groups of 15 each: Group sham; Group I/R (ischaemia/reperfusion); Group B (butorphanol postconditioning); Group B/N (butorphanol postconditioning + antagonist of κ-OR nor-binaltorphimine [Nor-BNI]); Group B/G (butorphanol postconditioning + nonselective ATP-sensitive potassium (KATP) channel blocker glibenclamide [GLI]). The left coronary anterior descending artery (LAD) was occluded for 30 min, followed by a 120-min reperfusion. Blood samples were obtained at the end of reperfusion for determination of serum tumour necrosis factor (TNF)-α and interleukin (IL)-6 concentrations. The hearts were then excised for determination of myocardial infarct size by triphenyltetrazolium chloride staining. The myocardial tissues were used for determination of the expression of myocardial superoxide dismutase (SOD), malondialdehyde (MDA) and myeloperoxidase (MPO). RESULTS Myocardial infarct size was significantly reduced in B (26.4 ± 1.83%), B/N (34.5 ± 1.56%) and B/G (31.5 ± 1.27%) Groups compared with Group I/R (46.8 ± 1.41%) (all P < 0. 001). The serum TNF-α and IL-6 concentrations and the MDA and MPO activities in the ischaemic area in B, B/N and B/G Groups were significantly lower than those in the I/R Group (all P < 0.001). In addition, myocardial infarct size, TNF-α and IL-6 concentrations and the MDA and MPO activities in B/N and B/G Groups were higher than those in the B Group (all P < 0.001). In contrast, SOD activity was significantly increased in B, B/N and B/G Groups, and SOD activity in B/N and B/G Groups was less than in the B Group (all P < 0

[Mesenteric flow in an experimental model of ischaemia-reperfusion in rats].

PubMed

Cáceres, F; Castañon, M; Lerena, J; Cusi, V; Badosa, J; Morales, L

2014-03-01

Maintained acute occlusion followed by reperfusion of the superior mesenteric artery (SMA) in a few hours can trigger irreversible bowel damage. The aim of the study was to determine the changes in mesenteric flow measured by colour Doppler Ultrasound and correlating with histological lesions in an experimental model of ischaemia-reperfusion. Three groups of Sprague-Dawley 17 day-old rats were studied (control, ischemia and reperfusion). The model used was ischaemia-reperfusion over the SMA. Intra-abdominal ultrasound was then performed. The parameters recorded were: Maximum systolic velocity (MSV), pulsatility index (PI), resistance (RI) and systole-diastole (S/D). The histological variables were: intestinal lesion (Wallace/Keenan-Chiu scale), morphometrics (mean villus height [MVH]), and goblet cells. The Spearman (rs) correlation was used. The MSV in the reperfusion group was 74.3 cm/s, the PI 7.33 and S/D 25.75 in the SMA, which were higher than the controls (41.35 cm/s; 3.12 and 12.45, respectively). A direct association (P<.01) was found between MSV, PI and S/D regarding: Wallace/Kennan scoring system (rs = 0.655; rs = 0.593; rs = 0.63) and the Chiu (rs = 0.569; rs = 0.522; rs = 0.47). While the correlation was the reverse (P<.01) when associated with the MVH (rs = -0,495; rs = -0,452; rs = -0,459) and goblet cells of the colon (rs = -0,525; rs = -0,45; rs = -0,518). The reperfusion phase increased mesenteric flow expressed by the MSV and PI and could significantly predict the potential bowel damage at macroscopic and microscopic level. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Baicalein, a Component of Scutellaria baicalensis, Attenuates Kidney Injury Induced by Myocardial Ischemia and Reperfusion.

PubMed

Lai, Chang-Chi; Huang, Po-Hsung; Yang, An-Han; Chiang, Shu-Chiung; Tang, Chia-Yu; Tseng, Kuo-Wei; Huang, Cheng-Hsiung

2016-02-01

Acute kidney injury is a common and severe complication of acute myocardial infarction and cardiac surgery. It results in increased mortality, morbidity, and duration of hospitalization. Baicalein is a component of the root of Scutellaria baicalensis, which has traditionally been used to treat cardiovascular and liver diseases in Asia. In this study, we investigated whether baicalein can attenuate kidney injury induced by myocardial ischemia and reperfusion in rats. Myocardial ischemia and reperfusion, induced by a 40-minute occlusion and a 3-hour reperfusion of the left anterior descending coronary artery, significantly increased blood urea nitrogen and creatinine levels in addition to causing histological changes in the kidneys. Kidney apoptosis was also significantly increased. Furthermore, myocardial ischemia and reperfusion significantly increased the serum levels of tumor necrosis factor-α, interleukin-1, and interleukin-6 as well as the tumor necrosis factor-α levels in the kidneys. Intravenous pretreatment with baicalein (in doses of 3, 10, or 30 mg/kg), however, significantly reduced the increases in the creatinine level, renal histological damage, and apoptosis induced by myocardial ischemia and reperfusion. In addition, the increases in the serum levels of tumor necrosis factor-α, interleukin-1, and interleukin-6, and of tumor necrosis factor-α in the kidneys were significantly reduced. Western blot analysis revealed that baicalein significantly increased Bcl-2 and reduced Bax in the kidneys. The phosphorylation of Akt and extracellular signal-regulated kinases 1 and 2 was also significantly increased. In conclusion, baicalein significantly attenuates kidney injury induced by myocardial ischemia and reperfusion. The underlying mechanisms might be related to the inhibition of apoptosis, possibly through the reduction of tumor necrosis factor-α production, the modulation of Bcl-2 and Bax, and the activation of Akt and extracellular signal

The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model.

PubMed

Lee, C-J; Kim, K-W; Lee, H-M; Nahm, F S; Lim, Y-J; Park, J-H; Kim, C-S

2007-02-01

Randomized study. To evaluate the effects of thalidomide on spinal cord ischemia/reperfusion injury via reduced TNF-alpha production. Animal experimental laboratory, Clinical Research Institute of Seoul National University Hospital, Seoul, Korea. Spinal cord ischemia was induced in rabbits by occluding the infrarenal aorta. Rabbits in group N did not undergo ischemic insult, but rabbits in groups C (the untreated group), THA, and THB underwent ischemic insult for 15 min. The THA and THB groups received thalidomide (20 mg/kg) intraperitoneally (i.p.) before ischemia, but only the THB group received thalidomide (i.p., 20 mg/kg) after 24 and 48 h of reperfusion. After evaluating neurologic functions at 1.5 h, 3, and 5 days of reperfusion, rabbits were killed for histopathologic examination and Western blot analysis of TNF-alpha. The THA and THB groups showed significantly less neurologic dysfunction than the C group at 1.5 h, 3, and 5 days of reperfusion. The number of normal spinal motor neurons in ventral gray matter was higher in THA and THB than in C, but no difference was observed between THA and THB. Western blot analysis showed a significantly higher level of TNF-alpha in C than in THA and THB at 1.5 h of reperfusion, but no difference was observed between C, THA, or THB at 3 or 5 days of reperfusion. Thalidomide treatment before ischemic insult reduces early phase ischemia/reperfusion injury of the spinal cord in rabbits.

Beneficial effects of remote organ ischemic preconditioning on micro-rheological parameters during liver ischemia-reperfusion in the rat.

PubMed

Magyar, Zsuzsanna; Mester, Anita; Nadubinszky, Gabor; Varga, Gabor; Ghanem, Souleiman; Somogyi, Viktoria; Tanczos, Bence; Deak, Adam; Bidiga, Laszlo; Oltean, Mihai; Peto, Katalin; Nemeth, Norbert

2018-04-14

Remote ischemic preconditioning (RIPC) can be protective against the damage. However, there is no consensus on the optimal amount of tissue, the number and duration of the ischemic cycles, and the timing of the preconditioning. The hemorheological background of the process is also unknown. To investigate the effects of remote organ ischemic preconditioning on micro-rheological parameters during liver ischemia-reperfusion in rats. In anesthetized rats 60-minute partial liver ischemia was induced with 120-minute reperfusion (Control, n = 7). In the preconditioned groups a tourniquet was applied on the left thigh for 3×10 minutes 1 hour (RIPC-1, n = 7) or 24 hours (RIPC-24, n = 7) prior to the liver ischemia. Blood samples were taken before the operation and during the reperfusion. Acid-base, hematological parameters, erythrocyte aggregation and deformability were tested. Lactate concentration significantly increased by the end of the reperfusion. Erythrocyte deformability was improved in the RIPC-1 group, erythrocyte aggregation increased during the reperfusion, particularly in the RIPC-24 group. RIPC alleviated several hemorheological changes caused by the liver I/R. However, the optimal timing of the RIPC cannot be defined based on these results.

Poloxamer 188 protects against ischemia-reperfusion injury in a murine hind-limb model.

PubMed

Murphy, Adrian D; McCormack, Michael C; Bichara, David A; Nguyen, John T; Randolph, Mark A; Watkins, Michael T; Lee, Raphael C; Austen, William G

2010-06-01

Ischemia-reperfusion injury can activate pathways generating reactive oxygen species, which can injure cells by creating holes in the cell membranes. Copolymer surfactants such as poloxamer 188 are capable of sealing defects in cell membranes. The authors postulated that a single-dose administration of poloxamer 188 would decrease skeletal myocyte injury and mortality following ischemia-reperfusion injury. Mice underwent normothermic hind-limb ischemia for 2 hours. Animals were treated with 150 microl of poloxamer 188 or dextran at three time points: (1) 10 minutes before ischemia; (2) 10 minutes before reperfusion; and (3) 2 or 4 hours after reperfusion. After 24 hours of reperfusion, tissues were analyzed for myocyte injury (histology) and metabolic dysfunction (muscle adenosine 5'-triphosphate). Additional groups of mice were followed for 7 days to assess mortality. When poloxamer 188 treatment was administered 10 minutes before ischemia, injury was reduced by 84 percent, from 50 percent injury in the dextran group to 8 percent injury in the poloxamer 188 group (p < 0.001). When administered 10 minutes before reperfusion, poloxamer 188 animals demonstrated a 60 percent reduction in injury compared with dextran controls (12 percent versus 29 percent). Treatment at 2 hours, but not at 4 hours, postinjury prevented substantial myocyte injury. Preservation of muscle adenosine 5'-triphosphate paralleled the decrease in myocyte injury in poloxamer 188-treated animals. Poloxamer 188 treatment significantly reduced mortality following injury (10 minutes before, 75 percent versus 25 percent survival, p = 0.0077; 2 hours after, 50 percent versus 8 percent survival, p = 0.032). Poloxamer 188 administered to animals decreased myocyte injury, preserved tissue adenosine 5'-triphosphate levels, and improved survival following hind-limb ischemia-reperfusion injury.

Effects of long-term treatment with eicosapentaenoic acid on the heart subjected to ischemia/reperfusion and hypoxia/reoxygenation in rats.

PubMed

Takeo, S; Nasa, Y; Tanonaka, K; Yabe, K; Nojiri, M; Hayashi, M; Sasaki, H; Ida, K; Yanai, K

1998-11-01

The effects of eicosapentaenoic acid (EPA) and long-term treatment with EPA-ethylester (EPA-E) were examined in perfused rat hearts subjected to ischemia/reperfusion and adult rat cardiomyocytes subjected to hypoxia/reoxygenation. EPA (0.1 microM) improved postischemic contractile dysfunction of the ischemic/reperfused heart. EPA (10 microM) attenuated hypoxia/reoxygenation-induced morphological deterioration of cardiomyocytes. The results suggest the presence of direct cardioprotective effects of EPA. Rats were orally treated for 4 weeks with 1 g/kg/day of EPA-E to elucidate ex vivo effects of EPA, and the fatty acid composition of cardiac phospholipids was determined. The percent ratio of EPA in total fatty acids of cardiac phospholipids increased whereas that of arachidonic acid decreased. The percent ratio of n-3/n-6 fatty acid did not increase. Treatment with EPA-E did not improve the post-ischemic contractile function, but attenuated the ischemia/reperfusion-induced release of prostaglandins during reperfusion. Treatment with EPA-E preserved a better morphological appearance of the cardiomyocytes subjected to hypoxia/reoxygenation. The results suggest that the mechanisms responsible for cytoprotective effects of hypoxic/reoxygenated cardiomyocytes or inhibition of metabolic alterations of the ischemic/reperfused heart by long-term EPA-E treatment did not contribute substantially to recovery of post-ischemic contractile dysfunction. The direct in vitro effects of EPA may play a role in the protection of the heart from ischemia/reperfusion or hypoxia/reoxygenation injury.

Ischemia/Reperfusion

PubMed Central

Kalogeris, Theodore; Baines, Christopher P.; Krenz, Maike; Korthuis, Ronald J.

2017-01-01

Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. PMID:28135002

Molecular mechanisms of liver ischemia reperfusion injury: Insights from transgenic knockout models

PubMed Central

Datta, Gourab; Fuller, Barry J; Davidson, Brian R

2013-01-01

Ischemia reperfusion injury is a major obstacle in liver resection and liver transplantation surgery. Understanding the mechanisms of liver ischemia reperfusion injury (IRI) and developing strategies to counteract this injury will therefore reduce acute complications in hepatic resection and transplantation, as well as expanding the potential pool of usable donor grafts. The initial liver injury is initiated by reactive oxygen species which cause direct cellular injury and also activate a cascade of molecular mediators leading to microvascular changes, increased apoptosis and acute inflammatory changes with increased hepatocyte necrosis. Some adaptive pathways are activated during reperfusion that reduce the reperfusion injury. IRI involves a complex interplay between neutrophils, natural killer T-cells cells, CD4+ T cell subtypes, cytokines, nitric oxide synthases, haem oxygenase-1, survival kinases such as the signal transducer and activator of transcription, Phosphatidylinositol 3-kinases/Akt and nuclear factor κβ pathways. Transgenic animals, particularly genetic knockout models, have become a powerful tool at elucidating mechanisms of liver ischaemia reperfusion injury and are complementary to pharmacological studies. Targeted disruption of the protein at the genetic level is more specific and maintained than pharmacological inhibitors or stimulants of the same protein. This article reviews the evidence from knockout models of liver IRI about the cellular and molecular mechanisms underlying liver IRI. PMID:23555157

Glycine ameliorates lung reperfusion injury after cold preservation in an ex vivo rat lung model.

PubMed

Omasa, Mitsugu; Fukuse, Tatsuo; Toyokuni, Shinya; Mizutani, Yoichi; Yoshida, Hiroshi; Ikeyama, Kazuyuki; Hasegawa, Seiki; Wada, Hiromi

2003-03-15

The role of glycine has not been investigated in lung ischemia-reperfusion injury after cold preservation. Furthermore, the role of apoptosis after reperfusion following cold preservation has not been fully understood. Lewis rats were divided into three groups (n=6 each). In the GLY(-) and GLY(+) groups, isolated lungs were preserved for 15 hr at 4 degrees C after a pulmonary artery (PA) flush using our previously developed preservation solution (ET-K; extracellular-type trehalose containing Kyoto), with or without the addition of glycine (5 mM). In the Fresh group, isolated lungs were reperfused immediately after a PA flush with ET-K. They were reperfused for 60 min with an ex vivo perfusion model. Pulmonary function, oxidative stress, apoptosis, and tumor necrosis factor (TNF)-alpha expression were assessed after reperfusion. Shunt fraction and peak inspiratory pressure after reperfusion in the GLY(-) group were significantly higher than those in the GLY(+) and Fresh groups. Oxidative damage and apoptosis in the alveolar epithelial cells of the GLY(-) group, assessed by immunohistochemical staining and quantification of 8-hydroxy-2'-deoxyguanosine and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling method, were significantly higher than those of the GLY(+) and Fresh groups. There were correlations among shunt fraction, oxidative damage, and apoptosis. There was no expression of TNF-alpha messenger RNA in all groups evaluated by the reverse transcription-polymerase chain reaction. Glycine attenuates ischemia/reperfusion injury after cold preservation by reducing oxidative damage and suppressing apoptosis independent of TNF-alpha in this model. The suppression of apoptosis might ameliorate lung function after reperfusion.

Activation of the Nrf2 defense pathway contributes to neuroprotective effects of phloretin on oxidative stress injury after cerebral ischemia/reperfusion in rats.

PubMed

Liu, Yu; Zhang, Lei; Liang, Jiangjiu

2015-04-15

Oxidative stress is considered a major contributing factor in cerebral ischemia/reperfusion injury. Phloretin, a dihydrochalcone belonging to the flavonoid family, is particularly rich in apples and apple-derived products. A large body of evidence demonstrates that phloretin exhibits anti-oxidant properties, and phloretin has potential implications for treating oxidative stress injuries in cerebral ischemia/reperfusion. Therefore, the neuroprotective and antioxidant effects of phloretin against ischemia/reperfusion injury, as well as related probable mechanisms, were investigated. The cerebral ischemic/reperfusion injury model was reproduced in male Sprague-Dawley rats through middle cerebral artery occlusion. At 24h after reperfusion, neurological score, infarct volume, and brain water content were assessed. Oxidative stress was evaluated by superoxide dismutases (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) levels. Nrf2 expression was measured by RT-PCR and western blot. Consequently, results showed that phloretin pretreatment for 14days significantly reduced infarct volume and brain edema, and ameliorated neurological scores in focal cerebral ischemia/reperfusion rats. SOD, GSH and GSH-Px activities were greatly decreased, and MDA levels significantly increased after ischemia/reperfusion injury. However, phloretin pretreatment dramatically suppressed these oxidative stress processes. Furthermore, phloretin upregulated Nrf2 mRNA and protein expression of in ischemia/reperfusion brain tissue. Taken together, phloretin exhibited neuroprotective effects in cerebral ischemia/reperfusion, and the mechanisms are associated with oxidative stress inhibition and Nrf2 defense pathway activation. Copyright © 2015 Elsevier B.V. All rights reserved.

Reperfusion therapy in ST-segment elevation myocardial infarction in the Veteran Administration Caribbean Healthcare System; search for improvement.

PubMed

Escabí-Mendoza, José

2008-01-01

Patients that present with acute STEMI have proven morbidity and mortality benefit from early reperfusion therapy. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend either fibrinolytic therapy within 30 minutes or a primary percutaneous coronary intervention (PPCI) within 90 minutes of patients arrival to the Emergency Department. Despite these recommendations, some patients do not receive reperfusion therapy and less than half receive it on time. Describe and analyze our reperfusion therapy performance in patients presenting with acute ST segment elevation myocardial infarct (STEMI) in the Veteran Administration Caribbean Healthcare System (VACHS), and determine potential causes for reperfusion therapy delays and develop strategies and a tailored algorithm according to our clinical findings and available institutional resources. Retrospective analysis of patients admitted to the VACHS with a discharge diagnosis of STEMI, from 01/01/2007 until 04/10/2008. A total of 55 patients met inclusion criteria for STEMI diagnosis. Of these, only 30 patients had active indication for reperfusion therapy. Reperfusion therapy was given in 97% of the cases, 69% with PPCI and 31% with fibrinolytic therapy (tenecteplase). In general the selection of reperfusion therapy seemed adherent to ACC/AHA STEMI guidelines. The reperfusion time goal was superior with thrombolytic therapy compared to PPCI, with 43% and 15% respectively. PPCI performed off regular tour of duty was significantly delayed compared to regular day shift, with a mean time of 221 and 113 minutes respectively (p=0.027). Most of the patients presenting with STEMI to the VACHS undergo reperfusion therapy. PPCI was the most frequent selected reperfusion approach. The PPCI time goal was infrequently met. The most significant cause for PPCI delay was related to performance off regular tour of duty. These finding support the implementation of a tailored STEMI reperfusion algorithm

Cardioprotection by modulation of mitochondrial respiration during ischemia–reperfusion: Role of apoptosis-inducing factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Aijun; Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030; Szczepanek, Karol

Highlights: •Blockade of electron transport prevents the loss of AIF from mitochondria during IR. •Blockade of electron transport decreases caspase-independent cell death during IR. •Mitochondrial AIF content is down-regulated in Harlequin mice. •Blockade of electron transport protects Harlequin mouse hearts during IR. •Amobarbital protection is partially dependent on mitochondrial AIF content. -- Abstract: The transient, reversible blockade of electron transport (BET) during ischemia or at the onset of reperfusion protects mitochondria and decreases cardiac injury. Apoptosis inducing factor (AIF) is located within the mitochondrial intermembrane space. A release of AIF from mitochondria into cytosol and nucleus triggers caspase-independent cell death.more » We asked if BET prevents the loss of AIF from mitochondria as a mechanism of protection in the buffer perfused heart. BET during ischemia with amobarbital, a rapidly reversible inhibitor of mitochondrial complex I, attenuated a release of AIF from mitochondria into cytosol, in turn decreasing the formation of cleaved and activated PARP-1. These results suggest that BET-mediated protection may occur through prevention of the loss of AIF from mitochondria during ischemia–reperfusion. In order to further clarify the role of mitochondrial AIF in BET-mediated protection, Harlequin (Hq) mice, a genetic model with mitochondrial AIF deficiency, were used to test whether BET could still decrease cell injury in Hq mouse hearts during reperfusion. BET during ischemia protected Hq mouse hearts against ischemia–reperfusion injury and improved mitochondrial function in these hearts during reperfusion. Thus, cardiac injury can still be decreased in the presence of down-regulated mitochondrial AIF content. Taken together, BET during ischemia protects both hearts with normal mitochondrial AIF content and hearts with mitochondrial AIF deficiency. Although preservation of mitochondrial AIF content plays a key role

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury.

PubMed

Pachori, Alok S; Melo, Luis G; Hart, Melanie L; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D; Stahl, Gregory L; Pratt, Richard E; Dzau, Victor J

2004-08-17

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

PubMed Central

Pachori, Alok S.; Melo, Luis G.; Hart, Melanie L.; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D.; Stahl, Gregory L.; Pratt, Richard E.; Dzau, Victor J.

2004-01-01

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury. PMID:15302924

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

NASA Astrophysics Data System (ADS)

Pachori, Alok S.; Melo, Luis G.; Hart, Melanie L.; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D.; Stahl, Gregory L.; Pratt, Richard E.; Dzau, Victor J.

2004-08-01

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

Proteomics/phosphoproteomics of left ventricular biopsies from patients with surgical coronary revascularization and pigs with coronary occlusion/reperfusion: remote ischemic preconditioning.

PubMed

Gedik, Nilgün; Krüger, Marcus; Thielmann, Matthias; Kottenberg, Eva; Skyschally, Andreas; Frey, Ulrich H; Cario, Elke; Peters, Jürgen; Jakob, Heinz; Heusch, Gerd; Kleinbongard, Petra

2017-08-09

Remote ischemic preconditioning (RIPC) by repeated brief cycles of limb ischemia/reperfusion reduces myocardial ischemia/reperfusion injury. In left ventricular (LV) biopsies from patients undergoing coronary artery bypass grafting (CABG), only the activation of signal transducer and activator of transcription 5 was associated with RIPC's cardioprotection. We have now used an unbiased, non-hypothesis-driven proteomics and phosphoproteomics approach to analyze LV biopsies from patients undergoing CABG and from pigs undergoing coronary occlusion/reperfusion without (sham) and with RIPC. False discovery rate-based statistics identified a higher prostaglandin reductase 2 expression at early reperfusion with RIPC than with sham in patients. In pigs, the phosphorylation of 116 proteins was different between baseline and early reperfusion with RIPC and/or with sham. The identified proteins were not identical for patients and pigs, but in-silico pathway analysis of proteins with ≥2-fold higher expression/phosphorylation at early reperfusion with RIPC in comparison to sham revealed a relation to mitochondria and cytoskeleton in both species. Apart from limitations of the proteomics analysis per se, the small cohorts, the sampling/sample processing and the number of uncharacterized/unverifiable porcine proteins may have contributed to this largely unsatisfactory result.

The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion

PubMed Central

Ertracht, Offir; Liani, Esti; Bachner-Hinenzon, Noa; Bar-Am, Orit; Frolov, Luba; Ovcharenko, Elena; Awad, Huda; Blum, Shany; Barac, Yaron; Amit, Tamar; Adam, Dan; Youdim, Moussa; Binah, Ofer

2011-01-01

BACKGROUND AND PURPOSE Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S-enantiomer of rasagiline, an anti-Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats. EXPERIMENTAL APPROACH The model consisted of 30-min occlusion of the left anterior descending artery followed by 4 or 24 h reperfusion. In addition, we investigated the possible mechanisms of cardioprotection in H9c2 cells and neonatal rat ventricular myocytes (NRVM) exposed to oxidative stress induced by H2O2. KEY RESULTS TVP1022 (20 and 40 mg·kg−1) administered 5 min before reperfusion followed by an additional dose 4 h after reperfusion reduced the infarct size and attenuated the decline in ventricular function. TVP1022 also attenuated I/R-induced deterioration in cardiac mitochondrial integrity evaluated by mitochondrial swelling capacity. In vitro, using H9c2 cells and NRVM, TVP1022 attenuated both serum free- and H2O2-induced damage, preserved mitochondrial membrane potential and Bcl-2 levels, inhibited mitochondrial cytochrome c release and the increase in cleaved caspase 9 and 3 levels, and enhanced the phosphorylation of protein kinase C and glycogen synthase kinase-3β. CONCLUSIONS AND IMPLICATIONS TVP1022 provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage resulting from I/R injuries. PMID:21323905

Effect of aminoguanidine on sciatic functional index, oxidative stress, and rate of apoptosis in an experimental rat model of ischemia-reperfusion injury.

PubMed

Alipour, Mohsen; Mohsen, Alipour; Gadiri-Soufi, Farhad; Farhad, Gadiri Soufi; Jafari, Mohammad-Reza; Mohammad-Reza, Jafari

2014-12-01

This study was conducted to investigate the potential protective effects of aminoguanidine (AG) on sciatic functional index (SFI), oxidative stress status, and apoptosis index using a rat model of experimental sciatic nerve ischemia-reperfusion injury (I/R). Treatment groups received 150 mg AG/kg body mass, 24 h after the induction of ischemia. After reperfusion for 2, 4, 7, 14, and 28 days, we evaluated measured SFI, plasma antioxidant enzymes, total antioxidant capacity (TAC), malondialdehyde (MDA), and index of apoptosis. SFI was significantly improved on the 7th and 14th day of reperfusion in the AG-treated groups. AG treatment resulted in the significant reduction of MDA levels on the 7th and 14th day of reperfusion. TAC was only increased after 7 days of reperfusion compared with the untreated group. SOD activity was decreased in both the untreated and AG-treated groups by comparison with the control, but did not show a significant change. GPx activity decreased only after 7 days of reperfusion. The maximal rate of apoptosis occurred on the 7th day of reperfusion. Treatment with AG significantly reduced this enhancement. AG exhibits positive effects against sciatic nerve I/R injury, possibly in part because of the protective effects of AG against apoptosis and I/R-induced oxidative stress.

Osthole prevents cerebral ischemia-reperfusion injury via the Notch signaling pathway.

PubMed

Guan, Junhong; Wei, Xiangtai; Qu, Shengtao; Lv, Tao; Fu, Qiang; Yuan, Ye

2017-08-01

Stroke is a common cerebrovascular disease in aging populations, and constitutes the second highest principle cause of mortality and the principle cause of permanent disability, and ischemic stroke is the primary form. Osthole is a coumarin derivative extracted from the fruits of Cnidium monnieri (L.) Cusson. In this study, we established a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and found that MCAO/R caused cerebral infarction, hippocampus neuronal injury and apoptosis, and also activated the Notch 1 signaling pathway. However, treatment with osthole further enhanced the activity of Notch 1 signaling and reduced the cerebral infarction as well as the hippocampus neuronal injury and apoptosis induced by MCAO/R in a dose-dependent manner. The same results were observed in a primary neuronal oxygen glucose deficiency/reperfusion (OGD/R) model in vitro, and the effect of osthole could be blocked by an inhibitor of Notch 1 signaling, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine tert-butyl ester (DAPT). Therefore, we demonstrated that osthole injection prevented rat ischemia-reperfusion injury via activating the Notch 1 signaling pathway in vivo and in vitro in a dose-dependent manner, which may be significant for clinical treatment of ischemic stroke.

A vigilant, hypoxia-regulated heme oxygenase-1 gene vector in the heart limits cardiac injury after ischemia-reperfusion in vivo.

PubMed

Tang, Yao Liang; Qian, Keping; Zhang, Y Clare; Shen, Leping; Phillips, M Ian

2005-12-01

The effect of a cardiac specific, hypoxia-regulated, human heme oxygenase-1 (hHO-1) vector to provide cardioprotection from ischemia-reperfusion injury was assessed. When myocardial ischemia and reperfusion is asymptomatic, the damaging effects are cumulative and patients miss timely treatment. A gene therapy approach that expresses therapeutic genes only when ischemia is experienced is a desirable strategy. We have developed a cardiac-specific, hypoxia-regulated gene therapy "vigilant vector'' system that amplifies cardioprotective gene expression. Vigilant hHO-1 plasmids, LacZ plasmids, or saline (n = 40 per group) were injected into mouse heart 2 days in advance of ischemia-reperfusion injury. Animals were exposed to 60 minutes of ischemia followed by 24 hours of reperfusion. For that term (24 hours) effects, the protein levels of HO-1, inflammatory responses, apoptosis, and infarct size were determined. For long-term (3 week) effects, the left ventricular remodeling and recovery of cardiac function were assessed. Ischemia-reperfusion resulted in a timely overexpression of HO-1 protein. Infarct size at 24 hours after ischemia-reperfusion was significantly reduced in the HO-1-treated animals compared with the LacZ-treated group or saline-treated group (P < .001). The reduction of infarct size was accompanied by a decrease in lipid peroxidant activity, inflammatory cell infiltration, and proapoptotic protein level in ischemia-reperfusion-injured myocardium. The long-term study demonstrated that timely, hypoxia-induced HO-1 overexpression is beneficial in conserving cardiac function and attenuating left ventricle remodelling. The vigilant HO-1 vector provides a protective therapy in the heart for reducing cellular damage during ischemia-reperfusion injury and preserving heart function.

Cardiac Myocyte-specific Knock-out of Calcium-independent Phospholipase A2γ (iPLA2γ) Decreases Oxidized Fatty Acids during Ischemia/Reperfusion and Reduces Infarct Size *

PubMed Central

Moon, Sung Ho; Mancuso, David J.; Sims, Harold F.; Liu, Xinping; Nguyen, Annie L.; Yang, Kui; Guan, Shaoping; Dilthey, Beverly Gibson; Jenkins, Christopher M.; Weinheimer, Carla J.; Kovacs, Attila; Abendschein, Dana; Gross, Richard W.

2016-01-01

Calcium-independent phospholipase A2γ (iPLA2γ) is a mitochondrial enzyme that produces lipid second messengers that facilitate opening of the mitochondrial permeability transition pore (mPTP) and contribute to the production of oxidized fatty acids in myocardium. To specifically identify the roles of iPLA2γ in cardiac myocytes, we generated cardiac myocyte-specific iPLA2γ knock-out (CMiPLA2γKO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA2γKO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA2γKO mice demonstrated attenuated Ca2+-induced mPTP opening that could be rapidly restored by the addition of palmitate and substantially reduced production of oxidized polyunsaturated fatty acids (PUFAs). Furthermore, myocardial ischemia/reperfusion (I/R) in CMiPLA2γKO mice (30 min of ischemia followed by 30 min of reperfusion in vivo) dramatically decreased oxidized fatty acid production in the ischemic border zones. Moreover, CMiPLA2γKO mice subjected to 30 min of ischemia followed by 24 h of reperfusion in vivo developed substantially less cardiac necrosis in the area-at-risk in comparison with their WT littermates. Furthermore, we found that membrane depolarization in murine heart mitochondria was sensitized to Ca2+ by the presence of oxidized PUFAs. Because mitochondrial membrane depolarization and calcium are known to activate iPLA2γ, these results are consistent with salvage of myocardium after I/R by iPLA2γ loss of function through decreasing mPTP opening, diminishing production of proinflammatory oxidized fatty acids, and attenuating the deleterious effects of abrupt increases in calcium ion on membrane potential during reperfusion. PMID:27453526

Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial.

PubMed

Kloner, Robert A; Forman, Mervyn B; Gibbons, Raymond J; Ross, Allan M; Alexander, R Wayne; Stone, Gregg W

2006-10-01

The purpose of this analysis was to determine whether the efficacy of adenosine vs. placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II). Patients presenting with ST-segment elevation anterior AMI were randomized to receive placebo vs. adenosine (50 or 70 microg/kg/min) for 3 h starting within 15 min of reperfusion therapy. In the present post hoc hypothesis generating study, the results were stratified according to the timing of reperfusion, i.e. > or = or < the median 3.17 h, and by reperfusion modality. In patients receiving reperfusion < 3.17 h, adenosine compared with placebo significantly reduced 1-month mortality (5.2 vs. 9.2%, respectively, P = 0.014), 6-month mortality (7.3 vs. 11.2%, P = 0.033), and the occurrence of the primary 6-month composite clinical endpoint of death, in-hospital CHF, or rehospitalization for CHF at 6 months (12.0 vs. 17.2%, P = 0.022). Patients reperfused beyond 3 h did not benefit from adenosine. In this post hoc analysis, 3 h adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 h onset of evolving anterior ST-segment elevation AMI enhanced early and late survival, and reduced the composite clinical endpoint of death or CHF at 6 months.

Interrupted reperfusion reduces the activation of NADPH oxidase after cerebral I/R injury.

PubMed

Shen, Jia; Bai, Xiao-Yin; Qin, Yuan; Jin, Wei-Wei; Zhou, Jing-Yin; Zhou, Ji-Ping; Yan, Ying-Gang; Wang, Qiong; Bruce, Iain C; Chen, Jiang-Hua; Xia, Qiang

2011-06-15

Interrupted reperfusion reduces ischemia/reperfusion (I/R) injury. This study was designed to determine whether NADPH oxidase participates in the neural protection against global I/R injury after interrupted reperfusion. Mice were randomly divided into five groups: sham (sham-operated), I/R (20-min global I/R), RR (I/R+interrupted reperfusion), Apo (I/R+apocynin administration), and RR+Apo. Behavioral tests (pole test, beam walking, and Morris water maze) and Nissl staining were undertaken in all five groups; superoxide levels, expression of gp91(phox) and p47(phox), p47(phox) translocation, and Rac1 activation were measured in the sham, I/R, and RR groups. The motor coordination, bradykinesia, and spatial learning and memory, as well as the neuron survival rates, were better in the RR, Apo, and RR+Apo groups than in the I/R group. The NADPH oxidase-dependent superoxide levels, p47(phox) and gp91(phox) expression, p47(phox) translocation, and Rac1 activation were lower in the RR group than in the I/R group. In conclusion, the neural protective effect of interrupted reperfusion is at least partly mediated by decreasing the expression and assembly of NADPH oxidase and the levels of NADPH oxidase-derived superoxide. The most striking reduction Rac1-GTP in the RR group suggests that interrupted reperfusion also acts on the activation of assembled NADPH oxidase by reducing the availability of Rac1-GTP. Copyright © 2011 Elsevier Inc. All rights reserved.

Cardiac arrest: resuscitation and reperfusion.

PubMed

Patil, Kaustubha D; Halperin, Henry R; Becker, Lance B

2015-06-05

The modern treatment of cardiac arrest is an increasingly complex medical procedure with a rapidly changing array of therapeutic approaches designed to restore life to victims of sudden death. The 2 primary goals of providing artificial circulation and defibrillation to halt ventricular fibrillation remain of paramount importance for saving lives. They have undergone significant improvements in technology and dissemination into the community subsequent to their establishment 60 years ago. The evolution of artificial circulation includes efforts to optimize manual cardiopulmonary resuscitation, external mechanical cardiopulmonary resuscitation devices designed to augment circulation, and may soon advance further into the rapid deployment of specially designed internal emergency cardiopulmonary bypass devices. The development of defibrillation technologies has progressed from bulky internal defibrillators paddles applied directly to the heart, to manually controlled external defibrillators, to automatic external defibrillators that can now be obtained over-the-counter for widespread use in the community or home. But the modern treatment of cardiac arrest now involves more than merely providing circulation and defibrillation. As suggested by a 3-phase model of treatment, newer approaches targeting patients who have had a more prolonged cardiac arrest include treatment of the metabolic phase of cardiac arrest with therapeutic hypothermia, agents to treat or prevent reperfusion injury, new strategies specifically focused on pulseless electric activity, which is the presenting rhythm in at least one third of cardiac arrests, and aggressive post resuscitation care. There are discoveries at the cellular and molecular level about ischemia and reperfusion pathobiology that may be translated into future new therapies. On the near horizon is the combination of advanced cardiopulmonary bypass plus a cocktail of multiple agents targeted at restoration of normal metabolism and

The cardioprotective efficacy of TVP1022 against ischemia/reperfusion injury and cardiac remodeling in rats.

PubMed

Malka, Assaf; Ertracht, Offir; Bachner-Hinenzon, Noa; Reiter, Irina; Binah, Ofer

2016-12-01

Following acute myocardial infarction (MI), early and successful reperfusion is the most effective strategy for reducing infarct size and improving the clinical outcome. However, immediate restoration of blood flow to the ischemic zone results in myocardial damage, defined as "reperfusion-injury". Whereas we previously reported that TVP1022 (the S-isomer of rasagiline, FDA-approved anti-Parkinson drug) decreased infarct size 24 h post ischemia reperfusion (I/R) in rats, in this study we investigated the chronic cardioprotective efficacy of TVP1022 14 days post-I/R. To simulate the clinical settings of acute MI followed by reperfusion therapy, we employed a rat model of left anterior descending artery occlusion for 30 min followed by reperfusion and a follow-up for 14 days. TVP1022 was initially administered postocclusion-prereperfusion, followed by chronic daily administrations. Cardiac performance and remodeling were evaluated using customary and advanced echocardiographic methods, hemodynamic measurements by Millar Mikro-Tip ® catheter, and histopathological techniques. TVP1022 administration markedly decreased the remodeling process as illustrated by attenuation of left ventricular enlargement and cardiac hypertrophy (both at the whole heart and the cellular level). Furthermore, TVP1022 inhibited cardiac fibrosis and reduced ventricular BNP levels. Functionally, TVP1022 treatment preserved cardiac wall motion. Specifically, the echocardiographic and most of the direct hemodynamic measures were pronouncedly improved by TVP1022. Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R model.

Hypoglycemia Prevents Increase in Lactic Acidosis During Reperfusion After Temporary Cerebral Ischemia in Rats

PubMed Central

Sappey-Marinier, Dominique; Chileuitt, Laureano; Weiner, Michael W.; Faden, Alan I.; Weinstein, Philip R.

2009-01-01

Sequential 31P and 1H MRS was used to measure cerebral phosphate metabolites, intracellular pH, and lactate in normoglycemic and hypoglycemic rats during 30 min of complete cerebral ischemia and 5.5 h of reperfusion. These results were correlated with brain levels of free fatty acids (FFAs), excitatory amino acids, cations, and water content at death. The lactate/N-acetyl aspartate ratio was not significantly different between groups before or during occlusion. During reperfusion, the ratio was higher in normoglycemic rats from 3 to 85 min (p≤ 0.05), and recovery time was faster in hypoglycemic rats (29 vs 45 min; p = 0.04), suggesting reduced lactate production and faster recovery of aerobic metabolism. During occlusion, significant but comparable decrease of intracellular pH occurred in each group. Intracellular pH was higher in hypoglycemic rats at 140 min and 260 min of reperfusion. Water content, Na and K+ concentrations, and FFA and excitatory amino acid levels were not significantly different between groups, but hypoglycemic rats had less depletion of levels of Mg2+ (p=0.011). These results show that hypoglycemia has a limited but potentially beneficial effect on postischemic lactic acidosis. PMID:8771092

Inhalation of Carbon Monoxide Reduces Skeletal Muscle Injury Following Hind Limb Ischemia Reperfusion Injury in Mice

PubMed Central

Patel, Rajendra; Albadawi, Hassan; Steudel, Wolfgang; Hashmi, Faraz F.; Kang, Jeanwan; Yoo, Hyung-Jin; Watkins, Michael T.

2011-01-01

Introduction The purpose of this study was to determine if inhaled carbon monoxide (CO) can ameliorate skeletal muscle injury, modulate endogenous heme oxygenase-1 (HO) expression, improve indices of tissue integrity and inflammation following hind limb ischemia reperfusion(IR). Methods C57BL6 mice inhaling CO (250ppm) or room air were subjected to 1.5 hrs of ischemia followed by limb reperfusion for either 3 or 6 hours (total treatment time of 4.5 or 7.5 hrs). After the initial period of reperfusion, all mice breathed only room air until 24 hours after the onset of ischemia. Mice were sacrificed at either the end of CO treatment or at 24 hours reperfusion. Skeletal muscle was subjected to histologic and biochemical analysis. Results CO treatment for 7.5 hours protected skeletal muscle from histologic and structural evidence of skeletal muscle injury. Serum and tissue cytokines were significantly reduced (p<0.05) in mice treated with CO for 7.5 hours. Tubulin, Heme Oxygenase, and ATP levels were higher in CO treated mice. Conclusions Inhaled CO protected muscle from structural injury and energy depletion following IR. PMID:22450026

Prophylactic Treatment with Cerium Oxide Nanoparticles Attenuate Hepatic Ischemia Reperfusion Injury in Sprague Dawley Rats.

PubMed

Manne, Nandini D P K; Arvapalli, Ravikumar; Graffeo, Vincent A; Bandarupalli, Venkata V K; Shokuhfar, Tolou; Patel, Sweetu; Rice, Kevin M; Ginjupalli, Gautam Kumar; Blough, Eric R

2017-01-01

Hepatic ischemia reperfusion is one the main causes for graft failure following transplantation. Although, the molecular events that lead to hepatic failure following ischemia reperfusion (IR) are diverse and complex, previous studies have shown that excessive formation of reactive oxygen species (ROS) are responsible for hepatic IR injury. Cerium oxide (CeO2) nanoparticles have been previously shown to act as an anti-oxidant and anti-inflammatory agent. Here, we evaluated the protective effects of CeO2 nanoparticles on hepatic ischemia reperfusion injury. Male Sprague Dawley rats were randomly assigned to one of the four groups: Control, CeO2 nanoparticle only, hepatic ischemia reperfusion (IR) group and hepatic ischemia reperfusion (IR) plus CeO2 nanoparticle group (IR+ CeO2). Partial warm hepatic ischemia was induced in left lateral and median lobes for 1h, followed by 6h of reperfusion. Animals were sacrificed after 6h of reperfusion and blood and tissue samples were collected and processed for various biochemical experiments. Prophylactic treatment with CeO2 nanoparticles (0.5mg/kg i.v (IR+CeO2 group)) 1 hour prior to hepatic ischemia and subsequent reperfusion injury lead to a decrease in serum levels of alanine aminotransaminase and lactate dehydrogenase at 6 hours after reperfusion. These changes were accompanied by significant decrease in hepatocyte necrosis along with reduction in several serum inflammatory markers such as macrophage derived chemokine, macrophage inflammatory protein-2, KC/GRO, myoglobin and plasminogen activator inhibitor-1. However, immunoblotting demonstrated no significant changes in the levels of apoptosis related protein markers such as bax, bcl2 and caspase 3 in IR and IR+ CeO2 groups at 6 hours suggesting necrosis as the main pathway for hepatocyte death. Taken together, these data suggest that CeO2 nanoparticles attenuate IR induced cell death and can be used as a prophylactic agent to prevent hepatic injury associated with graft

Intraperitoneal administration of apigenin in liver ischemia/reperfusion injury protective effects.

PubMed

Tsaroucha, Alexandra K; Tsiaousidou, Anastasia; Ouzounidis, Nikolaos; Tsalkidou, Evanthia; Lambropoulou, Maria; Giakoustidis, Dimitrios; Chatzaki, Ekaterini; Simopoulos, Constantinos

2016-11-01

Hepatic injury caused by ischemia/reperfusion (I/R) is a clinical problem associated with major liver surgery. Among other flavonoids, apigenin has shown a promising effect on I/R cases. In this study, we have investigated the effects of apigenin after liver I/R injury in rats. Forty eight rats were randomized into the following eight groups: (1) Control-sham group: rats subjected to the surgical procedure, except for liver I/R; (2) DMSO group: rats subjected to surgery, except for liver I/R given the apigenin solvent dimethyl-sulfoxide intraperitoneally; (3) C60 group; (4) C120 group; (5) C240 group: rats underwent liver ischemia for 45 min followed by reperfusion for 60 min, 120 min, and 240 min; (6) AP60 group; (7) AP120 group; (8) AP240 group: rats underwent liver ischemia for 45 min, and then given apigenin (5 mg) intraperitoneally followed by reperfusion for 60 min, 120 min, and 240 min. Reverse transcription polymerase chain reaction was performed on liver tissues to measure BCL-2/BAX expression, enzyme-linked immunosorbent assay to measure M30/M65 and ICAM-1. Immunohistochemistry was used to identify M30 biomarker in liver tissues. Quantitative variables were tested by Kolmogorov-Smirnov test, repeated measures analysis of variance/Friedman test. Gene levels were assessed by Student's t-test/Mann-Whitney U-test. BCL-2 levels were significantly higher in I/R apigenin groups than in I/R control groups. BAX levels were lower in the AP240 group than in C240 group. Prolongation of reperfusion resulted in increased activation of M30. ICAM-1 levels were lower in the AP240 group than in C240 group. Apigenin seems to inhibit the process of apoptosis and ameliorate the hepatic I/R injury.

Independent cellular effects of cold ischemia and reperfusion: experimental molecular study.

PubMed

Lledó-García, E; Humanes-Sánchez, B; Mojena-Sánchez, M; Rodrígez, J C J; Hernández-Fernández, C; Tejedor-Jorge, A; Fernández, A L

2013-04-01

There is less information available on cell cultures on the exclusive effects of either duration of cold ischemia (CI) or rewarming-reperfusion in the kidney subjected to initial warm ischemia (WI). Therefore, the goals of our work were: (1) to evaluate the consequences on tubular cellular viability of different durations of CI on a kidney after an initial period of WI, and (2) to analyze the additional effect on tubular cell viability of rewarming of the same kidney. Sixteen mini-pig were used. All the animals were performed a right nephrectomy after 45-minute occlusion of the vascular pedicle. The kidneys were then divided into 2 groups (phase 1): cold storage in university of wisconsin (UW) solution for 3 hours (group A, n = 8) at 4°C, or cold storage in UW for 12 hours (group B, n = 8) at 4°C. Four organs of group A and four organs of group B were autotrasplanted (AT) and reperfused for 1 hour (phase 2). Nephrectomy was finally done. Biopsies were taken from all groups to perform cultures of proximal tubule epithelium cells. The biopsies were subjected to studies of cellular morphological viability (contrast phase microscopy [CPM]) and quantitative (confluence cell [CC]) parameters. Phase of pure CI effects (phase 1): Both CC rate and CPM parameters were significantly lower in group B compared with group A, where cell activity reached almost normal results. Phase of CI + AT (phase 2): At produced additional harmful effects in cell cultures compared with those obtained in phase 1, more evident in group B cells. The presence of cold storage followed by rewarming-reperfusion induces independent and cumulative detrimental effects in viability of renal proximal tubule cells. CI periods ≤ 3 hours may ameliorate the injuries secondary to reperfusion in comparison with longer CI periods. Copyright © 2013 Elsevier Inc. All rights reserved.

Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury.

PubMed

Wang, Yanzhe; He, Zhiyi; Deng, Shumin

2016-01-01

Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance. The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed. UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect. UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway

Cross-linked polyhemoglobin-superoxide dismutase-catalase supplies oxygen without causing blood-brain barrier disruption or brain edema in a rat model of transient global brain ischemia-reperfusion.

PubMed

Powanda, D Douglas; Chang, Thomas M S

2002-01-01

In strokes, myocardial infarctions, severe sustained hemorrhagic shock, and donor organs, inadequate blood supply results in lack of oxygen to the tissue (ischemia). If ischemia is sustained, reperfusion with the needed oxygen can result in tissue injury (ischemia-reperfusion injury) due to formation of reactive oxygen species. We are studying an oxygen-carrying solution with anitoxidant activity formed by cross-linking hemoglobin, superoxide dismutase, and catalase to form PolyHb-SOD-CAT. The present report studies its effect on the blood-brain barrier and cerebral edema when used in a transient global brain ischemia-reperfusion rat model. We compare this solution to sham-control, oxygenated saline, stroma-free hemoglobin (SF-Hb), polymerized hemoglobin (PolyHb), and a mixture of SF-Hb, SOD, and CAT in free solution. The results show that the cross-linked PolyHb-SOD-CAT solution, unlike the other solutions, can supply oxygen to ischemic tissues without causing reperfusion injury in the transient global brain ischemia-reperfusion model.

Vinpocetine protects liver against ischemia-reperfusion injury.

PubMed

Zaki, Hala Fahmy; Abdelsalam, Rania Mohsen

2013-12-01

Hepatic ischemia-reperfusion (IR) injury is a clinical problem that leads to cellular damage and organ dysfunction mediated mainly via production of reactive oxygen species and inflammatory cytokines. Vinpocetine has long been used in cerebrovascular disorders. This study aimed to explore the protective effect of vinpocetine in IR injury to the liver. Ischemia was induced in rats by clamping the common hepatic artery and portal vein for 30 min followed by 30 min of reperfusion. Serum transaminases and liver lactate dehydrogenase (LDH) activities, liver inflammatory cytokines, oxidative stress biomarkers, and liver histopathology were assessed. IR resulted in marked histopathology changes in liver tissues coupled with elevations in serum transaminases and liver LDH activities. IR also increased the production of liver lipid peroxides, nitric oxide, and inflammatory cytokines interleukin-1β and interleukin-6, in parallel with a reduction in reduced glutathione and interleukin-10 in the liver. Pretreatment with vinpocetine protected against liver IR-induced injury, in a dose-dependent manner, as evidenced by the attenuation of oxidative stress as well as inflammatory and liver injury biomarkers. The effects of vinpocetine were comparable with that of curcumin, a natural antioxidant, and could be attributed to its antioxidant and anti-inflammatory properties.

[Ishemic-reperfusion syndrome prophylaxis in general hypothermia in experiment].

PubMed

Zubkov, V I; Khytryĭ, H P; Luk'ianchuk, V D; Shalamaĭ, A S

2009-05-01

The influence of general supercooling on rats were studied. The action of corvitin and pentoxiphillin on the prooxidant-antioxidant homeostasis for conditions of general supercooling were analysed. On the based of investigations results analysis of lipids peroxide oxidation indexes and antioxidant protection system in animals it were established, that corvitin in difference of pentoxiphillin give more significant protectory effect in conditions of ishemic-reperfusion syndrome.

Manipulations of core temperatures in ischemia-reperfusion lung injury in rabbits.

PubMed

Chang, Hung; Huang, Kun-Lun; Li, Min-Hui; Hsu, Ching-Wang; Tsai, Shih-Hung; Chu, Shi-Jye

2008-01-01

The present study was designed to determine the effect of various core temperatures on acute lung injury induced by ischemia-reperfusion (I/R) in our isolated rabbit lung model. Typical acute lung injury was successfully induced by 30 min of ischemia followed by 90 min of reperfusion observation. The I/R elicited a significant increase in pulmonary arterial pressure, microvascular permeability (measured by using the capillary filtration coefficient, Kfc), Delta Kfc ratio, lung weight gain and the protein concentration of the bronchoalveolar lavage fluid. Mild hypothermia significantly attenuated acute lung injury induced by I/R, all parameters having decreased significantly (p<0.05); conversely, mild hyperthermia did not further exacerbate acute lung injury. These experimental data suggest that mild hypothermia significantly ameliorated acute lung injury induced by ischemia-reperfusion in rabbits.

Effects of Chronic and Acute Zinc Supplementation on Myocardial Ischemia-Reperfusion Injury in Rats.

PubMed

Ozyıldırım, Serhan; Baltaci, Abdulkerim Kasim; Sahna, Engin; Mogulkoc, Rasim

2017-07-01

The present study aims to explore the effects of chronic and acute zinc sulfate supplementation on myocardial ischemia-reperfusion injury in rats. The study registered 50 adult male rats which were divided into five groups in equal numbers as follows: group 1, normal control; group 2, sham; group 3, myocardial ischemia reperfusion (My/IR): the group which was fed on a normal diet and in which myocardial I/R was induced; group 4, myocardial ischemia reperfusion + chronic zinc: (5 mg/kg i.p. zinc sulfate for 15 days); and group 5, myocardial ischemia reperfusion + acute zinc: the group which was administered 15 mg/kg i.p. zinc sulfate an hour before the operation and in which myocardial I/R was induced. The collected blood and cardiac tissue samples were analyzed using spectrophotometric method to determine levels of MDA, as an indicator of tissue injury, and GSH, as an indicator of antioxidant activity. The highest plasma and heart tissue MDA levels were measured in group 3 (p < 0.05). Group 5 had lower MDA values than group 3, while group 4 had significantly lower MDA values than groups 3 and 5 (p < 0.05). The highest erythrocyte GSH values were found in group 4 (p < 0.05). Erythrocyte GSH values in group 5 were higher than those in group 3 (p < 0.05). The highest GSH values in heart tissue were measured in group 4 (p < 0.05). The results of the study reveal that the antioxidant activity inhibited by elevated oxidative stress in heart ischemia reperfusion in rats is restored partially by acute zinc administration and markedly by chronic zinc supplementation.

Erdosteine and ebselen as useful agents in intestinal ischemia/reperfusion injury.

PubMed

Tunc, Turan; Uysal, Bulent; Atabek, Cuneyt; Kesik, Vural; Caliskan, Bahadir; Oztas, Emin; Ersoz, Nail; Oter, Sukru; Guven, Ahmet

2009-08-01

Reactive oxygen and nitrogen species generated during reperfusion of the tissue are characteristic of ischemia/reperfusion (I/R) injury. The purpose of the present study was to investigate whether erdosteine and ebselen, molecules with antioxidant properties and peroxynitrite scavenging capability, respectively, can reduce oxidative stress and histological damage in the rat small bowel subjected to mesenteric I/R injury. Forty Sprague-Dawley rats were divided into five groups equally: sham, I/R, I/R plus erdosteine, I/R plus ebselen, and I/R plus erdosteine and ebselen. Intestinal ischemia for 45 min and reperfusion for 3 d were carried out. Ileal specimens were obtained to determine the tissue levels of malondialdehide (MDA), protein carbonyl content (PCC), superoxide dismutase (SOD), glutathione peroxidase (GPx), nitrite/nitrate (NO(x)) level and histological changes. Intestinal I/R resulted in increased tissue MDA, PCC, and NO(x) levels and decreased SOD and GPx activities. Both erdosteine and ebselen alone significantly decreased MDA, PCC, and NO(x) levels and increased antioxidant enzymes activities, but all values were different from control. These changes almost returned to control values in the group treated with erdostein and ebselen. Histopathologically, the intestinal injury in rats treated with erdosteine and ebselen as well as combination were less than I/R group. Both erdosteine and ebselen were able to attenuate I/R injury of the intestine via inhibition of lipid peroxidation and protein oxidation, maintenance of antioxidant, and free radical scavenger properties. Nevertheless, combination treatment showed more promising results, suggesting that scavenging peroxynitrite nearby antioxidant activity is important in preventing intestinal I/R injury.

Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy

PubMed Central

Jin, Hang; Sun, Xin; Huang, Shuo; Zhang, Fu-Liang; Guo, Zhen-Ni

2018-01-01

Acute ischemic stroke is a common cause of morbidity and mortality worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes. Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury) has been found to play a key role in the process. Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death. Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier. In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage. This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage. PMID:29770166

Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts.

PubMed

Yang, Xi-Ming; Philipp, Sebastian; Downey, James M; Cohen, Michael V

2006-07-01

We investigated whether atrial natriuretic peptide (ANP) given just prior to reperfusion reduces infarction in rabbit hearts and whether protection is related to activation of protein kinase G (PKG). Isolated rabbit hearts were subjected to a 30-min period of regional ischemia; treated hearts received a 20-min infusion of ANP (0.1 microM) starting 5 min before 2 h of reperfusion. ANP infusion decreased infarction from 31.5+/-2.4% of the risk zone in untreated hearts to 12.5+/-2.0% (P<0.001). To explore mechanisms of protection ischemic hearts were treated simultaneously with ANP and isatin, a blocker of the natriuretic peptide receptor, shortly before reperfusion. ANP's protective effect was aborted (36.8+/-2.9% infarction). There is no acceptable blocker of protein kinase G that can be used in intact organs. However, 8-(4-chlorophenylthio)-guanosine 3', 5'-cyclic monophosphate (10 microM), a cell-permeable cGMP analog that directly activates PKG, was infused from 5 min before to 15 min after reperfusion. The PKG activator mimicked ANP's protection with only 18.2+/-3.6% infarction (P<0.001). 5-Hydroxyde-canoate (5-HD), a putative mitochondrial KATP channel (mKATP) inhibitor, abrogated ANP's protection (34.4+/-2.6% infarction). Unexpectedly, 1H-[1,2,4]oxadiazole- [4,3-a]quinoxalin-1-one (ODQ), a blocker of soluble guanylyl cyclase also prevented ANP's infarct-sparing effect. It is unclear whether this observation implicated participation of soluble guanylyl cyclase in the mechanism or simply a lack of selectivity of ODQ. Finally the reperfusion injury salvage kinases (RISK), phosphatidylinositol 3-kinase and extracellular signal-regulated kinase, were implicated in ANP's mechanism since either wortmannin or PD98059 infused at reperfusion prevented ANP's infarct-sparing effect. ANP administered just prior to reperfusion protects hearts against infarction, likely by activation of PKG, opening of mKATP, and stimulation of downstream kinases.

Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema

PubMed Central

Zanotti, Giorgio; Casiraghi, Monica; Abano, John B.; Tatreau, Jason R.; Sevala, Mayura; Berlin, Hilary; Smyth, Susan; Funkhouser, William K.; Burridge, Keith; Randell, Scott H.; Egan, Thomas M.

2009-01-01

Toll-like receptors (TLRs) of the innate immune system contribute to noninfectious inflammatory processes. We employed a murine model of hilar clamping (1 h) with reperfusion times between 15 min and 3 h in TLR4-sufficient (C3H/OuJ) and TLR4-deficient (C3H/HeJ) anesthetized mice with additional studies in chimeric and myeloid differentiation factor 88 (MyD88)- and TLR4-deficient mice to determine the role of TLR4 in lung ischemia-reperfusion injury. Human pulmonary microvascular endothelial monolayers were subjected to simulated warm ischemia and reperfusion with and without CRX-526, a competitive TLR4 inhibitor. Functional TLR4 solely on pulmonary parenchymal cells, not bone marrow-derived cells, mediates early lung edema following ischemia-reperfusion independent of MyD88. Activation of MAPKs and NF-κB was significantly blunted and/or delayed in lungs of TLR4-deficient mice as a consequence of ischemia-reperfusion injury, but edema development appeared to be independent of activation of these signaling pathways. Pretreatment with a competitive TLR4 inhibitor prevented edema in vivo and reduced actin cytoskeletal rearrangement and gap formation in pulmonary microvascular endothelial monolayers subjected to simulated warm ischemia and reperfusion. In addition to its well-accepted role to alter gene transcription, functioning TLR4 on pulmonary parenchymal cells plays a key role in very early and profound pulmonary edema in murine lung ischemia-reperfusion injury. This may be due to a novel mechanism: regulation of endothelial cell cytoskeleton affecting microvascular endothelial cell permeability. PMID:19376887

4‑Phenylbutyrate protects rat skin flaps against ischemia‑reperfusion injury and apoptosis by inhibiting endoplasmic reticulum stress.

PubMed

Yue, Zhen-Shuang; Zeng, Lin-Ru; Quan, Ren-Fu; Tang, Yang-Hua; Zheng, Wen-Jie; Qu, Gang; Xu, Can-Da; Zhu, Fang-Bing; Huang, Zhong-Ming

2016-02-01

4‑phenylbutyrate (4‑PBA) is a low molecular weight fatty acid, which has been demonstrated to regulate endoplasmic reticulum (ER) stress. ER stress‑induced cell apoptosis has an important role in skin flap ischemia; however, a pharmacological approach for treating ischemia‑induced ER dysfunction has yet to be reported. In the present study, the effects of 4‑PBA‑induced ER stress inhibition on ischemia‑reperfusion injury were investigated in the skin flap of rats, and transcriptional regulation was examined. 4‑PBA attenuated ischemia‑reperfusion injury and inhibited cell apoptosis in the skin flap. Furthermore, 4‑PBA reversed the increased expression levels of two ER stress markers: CCAAT/enhancer-binding protein‑homologous protein and glucose‑regulated protein 78. These results suggested that 4‑PBA was able to protect rat skin flaps against ischemia‑reperfusion injury and apoptosis by inhibiting ER stress marker expression and ER stress‑mediated apoptosis. The beneficial effects of 4‑PBA may prove useful in the treatment of skin flap ischemia‑reperfusion injury.

Effects of dexmedetomidine on microregional O2 balance during reperfusion after focal cerebral ischemia.

PubMed

Chi, Oak Z; Grayson, Jeremy; Barsoum, Sylviana; Liu, Xia; Dinani, Aliraza; Weiss, Harvey R

2015-01-01

This study was performed to determine whether there is an association between microregional O2 balance and neuronal survival in cerebral ischemia-reperfusion using dexmedetomidine, an α2-adrenoreceptor agonist and a sedative. Rats were subjected to 1 hour middle cerebral artery occlusion and a 2-hour reperfusion. During reperfusion, normal saline (n = 14) or dexmedetomidine 1 μg/kg/minute (n = 14) was infused intravenously. At 2 hours of reperfusion, regional cerebral blood flow using (14)C-iodoantipyrine autoradiography, microregional arterial and venous (20-60 μm in diameter) O2 saturation (SvO2) using cryomicrospectrophotometry, and the size of cortical infarction were determined. Ischemia-reperfusion decreased microregional SvO2 (52.9 ± 3.7% vs. 61.1 ± .6%, P < .005) with increased variation or heterogeneity (P < .0001) with similar regional cerebral blood flow and O2 consumption. Dexmedetomidine during reperfusion decreased the heterogeneity of SvO2 that was analyzed with an analysis of variance (P < .01) and reported as coefficient of variation (100 × standard deviation/Mean) (11.8 vs. 16.4). The number of veins with O2 saturation less than 50% decreased with dexmedetomidine (13/80 vs. 27/81, P < .01). The percentage of cortical infarct in total cortex was smaller with dexmedetomidine (8.3 ± 2.2% vs. 12.6 ± 1.5%, P < .005). In the cerebral ischemic reperfused cortex, dexmedetomidine decreased the heterogeneity of SvO2 and the number of small veins with low O2 saturation suggesting improved microregional O2 supply/consumption balance. The improvement was accompanied by the reduced size of cortical infarction. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Silencing of long noncoding RNA AK139328 attenuates ischemia/reperfusion injury in mouse livers.

PubMed

Chen, Zhenzhen; Jia, Shi; Li, Danhua; Cai, Junyan; Tu, Jian; Geng, Bin; Guan, Youfei; Cui, Qinghua; Yang, Jichun

2013-01-01

Recently, increasing evidences had suggested that long noncoding RNAs (LncRNAs) are involved in a wide range of physiological and pathophysiological processes. Here we determined the LncRNA expression profile using microarray technology in mouse livers after ischemia/reperfusion treatment. Seventy one LncRNAs were upregulated, and 27 LncRNAs were downregulated in ischemia/reperfusion-treated mouse livers. Eleven of the most significantly deregulated LncRNAs were further validated by quantitative PCR assays. Among the upregulated LncRNAs confirmed by quantitative PCR assays, AK139328 exhibited the highest expression level in normal mouse livers. siRNA-mediated knockdown of hepatic AK139328 decreased plasma aminotransferase activities, and reduced necrosis area in the livers with a decrease in caspase-3 activation after ischemia/reperfusion treatment. In ischemia/reperfusion liver, knockdown of AK139328 increased survival signaling proteins including phosphorylated Akt (pAkt), glycogen synthase kinase 3 (pGSK3) and endothelial nitric oxide synthase (peNOS). Furthermore, knockdown of AK139328 also reduced macrophage infitration and inhibited NF-κB activity and inflammatory cytokines expression. In conclusion, these findings revealed that deregulated LncRNAs are involved in liver ischemia/reperfusion injury. Silencing of AK139328 ameliorated ischemia/reperfusion injury in the liver with the activation of Akt signaling pathway and inhibition of NF-κB activity. LncRNA AK139328 might be a novel target for diagnosis and treatment of liver surgery or transplantation.

The incidence of dysphagia in patients receiving cerebral reperfusion therapy poststroke.

PubMed

Ribeiro, Priscila W; Cola, Paula C; Gatto, Ana R; da Silva, Roberta G; Luvizutto, Gustavo J; Braga, Gabriel P; Schelp, Arthur O; de Arruda Henry, Maria A C; Bazan, Rodrigo

2014-07-01

The high prevalence of dysphagia after stroke leads to increased mortality, and cerebral reperfusion therapy has been effective in reducing neurologic deficits. The aim of this study was to investigate the severity and evolution of dysphagia and the occurrence of pneumonia in patients submitted to cerebral reperfusion therapy. Seventy ischemic stroke patients were evaluated. Of these, 35 patients (group 1) were submitted to cerebral reperfusion therapy and 35 (group 2) did not receive thrombolytic treatment. The following were evaluated: severity of dysphagia by means of videofluoroscopy, evolution of oral intake rate by means of the Functional Oral Intake Scale, and the occurrence of pneumonia by international protocol. The relation between the severity of dysphagia and the occurrence of pneumonia with the treatment was evaluated through the chi-square test; the daily oral intake rate and its relation to the treatment were assessed by the Mann-Whitney test and considered significant if P is less than .05. The moderate and severe degrees of dysphagia were more frequent (P=.013) among the patients who were not submitted to cerebral reperfusion therapy. The daily oral intake evolved independently of the treatment type, without statistical significance when compared between the groups, whereas pneumonia occurred more frequently in group 2 (28%) in relation to group 1 (11%) and was associated with the worst degrees of dysphagia (P=.045). We can conclude that there is improvement in the oral intake rate in both groups, with lower severity of dysphagia and occurrence of pneumonia in ischemic stroke patients submitted to cerebral reperfusion therapy. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Hydrogen Gas Attenuates Myocardial Ischemia Reperfusion Injury Independent of Postconditioning in Rats by Attenuating Endoplasmic Reticulum Stress-Induced Autophagy.

PubMed

Gao, Yunan; Yang, Hongxiao; Chi, Jing; Xu, Qiannan; Zhao, Luqi; Yang, Weijia; Liu, Weifan; Yang, Wei

2017-01-01

To study the effect of inhaling hydrogen gas on myocardial ischemic/reperfusion(I/R) injury in rats. Seventy male Wistar albino rats were divided into five groups at random as the sham group (Sham). The I/R group (I/R), The ischemic postconditioning group (IPo), The I/R plus hydrogen group (IH2) and the ischemic postconditioning plus hydrogen group (IPoH2). The Sham group was without coronary occlusion. In I/R group, Ischemic/reperfusion injury was induced by coronary occlusion for 1 hour. Followed by 2 hours of reperfusion. In the IPo and IPoH2 group, four cycles of 1 min reperfusion/1 min ischemia was given at the end of 1 hour coronary occlusion. While 2% hydrogen was administered by inhalation 5 min before reperfusion till 2 hours after reperfusion in both the IPoH2 and IH2 group. The heart and blood samples were harvested at the end of the surgical protocol. Then the myocardium cell endoplasmic reticulum(ER) stress and autophagy was observed by electron microscope. In addition, the cardiac ER stress and autophagy related proteins expression were detected by Western blotting analysis. Both inhaling 2% hydrogen and ischemic postconditioning treatment reduced the ischemic size and serum troponin I level in rats with I/R injury, and inhaling hydrogen showed a more curative effect compared with ischemic postconditioning treatment. Meanwhile inhaling hydrogen showed a better protective effect in attenuating tissue reactive oxygen species. Malondialdehyde levels and immunoreactivities against 8-hydroxy-2'-deoxyguanosine and inhibiting cardiac endoplasmic reticulum stress and down-regulating autophagy as compared with ischemic postconditioning treatment. These results revealed a better protective effect of hydrogen on myocardial ischemic/reperfusion injury in rats by attenuating endoplasmic reticulum stress and down-regulating autophagy compared with ischemic postconditioning treatment. © 2017 The Author(s). Published by S. Karger AG, Basel.

Ghrelin protects the heart against ischemia/reperfusion injury via inhibition of TLR4/NLRP3 inflammasome pathway.

PubMed

Wang, Qin; Lin, Ping; Li, Peng; Feng, Li; Ren, Qian; Xie, Xiaofeng; Xu, Jing

2017-10-01

The aim of this study was to investigate the cardioprotective effects of ghrelin against myocardial ischemia/reperfusion (I/R) injury and the underlying mechanism. Sprague-Dawley rats were randomized into Sham, I/R and I/R+ghrelin groups. After 30 minutes ischemia, ghrelin (8nmol/kg) was injected intraperitoneally at the time of reperfusion in the I/R+ghrelin group. Then hemodynamic parameters were observed at 24h after reperfusion. Ghrelin exhibited dramatic improvement in cardiac functions, as manifested by increased LVSP and ±dP/dt max and decreased LVDP. At 24h after reperfusion, ghrelin significantly attenuated the myocardial infarction area and apoptosis, accompanied with a decrease in the levels of the myocyte injury marker enzymes. Oxidative stress injury and inflammatory response were also relieved by ghrelin. Western blot showed that the expression of TLR4, NLRP3, and caspase-1 were obviously increased in I/R group, while ghrelin significantly inhibited the I/R-induced TLR4, NLRP3, and caspase-1 expression. Ghrelin could inhibit the increased protein levels of NLRP3, caspase-1, and IL-1β induced by lipopolysacharide in primary cultured cardiomyocytes of neonatal rats. Ghrelin protected the heart against I/R injury by inhibiting oxidative stress and inflammation via TLR4/NLRP3 signaling pathway. Our results might provide new strategy and target for treatment of myocardial ischemia/reperfusion injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Vagal modulation of high mobility group box-1 protein mediates electroacupuncture-induced cardioprotection in ischemia-reperfusion injury.

PubMed

Zhang, Juan; Yong, Yue; Li, Xing; Hu, Yu; Wang, Jian; Wang, Yong-qiang; Song, Wei; Chen, Wen-ting; Xie, Jian; Chen, Xue-mei; Lv, Xin; Hou, Li-li; Wang, Ke; Zhou, Jia; Wang, Xiang-rui; Song, Jian-gang

2015-10-26

Excessive release of high mobility group box-1 (HMGB1) protein from ischemic cardiomyocytes activates inflammatory cascades and enhances myocardial injury after reperfusion. Here we report evidence that electroacupuncture of mice at Neiguan acupoints can inhibit the up-regulation of cardiac HMGB1 following myocardial ischemia and attenuate the associated inflammatory responses and myocardial injury during reperfusion. These benefits of electroacupuncture were partially reversed by administering recombinant HMGB1 to the mice, and further potentiated by administering anti-HMGB1 antibody. Electroacupuncture-induced inhibition of HMGB1 release was markedly reduced by unilateral vagotomy or administration of nicotinic receptor antagonist, but not by chemical sympathectomy. The cholinesterase inhibitor neostigmine mimicked the effects of electroacupuncture on HMGB1 release and myocardial ischemia reperfusion injury. Culture experiments with isolated neonatal cardiomyocytes showed that acetylcholine, but not noradrenaline, inhibited hypoxia-induced release of HMGB1 via a α7nAchR-dependent pathway. These results suggest that electroacupuncture acts via the vagal nerve and its nicotinic receptor-mediated signaling to inhibit HMGB1 release from ischemic cardiomyocytes. This helps attenuate pro-inflammatory responses and myocardial injury during reperfusion.

Vagal modulation of high mobility group box-1 protein mediates electroacupuncture-induced cardioprotection in ischemia-reperfusion injury

PubMed Central

Zhang, Juan; Yong, Yue; Li, Xing; Hu, Yu; Wang, Jian; Wang, Yong-qiang; Song, Wei; Chen, Wen-ting; Xie, Jian; Chen, Xue-mei; Lv, Xin; Hou, Li-li; Wang, Ke; Zhou, Jia; Wang, Xiang-rui; Song, Jian-gang

2015-01-01

Excessive release of high mobility group box-1 (HMGB1) protein from ischemic cardiomyocytes activates inflammatory cascades and enhances myocardial injury after reperfusion. Here we report evidence that electroacupuncture of mice at Neiguan acupoints can inhibit the up-regulation of cardiac HMGB1 following myocardial ischemia and attenuate the associated inflammatory responses and myocardial injury during reperfusion. These benefits of electroacupuncture were partially reversed by administering recombinant HMGB1 to the mice, and further potentiated by administering anti-HMGB1 antibody. Electroacupuncture-induced inhibition of HMGB1 release was markedly reduced by unilateral vagotomy or administration of nicotinic receptor antagonist, but not by chemical sympathectomy. The cholinesterase inhibitor neostigmine mimicked the effects of electroacupuncture on HMGB1 release and myocardial ischemia reperfusion injury. Culture experiments with isolated neonatal cardiomyocytes showed that acetylcholine, but not noradrenaline, inhibited hypoxia-induced release of HMGB1 via a α7nAchR-dependent pathway. These results suggest that electroacupuncture acts via the vagal nerve and its nicotinic receptor-mediated signaling to inhibit HMGB1 release from ischemic cardiomyocytes. This helps attenuate pro-inflammatory responses and myocardial injury during reperfusion. PMID:26499847

Upregulation of heme oxygenase-1 protected against brain damage induced by transient cerebral ischemia-reperfusion injury in rats.

PubMed

Lu, Xiufang; Gu, Renjun; Hu, Weimin; Sun, Zhitang; Wang, Gaiqing; Wang, Li; Xu, Yuming

2018-06-01

The aim of the present study was to identify the effect of heme oxygenase (HO)-1 gene on cerebral ischemia-reperfusion injury. Sprague-Dawley rats were divided randomly into four groups: Sham group, vehicle group, empty adenovirus vector (Ad) group and recombinant HO-1 adenovirus (Ad-HO-1) transfection group. Rats in the vehicle, Ad and Ad-HO-1 groups were respectively injected with saline, Ad or Ad-HO-1 for 3 days prior to cerebral ischemia-reperfusion injury. Subsequently, the middle cerebral artery occlusion method was used to establish the model of cerebral ischemia-reperfusion injury. Following the assessment of neurological function, rats were sacrificed, and the infarction volume and apoptotic index in rat brains were measured. Furthermore, the protein expression levels of HO-1 in brain tissues were detected using western blot analysis. Results indicated that the neurological score of the Ad-HO-1 group was significantly increased compared with the Ad or vehicle groups, respectively (P<0.001). The volume of cerebral infarction and the index score of neuronal apoptosis in the vehicle and Ad groups was significantly increased compared with the Ad-HO-1 group (P<0.01). The death of neuronal cells following cerebral ischemia-reperfusion injury reduced remarkably induced by over-expression of HO-1. These findings suggest a neuroprotective role of HO-1 against brain injury induced by transient cerebral ischemia-reperfusion injury.

Defibrotide reduces infarct size in a rabbit model of experimental myocardial ischaemia and reperfusion.

PubMed Central

Thiemermann, C.; Thomas, G. R.; Vane, J. R.

1989-01-01

1. Defibrotide, a single-stranded polydeoxyribonucleotide obtained from bovine lungs, has significant anti-thrombotic, pro-fibrinolytic and prostacyclin-stimulating properties. 2. The present study was designed to evaluate the effects of defibrotide on infarct size and regional myocardial blood flow in a rabbit model of myocardial ischaemia and reperfusion. 3. Defibrotide (32 mg kg-1 bolus + 32 mg kg-1 h-1, i.v.) either with or without co-administration of indomethacin (5 mg kg-1 x 2, i.v.) was administered 5 min after occlusion of the left anterior-lateral coronary artery and continued during the 60 min occlusion and subsequent 3 h reperfusion periods. 4. Defibrotide significantly attenuated the ischaemia-induced ST-segment elevation and abolished the reperfusion-related changes (R-wave reduction and Q-wave development) in the electrocardiogram. In addition, defibrotide significantly improved myocardial blood flow in normal and in ischaemic, but not in infarcted sections of the heart. The improvement in blood flow in normal perfused myocardium, but not in the ischaemic area was prevented by indomethacin. 5. Although the area at risk was similar in all animal groups studied, defibrotide treatment resulted in a 51% reduction of infarct size. Indomethacin treatment abolished the reduction of infarct size seen with defibrotide alone. 6. The data demonstrate a considerable cardioprotective effect of defibrotide in the reperfused ischaemic rabbit myocardium. This effect may be related, at least in part, to a stimulation of endogenous prostaglandin formation. Other possible mechanisms are discussed. PMID:2758223

p53 participates in the protective effects of ischemic post-conditioning against OGD-reperfusion injury in primary cultured spinal cord neurons.

PubMed

Li, Jinquan; Chen, Gong; Gao, Xinjie; Shen, Chao; Zhou, Ping; Wu, Xing; Che, Xiaoming; Xie, Rong

2017-01-18

Spinal cord ischemia-reperfusion (I/R) injury is a severe clinical condition, while the mechanism is still not clarified and the therapeutic approach is limited. Ischemia post-conditioning (PC) has been found to have the protective effects against I/R injury in brain. Recently p53 has been reported to take part in the regulation and protection of I/R injury. We hypothesize that PC has the protective effects in primary cultured spinal cord neurons against ischemia-reperfusion injury, and MDM2-p53 signaling pathway may involve in its protective mechanism. In this study, we used an OGD (oxygen and glucose deprivation)-reperfusion model in primary cultured spinal cord neurons to simulate the I/R injury of spinal cord in vitro, and PC was conducted by 3 cycles of 15min restoration of glucose and oxygen with 15min OGD, followed by 6h fully restoration as reperfusion. Lentiviral vectors were used to knock down MDM2 or over-express p53 genes in primary cultured spinal cord neurons. The results showed that 3 cycles of 15min PC generated the most significant protective effects in primary cultured spinal cord neurons against OGD-reperfusion injury. The levels of MDM2 were decreased while p53, Bax, and cleaved Caspase 3 were increased under OGD-reperfusion condition. PC could significantly reverse the down-regulation of MDM2 and up-regulation of p53, Bax, and cleaved Caspase 3 by OGD-reperfusion injury. Moreover, MDM2 knockdown or p53 over-expression could induce the cleaved Caspase 3 expression and blocked the protective effects of PC in primary cultured spinal cord neurons against OGD-reperfusion injury. In conclusion, our work demonstrated that MDM2-p53 pathway plays a pivotal role in the protective effect of PC against OGD-reperfusion injury and PC may be a feasible therapy strategy in the treatment for spinal cord I/R injury. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Natural history of the spontaneous reperfusion of human cerebral infarcts as assessed by 99mTc HMPAO SPECT

PubMed Central

Bowler, J; Wade, J; Jones, B; Nijran, K; Steiner, T

1998-01-01

OBJECTIVE—Little is known about the effect of spontaneous reperfusion of human cerebral infarcts. Single photon emission computerised tomography (SPECT) data were analysed from a study using 99Tcm HMPAO (99Tcm hexamethylpropyleneamine oxime) in human cerebral infarction for the frequency of reperfusion and to see if it affected infarct size, oedema, haemorrhagic transformation, or functional outcome.
METHODS—Fifty sequential cases of ischaemic stroke were studied with 124 99Tcm HMPAO SPECT at around one day, one week, and three months after stroke along with detailed clinical and functional assessments.
RESULTS—Visually apparent reperfusion occurred in 14 of 50 patients (28%) with a mean delay of 5.8 days and reperfusion was seen in seven others in whom it was identified on the basis of changes in perfusion deficit volume. It occurred in 13 of 23 embolic events but only in three of 23 other events. In only two cases did spontaneous reperfusion occur early enough to preserve tissue or function. Reperfusion did not otherwise reduce infarct size, or improve clinical or functional outcome, and was not associated with oedema but an association with haemorrhagic transformation was suggested. Reperfusion significantly decreased the apparent perfusion defect as measured by SPECT one week from the ictus, but was mostly non-nutritional and transient. The mean volume of tissue preserved by nutritional reperfusion was 10 cm3, but this was unequally distributed between cases. Late washout of 99Tcm HMPAO from areas of hyperaemic reperfusion may be a good prognostic marker but is a rare phenomenon and too insensitive to be of general applicability.
CONCLUSIONS—Spontaneous reperfusion after cerebral infarction occurs in 42% of cases within the first week but is associated with clinical improvement in only 2%. It has few adverse consequences although it may be associated with haemorrhagic transformation.

 PMID:9436735

Hydrogen peroxide changes in ischemic and reperfused heart. Cytochemistry and biochemical and X-ray microanalysis.

PubMed Central

Slezak, J.; Tribulova, N.; Pristacova, J.; Uhrik, B.; Thomas, T.; Khaper, N.; Kaul, N.; Singal, P. K.

1995-01-01

Active oxygen species including hydrogen peroxide (H2O2) play a major role in ischemia-reperfusion injury. In the present study, changes in myocardial H2O2 content as well as its subcellular distribution were examined in rat hearts subjected to ischemia-reperfusion. Isolated perfused rat hearts were made globally ischemic for 20 or 30 minutes and were reperfused for different durations. H2O2 content in these hearts was studied biochemically and changes were correlated with the recovery of function. These hearts were also analyzed for subcellular distribution of H2O2. Optimal conditions of tissue processing as well as incubation medium were established for reacting cerium chloride with H2O2 to form cerium perhydroxide, an insoluble electron-dense product. The chemical composition of these deposits was confirmed by x-ray micro-analysis. Global ischemia caused complete contractile failure in minutes and after 30 minutes of ischemia, these was a > 250% increase in the myocardial H2O2 content. Depressed contractile function recovery in the early phase of reperfusion was accompanied by approximately a 600% increase in the myocardial H2O2 content. Brief pre-fixation with low concentrations of glutaraldehyde, inhibition of alkaline phosphatase, glutathione peroxidase, and catalase, post-fixation but no post-osmication, and no counterstaining yielded the best cytochemical definition of H2O2. In normal hearts, extremely small amounts of cerium hydroperoxide precipitates were located on the endothelial cells. X-ray microanalysis confirmed the presence of cerium in the reaction product. Ischemia resulted in a stronger reaction, particularly on the sarcolemma as well as abluminal side of the endothelial cells; and upon reperfusion, cerium precipitate reaction at these sites was more intense. In the reperfused hearts, the reaction product also appeared within mitochondria between the cristae as well as on the myofibrils, but Z-lines were devoid of any precipitate. The data

Physical exercise prevents motor disorders and striatal oxidative imbalance after cerebral ischemia-reperfusion.

PubMed

Sosa, P M; Schimidt, H L; Altermann, C; Vieira, A S; Cibin, F W S; Carpes, F P; Mello-Carpes, P B

2015-09-01

Stroke is the third most common cause of death worldwide, and most stroke survivors present some functional impairment. We assessed the striatal oxidative balance and motor alterations resulting from stroke in a rat model to investigate the neuroprotective role of physical exercise. Forty male Wistar rats were assigned to 4 groups: a) control, b) ischemia, c) physical exercise, and d) physical exercise and ischemia. Physical exercise was conducted using a treadmill for 8 weeks. Ischemia-reperfusion surgery involved transient bilateral occlusion of the common carotid arteries for 30 min. Neuromotor performance (open-field and rotarod performance tests) and pain sensitivity were evaluated beginning at 24 h after the surgery. Rats were euthanized and the corpora striata was removed for assay of reactive oxygen species, lipoperoxidation activity, and antioxidant markers. Ischemia-reperfusion caused changes in motor activity. The ischemia-induced alterations observed in the open-field test were fully reversed, and those observed in the rotarod test were partially reversed, by physical exercise. Pain sensitivity was similar among all groups. Levels of reactive oxygen species and lipoperoxidation increased after ischemia; physical exercise decreased reactive oxygen species levels. None of the treatments altered the levels of antioxidant markers. In summary, ischemia-reperfusion resulted in motor impairment and altered striatal oxidative balance in this animal model, but those changes were moderated by physical exercise.

AP39, a mitochondria‐targeting hydrogen sulfide (H2S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling

PubMed Central

Karwi, Qutuba G; Bornbaum, Julia; Boengler, Kerstin; Torregrossa, Roberta; Whiteman, Matthew; Wood, Mark E; Schulz, Rainer

2017-01-01

Background and Purpose H2S protects myocardium against ischaemia/reperfusion injury. This protection may involve the cytosolic reperfusion injury salvage kinase (RISK) pathway, but direct effects on mitochondrial function are possible. Here, we investigated the potential cardioprotective effect of a mitochondria‐specific H2S donor, AP39, at reperfusion against ischaemia/reperfusion injury. Experimental Approach Anaesthetized rats underwent myocardial ischaemia (30 min)/reperfusion (120 min) with randomization to receive interventions before reperfusion: vehicle, AP39 (0.01, 0.1, 1 μmol·kg−1), or control compounds AP219 and ADT‐OH (1 μmol·kg−1). LY294002, L‐NAME or ODQ were used to investigate the involvement of the RISK pathway. Myocardial samples harvested 5 min after reperfusion were analysed for RISK protein phosphorylation and isolated cardiac mitochondria were used to examine the direct mitochondrial effects of AP39. Key Results AP39, dose‐dependently, reduced infarct size. Inhibition of either PI3K/Akt, eNOS or sGC did not affect this effect of AP39. Western blot analysis confirmed that AP39 did not induce phosphorylation of Akt, eNOS, GSK‐3β or ERK1/2. In isolated subsarcolemmal and interfibrillar mitochondria, AP39 significantly attenuated mitochondrial ROS generation without affecting respiratory complexes I or II. Furthermore, AP39 inhibited mitochondrial permeability transition pore (PTP) opening and co‐incubation of mitochondria with AP39 and cyclosporine A induced an additive inhibitory effect on the PTP. Conclusion and Implications AP39 protects against reperfusion injury independently of the cytosolic RISK pathway. This cardioprotective effect could be mediated by inhibiting PTP via a cyclophilin D‐independent mechanism. Thus, selective delivery of H2S to mitochondria may be therapeutically applicable for employing the cardioprotective utility of H2S. PMID:27930802

Restoration of normal pH triggers ischemia-reperfusion injury in lung by Na+/H+ exchange activation.

PubMed

Moore, T M; Khimenko, P L; Taylor, A E

1995-10-01

The effects of acidotic extracellular pH and Na+/H+ exchange inhibition on ischemia-reperfusion (I/R)-induced microvascular injury were studied in the isolated, buffer-perfused rat lung. When lungs were subjected to 45 min of ischemia followed by 30 min of reperfusion, the capillary filtration coefficient (Kfc) increased significantly, resulting in a change in Kfc (delta Kfc) of 0.360 +/- 0.09 ml.min-1.cmH2O-1.100 g-1. Addition of hydrochloric acid to the perfusate before ischemia at a concentration sufficient to reduce perfusate pH from 7.38 +/- 0.03 to 7.09 +/- 0.04 completely prevented the increase in Kfc associated with I/R (delta Kfc = 0.014 +/- 0.034 ml.min-1.cmH2O-1.100 g-1). Addition of a Na+/H+ exchange inhibitor, 5-(N,N-dimethyl)-amiloride, to the perfusate either before ischemia or at reperfusion also prevented the I/R-induced permeability increase (delta Kfc = 0.01 +/- 0.02 and -0.001 +/- 0.02 ml.min-1.cmH2O-1.100 g-1, respectively). We conclude that restoration of flow at physiological pH to the postischemic lung activates the Na+/H+ exchange system, which may represent the "triggering mechanism" responsible for initiating reperfusion-induced microvascular injury.

The effect of mitochondrial calcium uniporter on mitochondrial fission in hippocampus cells ischemia/reperfusion injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Lantao; Li, Shuhong; Wang, Shilei, E-mail: wshlei@aliyun.com

The mitochondrial calcium uniporter (MCU) transports free Ca{sup 2+} into the mitochondrial matrix, maintaining Ca{sup 2+} homeostasis, thus regulates the mitochondrial morphology. Previous studies have indicated that there was closely crosstalk between MCU and mitochondrial fission during the process of ischemia/reperfusion injury. This study constructed a hypoxia reoxygenation model using primary hippocampus neurons to mimic the cerebral ischemia/reperfusion injury and aims to explore the exactly effect of MCU on the mitochondrial fission during the process of ischemia/reperfusion injury and so as the mechanisms. Our results found that the inhibitor of the MCU, Ru360, decreased mitochondrial Ca{sup 2+} concentration, suppressed themore » expression of mitochondrial fission protein Drp1, MIEF1 and Fis1, and thus improved mitochondrial morphology significantly. Whereas spermine, the agonist of the MCU, had no significant impact compared to the I/R group. This study demonstrated that the MCU regulates the process of mitochondrial fission by controlling the Ca{sup 2+} transport, directly upregulating mitochondrial fission proteins Drp1, Fis1 and indirectly reversing the MIEF1-induced mitochondrial fusion. It also provides new targets for brain protection during ischemia/reperfusion injury. - Highlights: • We study MCU with primary neuron culture. • MCU induces mitochondrial fission. • MCU reverses MIEF1 effect.« less

Time-dependent alterations in serum NO concentration after oral administration of l-arginine, l-NAME, and allopurinol in intestinal ischemia/reperfusion

PubMed Central

Yanni, Amalia E; Margaritis, Eleutherios; Liarakos, Nikolaos; Pantopoulou, Alkisti; Poulakou, Maria; Kostakis, Maria; Perrea, Despoina; Kostakis, Alkis

2008-01-01

Objective To study the effect of oral administration of a nitric oxide (NO) donor l-arginine (l-Arg), a NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) and an inhibitor of xanthine oxidase, allopurinol (Allo), on serum NO concentration and catalase activity after intestinal ischemia/reperfusion (I/R) in rats. Methods Male Wistar rats received per os l-Arg (800 mg/kg) or l-NAME (50 mg/kg) or Allo (100 mg/kg) 24 hrs, 12 hrs and 1 hr before underwent 1 hr occlusion of superior mesenteric artery followed by 1 hr of reperfusion (l-Arg(IR1), l-NAME(IR1) and Allo(IR1) respectively) or 1 hr occlusion followed by 8 hrs of reperfusion (l-Arg(IR8), l-NAME(IR8) and Allo(IR8) respectively). There was one group underwent 1 hr occlusion (I), a group underwent 1 hr occlusion followed by 1 hr reperfusion (IR1), a group subjected to 1 hr occlusion followed by 8 hrs of reperfusion (IR8) and a last group that served as control (C). Serum NO concentration and catalase activity were measured. Results After 1 hr of reperfusion serum NO concentration was elevated in IR1 and l-Arg(IR1) groups compared with group C but not in l-NAME(IR1) and Allo(IR1) group. Catalase activity was enhanced in l-NAME(IR1) group. Interestingly, serum NO concentration was increased after 8 hrs of reperfusion in all groups (IR8, l-Arg(IR8), l-NAME(IR8) and Allo(IR8)) compared with control while catalase activity did not show significant difference in any group. Conclusions The results of the present study show that NO concentration is elevated in serum after intestinal I/R and the elevation sustained after administration of l-Arg but not after administration of l-NAME or Allo after 1 hr reperfusion. However, after 8 hrs of reperfusion NO concentration was increased in all groups studied, focusing attention on its possible important role in a complicated situation such as intestinal I/R that involves intestine and other organs. Serum catalase activity does not seem to be affected by per os

Two-photon imaging during prolonged middle cerebral artery occlusion in mice reveals recovery of dendritic structure after reperfusion.

PubMed

Li, Ping; Murphy, Timothy H

2008-11-12

Filament occlusion of the middle cerebral artery (MCA) is a well accepted animal model of focal ischemia. Advantages of the model are relatively long occlusion times and a large penumbra region that simulates aspects of human stroke. Here, we use two-photon and confocal microscopy in combination with regional measurement of blood flow using laser speckle to assess the spatial relationship between the borders of the MCA ischemic territory and loss of dendrite structure, as well as the effect of reperfusion on dendritic damage in adult YFP (yellow fluorescent protein) and GFP (green fluorescent protein) C57BL/6 transgenic mice with fluorescent (predominantly layer 5) neurons. By examining the spatial extent of dendritic damage, we determined that 60 min of MCA occlusion produced a core with severe structural damage that did not recover after reperfusion (begins approximately 3.8 mm lateral to midline), a reversibly damaged area up to 0.6 mm medial to the core that recovered after reperfusion (penumbra), and a relatively structurally intact area ( approximately 1 mm wide; medial penumbra) with hypoperfusion. Loss of structure was preceded by a single ischemic depolarization 122.1 +/- 10.2 s after occlusion onset. Reperfusion of animals after 60 min of ischemia was not associated with exacerbation of damage (reperfusion injury) and resulted in a significant restoration of blebbed dendritic structure, but only within approximately 0.6 mm lateral of the dendritic damage structural border. In summary, we find that recovery of dendritic structure can occur after reperfusion after even 60 min of ischemia, but is likely restricted to a relatively small penumbra region with partial blood flow or oxygenation.

Importance of tissue perfusion in ST segment elevation myocardial infarction patients undergoing reperfusion strategies: role of adenosine.

PubMed

Forman, Mervyn B; Jackson, Edwin K

2007-11-01

High risk ST segment elevation myocardial infarction (STEMI) patients undergoing reperfusion therapy continue to exhibit significant morbidity and mortality due in part to myocardial reperfusion injury. Importantly, preclinical studies demonstrate that progressive microcirculatory failure (the "no-reflow" phenomenon) contributes significantly to myocardial reperfusion injury. Diagnostic techniques to measure tissue perfusion have validated this concept in humans, and it is now clear that abnormal tissue perfusion occurs frequently in STEMI patients undergoing reperfusion therapy. Moreover, because tissue perfusion correlates poorly with epicardial blood flow (TIMI flow grade), clinical studies show that tissue perfusion is an independent predictor of early and late mortality in STEMI patients and is associated with infarct size, ventricular function, CHF and ventricular arrhythmias. The mechanisms responsible for abnormal tissue perfusion are multifactorial and include both mechanical obstruction and vasoconstrictor humoral factors. Adenosine, an endogenous nucleoside, maintains microcirculatory flow following reperfusion by activating four well-characterized extracellular receptors. Because activation of adenosine receptors attenuates the mechanical and functional mechanisms leading to the "no reflow" phenomenon and activates other cardioprotective pathways as well, it is not surprising that both experimental and clinical studies show striking myocardial salvage with intravenous infusions of adenosine administered in the peri-reperfusion period. For example, a post hoc analysis of the AMISTAD II trial indicates a significant reduction in 1 and 6-month mortality in STEMI patients undergoing reperfusion therapy who are treated with adenosine within 3 hours of symptoms. In conclusion, adenosine's numerous cardioprotective effects, including attenuation of the "no-reflow" phenomenon, support its use in high risk STEMI undergoing reperfusion.

The effect of melatonin on bacterial translocation following ischemia/reperfusion injury in a rat model of superior mesenteric artery occlusion.

PubMed

Ozban, Murat; Aydin, Cagatay; Cevahir, Nural; Yenisey, Cigdem; Birsen, Onur; Gumrukcu, Gulistan; Aydin, Berrin; Berber, Ibrahim

2015-03-08

Acute mesenteric ischemia is a life-threatening vascular emergency resulting in tissue destruction due to ischemia-reperfusion injury. Melatonin, the primary hormone of the pineal gland, is a powerful scavenger of reactive oxygen species (ROS), including the hydroxyl and peroxyl radicals, as well as singlet oxygen, and nitric oxide. In this study, we aimed to investigate whether melatonin prevents harmful effects of superior mesenteric ischemia-reperfusion on intestinal tissues in rats. Rats were randomly divided into three groups, each having 10 animals. In group I, the superior mesenteric artery (SMA) was isolated but not occluded. In group II and group III, the SMA was occluded immediately distal to the aorta for 60 minutes. After that, the clamp was removed and the reperfusion period began. In group III, 30 minutes before the start of reperfusion, 10 mg/kg melatonin was administered intraperitonally. All animals were sacrified 24 hours after reperfusion. Tissue samples were collected to evaluate the I/R-induced intestinal injury and bacterial translocation (BT). There was a statistically significant increase in myeloperoxidase activity, malondialdehyde levels and in the incidence of bacterial translocation in group II, along with a decrease in glutathione levels. These investigated parameters were found to be normalized in melatonin treated animals (group III). We conclude that melatonin prevents bacterial translocation while precluding the harmful effects of ischemia/reperfusion injury on intestinal tissues in a rat model of superior mesenteric artery occlusion.

Expression of Bcl-2 and NF-κB in brain tissue after acute renal ischemia-reperfusion in rats.

PubMed

Zhang, Na; Cheng, Gen-Yang; Liu, Xian-Zhi; Zhang, Feng-Jiang

2014-05-01

To investigate the effect of acute renal ischemia reperfusion on brain tissue. Fourty eight rats were randomly divided into four groups (n=12): sham operation group, 30 min ischemia 60 min reperfusion group, 60 min ischemia 60 min reperfusion group, and 120 min ischemia 60 min reperfusion group. The brain tissues were taken after the experiment. TUNEL assay was used to detect the brain cell apoptosis, and western blot was used to detect the expression of apoptosis-related proteins and inflammatory factors. Renal ischemia-reperfusion induced apoptosis of brain tissues, and the apoptosis increased with prolongation of ischemia time. The detection at the molecular level showed decreased Bcl-2 expression, increased Bax expression, upregulated expression of NF-κB and its downstream factor COX-2/PGE2. Acute renal ischemia-reperfusion can cause brain tissue damage, manifested as induced brain tissues apoptosis and inflammation activation. Copyright © 2014 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Timing of xenon-induced delayed postconditioning to protect against spinal cord ischaemia-reperfusion injury in rats.

PubMed

Yang, Y W; Cheng, W P; Lu, J K; Dong, X H; Wang, C B; Zhang, J; Zhao, L Y; Gao, Z F

2014-07-01

This study was designed to assess the neuroprotective effect of xenon-induced delayed postconditioning on spinal cord ischaemia-reperfusion injury (IRI) and to determine the time of administration for best neuroprotection in a rat model of spinal cord IRI. Fifty male rats were randomly divided equally into a sham group, control group, and three xenon postconditioning groups (n=10 per group). The control group underwent spinal cord IRI and immediately inhaled 50% nitrogen/50% oxygen for 3 h at the initiation of reperfusion. The three xenon postconditioning groups underwent the same surgical procedure and immediately inhaled 50% xenon/50% oxygen for 3 h at the initiation of reperfusion or 1 and 2 h after reperfusion. The sham operation group underwent the same surgical procedure without aortic occlusion, and inhaled 50% nitrogen/50% oxygen. Neurological function was assessed using the Basso, Beattie, and Bresnahan score at 4, 24, and 48 h of reperfusion. Histological examination was performed using Nissl staining and immunohistochemistry, and apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling staining. Compared with the control group, the three xenon postconditioning groups showed improvements in neurological outcomes, and had more morphologically normal neurones at 48 h of reperfusion. Apoptotic cell death was reduced and the ratio of Bcl-2/Bax immunoreactivity increased in xenon-treated rats compared with controls. Xenon postconditioning up to 2 h after reperfusion provided protection against spinal cord IRI in rats, but the greatest neuroprotection occurred with administration of xenon for 1 h at reperfusion. © The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Recombinant human-activated protein C inhibits cardiomyocyte apoptosis in a rat model of myocardial ischemia-reperfusion.

PubMed

Pirat, Bahar; Muderrisoglu, Haldun; Unal, Muge Tecder; Ozdemir, Handan; Yildirir, Aylin; Yucel, Muammer; Turkoglu, Suna

2007-02-01

Myocardial apoptosis is recognized as a major mechanism of cell death during ischemia-reperfusion. In this study, we assessed the hypothesis that activated protein C may have a cardioprotective effect via preventing apoptosis in a rat model of myocardial ischemia-reperfusion. Thirty male Sprague-Dawley rats were anesthetized, instrumented for hemodynamic measurements and ventilated mechanically. Twenty rats were subjected to 20 min of left anterior descending coronary artery occlusion and 2 h of reperfusion. They were randomly assigned to receive intravenous Ringer lactate (vehicle) or activated protein C (2 mg/kg/h) 10 min after occlusion and during reperfusion. The other 10 rats were sham-operated. At the end of the reperfusion period, serum samples were obtained for evaluation of creatine kinase, C-reactive protein and tumor necrosis factor-alpha. Apoptosis was measured quantitatively by the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling method. Serum creatine kinase, C-reactive protein and tumor necrosis factor-alpha values and percentage of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling- positive myocyte nuclei demonstrated negligible myocardial injury in sham-operated controls. During reperfusion, mean arterial pressures were significantly higher in activated protein C-treated rats than in the control group (68.2+/-10.3 vs. 55.4+/-11.6 mmHg, P=0.01). Number of apoptotic cells was significantly reduced from 47.7 to 24.8% with activated protein C administration (P=0.008). No difference was seen between activated protein C-treated and untreated animals with respect to creatine kinase, C-reactive protein and tumor necrosis factor-alpha levels. Treatment with activated protein C significantly improved hemodynamics after ischemia-reperfusion and reduced ischemia-reperfusion-induced myocardial apoptosis in rats.

Evaluation of the Effects of Atorvastatin and Ischemic Postconditioning Preventing on the Ischemia and Reperfusion Injury: Experimental Study in Rats

PubMed Central

Pontes, Henrique Budib Dorsa; Pontes, José Carlos Dorsa Vieira; de Azevedo Neto, Euler; Vendas, Giovanna Serra da Cruz; Miranda, João Victor Cunha; Dias, Letícia do Espírito Santos; Oliva, João Victor Durães Gomes; de Almeida, Murilo Henrique Martins; Chaves, Ian de Oliveira; Sampaio, Tricia Luna; dos Santos, Carlos Henrique Marques; Dourado, Doroty Mesquita

2018-01-01

Introduction Reperfusion injury leads to systemic morphological and functional pathological alterations. Some techniques are already estabilished to attenuate the damage induced by reperfusion. Ischemic preconditioning is one of the standard procedures. In the last 20 years, several experimental trials demonstrated that the ischemic postconditioning presents similar effectiveness. Recently experimental trials demonstrated that statins could be used as pharmacological preconditioning. Methods 41 Wistar rats (Rattus norvegicus albinus) were distributed in 5 groups: Ischemia and Reperfusion (A), Ischemic Postconditioning (B), Statin (C), Ischemic Postconditioning + Statins (D) and SHAM (E). After euthanasia, lungs, liver, kidneys and ileum were resected and submitted to histopathological analysis. Results The average of lung parenchymal injury was A=3.6, B=1.6, C=1.2, D=1.2, E=1 (P=0.0029). The average of liver parenchymal injury was A=3, B=1.5, C=1.2, D=1.2, E = 0 (P<0.0001). The average of renal parenchymal injury was A=4, B=2.44, C=1.22, D=1.11, E=1 (P<0.0001). The average of intestinal parenchymal injury was A=2, B=0.66, C=0, D=0, E=0 (P=0.0006). The results were submitted to statistics applying Kruskal-Wallis test, estabilishing level of significance P<0.05. Conclusion Groups submitted to ischemic postconditioning, to pre-treatment with statins and both methods associated demonstrated less remote reperfusion injuries, compared to the group submitted to ischemia and reperfusion without protection. PMID:29617505

Mitochondrial JNK activation triggers autophagy and apoptosis and aggravates myocardial injury following ischemia/reperfusion.

PubMed

Xu, Jie; Qin, Xinghua; Cai, Xiaoqing; Yang, Lu; Xing, Yuan; Li, Jun; Zhang, Lihua; Tang, Ying; Liu, Jiankang; Zhang, Xing; Gao, Feng

2015-02-01

c-Jun N-terminal kinase (JNK) is a stress-activated mitogen-activated protein kinase that plays a central role in initiating apoptosis in disease conditions. Recent studies have shown that mitochondrial JNK signaling is partly responsible for ischemic myocardial dysfunction; however, the underlying mechanism remains unclear. Here we report for the first time that activation of mitochondrial JNK, rather than JNK localization on mitochondria, induces autophagy and apoptosis and aggravates myocardial ischemia/reperfusion injury. Myocardial ischemia/reperfusion induced a dominant increase of mitochondrial JNK phosphorylation, while JNK mitochondrial localization was reduced. Treatment with Tat-SabKIM1, a retro-inverso peptide which blocks JNK interaction with mitochondria, decreased mitochondrial JNK activation without affecting JNK mitochondrial localization following reperfusion. Tat-SabKIM1 treatment reduced Bcl2-regulated autophagy, cytochrome c-mediated apoptosis and myocardial infarct size. Notably, selective inhibition of mitochondrial JNK activation using Tat-SabKIM1 produced a similar infarct size-reducing effect as inhibiting universal JNK activation with JNK inhibitor SP600125. Moreover, insulin-treated animals exhibited significantly dampened mitochondrial JNK activation accompanied by reduced infarct size and diminished autophagy and apoptosis following reperfusion. Taken together, these findings demonstrate that mitochondrial JNK activation, rather than JNK mitochondrial localization, induces autophagy and apoptosis and exacerbates myocardial ischemia/reperfusion injury. Insulin selectively inhibits mitochondrial JNK activation, contributing to insulin cardioprotection against myocardial ischemic/reperfusion injury. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

Transport mechanism of L-[14C]glutamate in cortical slices and synaptosomes of rabbits exposed to brain ischemia and reperfusion.

PubMed

Solyakov, L; Dobrota, D; Drany, O; Vachova, M; Machac, S; Mezesova, V; Bachurin, S; Lombardi, V

1995-01-01

Changes in the functioning of the glutamatergic system in rabbit brain were studied after partial brain ischemia and reperfusion. In vitro studies were conducted relating to the release of L-[14C]glutamate from cortical brain slices, L-[14C]glutamate uptake in synaptosomes, and 45Ca uptake in synaptosomes. It was found that basal release of L-[14C]glutamate from rabbit brain cortical slices after 30 min of partial ischemia and 1 d of reperfusion was essentially without change compared to the control values. After 3 d of reperfusion, there was an increase in basal release of L-[14C]glutamate from rabbit brain cortical slices. K+ stimulated release of L-[14C]glutamate in normal Krebs-Ringer medium was essentially the same in the control group and in the experimental group after 30 min of ischemia. The K+ stimulated release of L-[14C]glutamate independent of calcium was increased to 145% after 30 min of ischemia and 1 d of reperfusion. The decreased Km value at the glutamate transporter may have contributed to this difference. Kinetic parameters of the L-[14C]glutamate uptake (Km and Vmax) in synaptosomes from rabbit brain were significantly lower after 30 min of ischemia. The authors discovered that during the reperfusion period, Vmax was almost the same as in the control group. The activity of the Na+/Ca2+ exchanger in synaptosomes of rat brain was about 70% of the control values after 30 min of ischemia and 72 h of reperfusion. According to our results, increased L-[14C]glutamate release after 30 min of ischemia appears to be the result of higher intracellular calcium concentration and possibly also of a higher uptake of glutamate.

CD4+ Foxp3+ T-cells contribute to myocardial ischemia-reperfusion injury.

PubMed

Mathes, Denise; Weirather, Johannes; Nordbeck, Peter; Arias-Loza, Anahi-Paula; Burkard, Matthias; Pachel, Christina; Kerkau, Thomas; Beyersdorf, Niklas; Frantz, Stefan; Hofmann, Ulrich

2016-12-01

The present study analyzed the effect of CD4 + Forkhead box protein 3 negative (Foxp3 - ) T-cells and Foxp3 + CD4 + T-cells on infarct size in a mouse myocardial ischemia-reperfusion model. We examined the infarct size as a fraction of the area-at-risk as primary study endpoint in mice after 30minutes of coronary ligation followed by 24hours of reperfusion. CD4 + T-cell deficient MHC-II KO mice showed smaller histologically determined infarct size (34.5±4.7% in MHCII KO versus 59.4±4.9% in wildtype (WT)) and better preserved ejection fraction determined by magnetic resonance tomography (56.9±2.8% in MHC II KO versus 39.0±4.2% in WT). MHC-II KO mice also displayed better microvascular perfusion than WT mice after 24hours of reperfusion. Also CD4 + T-cell sufficient OT-II mice, which express an in this context irrelevant T-cell receptor, revealed smaller infarct sizes compared to WT mice. However, MHC-II blocking anti-I-A/I-E antibody treatment was not able to reduce infarct size indicating that autoantigen recognition is not required for the activation of CD4 + T-cells during reperfusion. Flow-cytometric analysis also did not detect CD4 + T-cell activation in heart draining lymph nodes in response to 24hours of ischemia-reperfusion. Adoptive transfer of CD4 + T-cells in CD4 KO mice increased the infarct size only when including the Foxp3 + CD25 + subset. Depletion of CD4 + Foxp3 + T-cells in DEREG mice enabling specific conditional ablation of this subset by treatment with diphtheria toxin attenuated infarct size as compared to diphtheria toxin treated WT mice. CD4 + Foxp3 + T-cells enhance myocardial ischemia-reperfusion injury. CD4 + T-cells exert injurious effects without the need for prior activation by MHC-II restricted autoantigen recognition. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacological postconditioning with atorvastatin calcium attenuates myocardial ischemia/reperfusion injury in diabetic rats by phosphorylating GSK3β.

PubMed

Chen, Linyan; Cai, Ping; Cheng, Zhendong; Zhang, Zaibao; Fang, Jun

2017-07-01

Diabetes is an independent risk factor for myocardial ischemia, and many epidemiological data and laboratory studies have revealed that diabetes significantly exacerbated myocardial ischemia/reperfusion injury and ameliorated protective effects. The present study aimed to determine whether pharmacological postconditioning with atorvastatin calcium lessened diabetic myocardial ischemia/reperfusion injury, and investigated the role of glycogen synthase kinase (GSK3β) in this. A total of 72 streptozotocin-induced diabetic rats were randomly divided into six groups, and 24 age-matched male non-diabetic Sprague-Dawley rats were randomly divided into two groups. Rats all received 40 min myocardial ischemia followed by 180 min reperfusion, except sham-operated groups. Compared with the non-diabetic ischemia/reperfusion model group, the diabetic ischemia/reperfusion group had a comparable myocardial infarct size, but a higher level of serum cardiac troponin I (cTnI) and morphological alterations to their myocardial cells. Compared with the diabetic ischemia/reperfusion group, the group that received pharmacological postconditioning with atorvastatin calcium had smaller myocardial infarct sizes, lower levels of cTnI, reduced morphological alterations to myocardial cells, higher levels of p-GSK3β, heat shock factor (HSF)-1 and heat shock protein (HSP)70. The cardioprotective effect conferred by atorvastatin calcium did not attenuate myocardial ischemia/reperfusion injury following application of TDZD-8, which phosphorylates and inactivates GSK3β. Pharmacological postconditioning with atorvastatin calcium may attenuate diabetic heart ischemia/reperfusion injury in the current context. The phosphorylation of GSK3β serves a critical role during the cardioprotection in diabetic rats, and p-GSK3β may accelerate HSP70 production partially by activating HSF-1 during myocardial ischemic/reperfusion injury.

Thymoquinone protects end organs from abdominal aorta ischemia/reperfusion injury in a rat model.

PubMed

Aydin, Mehmet Salih; Kocarslan, Aydemir; Kocarslan, Sezen; Kucuk, Ahmet; Eser, İrfan; Sezen, Hatice; Buyukfirat, Evren; Hazar, Abdussemet

2015-01-01

Previous studies have demonstrated that thymoquinone has protective effects against ischemia reperfusion injury to various organs like lungs, kidneys and liver in different experimental models. We aimed to determine whether thymoquinone has favorable effects on lung, renal, heart tissues and oxidative stress in abdominal aorta ischemia-reperfusion injury. Thirty rats were divided into three groups as sham (n=10), control (n=10) and thymoquinone (TQ) treatment group (n=10). Control and TQ-treatment groups underwent abdominal aorta ischemia for 45 minutes followed by a 120-min period of reperfusion. In the TQ-treatment group, thymoquinone was given 5 minutes. before reperfusion at a dose of 20 mg/kg via an intraperitoneal route. Total antioxidant capacity, total oxidative status (TOS), and oxidative stress index (OSI) in blood serum were measured and lung, kidney, and heart tissue histopathology were evaluated with light microscopy. Total oxidative status and oxidative stress index activity in blood samples were statistically higher in the control group compared to the sham and TQ-treatment groups (P<0.001 for TOS and OSI). Control group injury scores were statistically higher compared to sham and TQ-treatment groups (P<0.001 for all comparisons). Thymoquinone administered intraperitoneally was effective in reducing oxidative stress and histopathologic injury in an acute abdominal aorta ischemia-reperfusion rat model.

Noscapine protects OLN-93 oligodendrocytes from ischemia-reperfusion damage: Calcium and nitric oxide involvement.

PubMed

Nadjafi, S; Ebrahimi, S-A; Rahbar-Roshandel, N

2015-12-01

This study was carried out to evaluate the effects of noscapine, a benzylisoquinoline alkaloid from opium poppy, on oligodendrocyte during ischemia/reperfusion-induced excitotoxic injury. Changes in intracellular calcium levels due to chemical ischemia and nitric oxide (NO) production during ischemia/reperfusion were evaluated as the hallmarks of ischemia-derived excitotoxic event. OLN-93 cell line (a permanent immature rat oligodendrocyte) was used as a model of oligodendrocyte. 30- or 60-minute-oxygen-glucose deprivation/24 hours reperfusion were used to induce excitotoxicity. MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay was used to evaluate cell viability. Ratiometric fluorescence microscopy using Ca(2+)-sensitive indicator Fura-2/AM was utilized to assess intracellular calcium levels. NO production was evaluated by Griess method. Noscapine (4 μM) significantly attenuated intracellular Ca(2+) elevation (P < 0.001). Also, noscapine significantly decreased NO production during a 30-minute oxygen-glucose deprivation/reperfusion (P < 0.01). The inhibitory effect of noscapine (4 μM) on intracellular Ca(2+) was greater than ionotropic glutamate receptors antagonists. Noscapine is protective against ischemia/reperfusion-induced excitotoxic injury in OLN-93 oligodendrocyte. This protective effect seems to be related to attenuation of intracellular Ca(2+) overload and NO production.

Effects of acetylpuerarin on hippocampal neurons and intracellular free calcium subjected to oxygen-glucose deprivation/reperfusion in primary culture.

PubMed

Liu, Rui; Wei, Xin-bing; Zhang, Xiu-Mei

2007-05-25

This study was undertaken to find out the effects of acetylpuerarin on hippocampal neurons and intracellular free calcium in primary culture subjected to oxygen-glucose deprivation/reperfusion. According to different reperfusion time (1 h, 6 h, 12 h, 24 h), three concentrations (1.6 micromol l(-1), 0.4 micromol l(-1), 0.1 micromol l(-1)) of acetylpuerarin, and MK-801 (10 micromol l(-1)), a positive control drug, neurons were randomly divided into 21 groups. Each group was observed by inverted phase contrast microscope; neuron viability was measured by the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT); intracellular Ca(2+) was observed by Fura-2/AM ester through fluorospectrophotometer. The injured neurons were protected and degeneration and necrosis were alleviated in treatment groups of acetylpuerarin and MK-801. Acetylpuerarin increased the neuron viability at high, middle and low concentrations. Fluorescence detection results showed that the calcium concentration in the group treated with acetylpuerarin and MK-801 was lowered in each reperfusion time. Our results demonstrated that acetylpuerarin could protect the hippocampal neurons from ischemia-reperfusion injury in rats by alleviating the morphological damage, increasing neuron viability and decreasing calcium concentration in neuron.

Blocking neutrophil integrin activation prevents ischemia-reperfusion injury.

PubMed

Yago, Tadayuki; Petrich, Brian G; Zhang, Nan; Liu, Zhenghui; Shao, Bojing; Ginsberg, Mark H; McEver, Rodger P

2015-07-27

Neutrophil recruitment, mediated by β2 integrins, combats pyogenic infections but also plays a key role in ischemia-reperfusion injury and other inflammatory disorders. Talin induces allosteric rearrangements in integrins that increase affinity for ligands (activation). Talin also links integrins to actin and other proteins that enable formation of adhesions. Structural studies have identified a talin1 mutant (L325R) that perturbs activation without impairing talin's capacity to link integrins to actin and other proteins. Here, we found that mice engineered to express only talin1(L325R) in myeloid cells were protected from renal ischemia-reperfusion injury. Dissection of neutrophil function in vitro and in vivo revealed that talin1(L325R) neutrophils had markedly impaired chemokine-induced, β2 integrin-mediated arrest, spreading, and migration. Surprisingly, talin1(L325R) neutrophils exhibited normal selectin-induced, β2 integrin-mediated slow rolling, in sharp contrast to the defective slow rolling of neutrophils lacking talin1 or expressing a talin1 mutant (W359A) that blocks talin interaction with integrins. These studies reveal the importance of talin-mediated activation of integrins for renal ischemia-reperfusion injury. They further show that neutrophil arrest requires talin recruitment to and activation of integrins. However, although neutrophil slow rolling requires talin recruitment to integrins, talin-mediated integrin activation is dispensable. © 2015 Yago et al.

Blocking neutrophil integrin activation prevents ischemia–reperfusion injury

PubMed Central

Yago, Tadayuki; Petrich, Brian G.; Zhang, Nan; Liu, Zhenghui; Shao, Bojing; Ginsberg, Mark H.

2015-01-01

Neutrophil recruitment, mediated by β2 integrins, combats pyogenic infections but also plays a key role in ischemia–reperfusion injury and other inflammatory disorders. Talin induces allosteric rearrangements in integrins that increase affinity for ligands (activation). Talin also links integrins to actin and other proteins that enable formation of adhesions. Structural studies have identified a talin1 mutant (L325R) that perturbs activation without impairing talin’s capacity to link integrins to actin and other proteins. Here, we found that mice engineered to express only talin1(L325R) in myeloid cells were protected from renal ischemia–reperfusion injury. Dissection of neutrophil function in vitro and in vivo revealed that talin1(L325R) neutrophils had markedly impaired chemokine-induced, β2 integrin–mediated arrest, spreading, and migration. Surprisingly, talin1(L325R) neutrophils exhibited normal selectin-induced, β2 integrin–mediated slow rolling, in sharp contrast to the defective slow rolling of neutrophils lacking talin1 or expressing a talin1 mutant (W359A) that blocks talin interaction with integrins. These studies reveal the importance of talin-mediated activation of integrins for renal ischemia–reperfusion injury. They further show that neutrophil arrest requires talin recruitment to and activation of integrins. However, although neutrophil slow rolling requires talin recruitment to integrins, talin-mediated integrin activation is dispensable. PMID:26169939

Reperfusion-Associated Hemorrhagic Transformation in SHR Rats

PubMed Central

Henning, Erica C.; Latour, Lawrence L.; Hallenbeck, John M.; Warach, Steven

2016-01-01

Background and Purpose Symptomatic hemorrhagic transformation (HT) is the most important complicating factor after treatment with intravenous tissue plasminogen activator. In this study, we used multimodal magnetic resonance imaging to investigate the incidence and severity of reperfusion-based HT in spontaneously hypertensive rats after ischemia/reperfusion. Methods Twenty male spontaneously hypertensive rats were subjected to 30 minutes of middle cerebral artery occlusion via the suture model. Diffusion-weighted, T2-weighted, and gradient-echo imaging were performed on days 1, 2, 3, 4, and 7 for longitudinal evaluation of lesion evolution, vasogenic edema, and HT, respectively. Findings on gradient-echo images were classified according to the severity of hemorrhage: no HT; punctate or small petechial hemorrhage (HI-1); confluent petechial hemorrhage (HI-2); hematoma with absent/mild space-occupying effect (PH-1, ≤30% lesion volume); and hematoma with significant space-occupying effect and potential perihematomal edema (PH-2, >30% lesion volume). Histopathologic evaluation of HT was performed after final imaging for comparison with magnetic resonance imaging results. Results Final hemorrhage scores based on severity were as follows: HI-1 23.1%, HI-2 30.8%, PH-1 30.8%, and PH-2 15.4%. Similar to clinical observations, only PH-2 was associated with neurologic deterioration and associated weight loss. Conclusions This model has a high incidence of parenchymal hematomas (46.2%) and therefore is appropriate for the evaluation of novel therapeutics targeting blood-brain barrier integrity and the reduction of symptomatic HT events (PH-2), as well as those potentially “at risk” for neurologic deterioration (PH-1). PMID:18757286

The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion.

PubMed

Ertracht, Offir; Liani, Esti; Bachner-Hinenzon, Noa; Bar-Am, Orit; Frolov, Luba; Ovcharenko, Elena; Awad, Huda; Blum, Shany; Barac, Yaron; Amit, Tamar; Adam, Dan; Youdim, Moussa; Binah, Ofer

2011-06-01

Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S-enantiomer of rasagiline, an anti-Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats. The model consisted of 30-min occlusion of the left anterior descending artery followed by 4 or 24 h reperfusion. In addition, we investigated the possible mechanisms of cardioprotection in H9c2 cells and neonatal rat ventricular myocytes (NRVM) exposed to oxidative stress induced by H(2) O(2) . TVP1022 (20 and 40 mg·kg(-1) ) administered 5 min before reperfusion followed by an additional dose 4 h after reperfusion reduced the infarct size and attenuated the decline in ventricular function. TVP1022 also attenuated I/R-induced deterioration in cardiac mitochondrial integrity evaluated by mitochondrial swelling capacity. In vitro, using H9c2 cells and NRVM, TVP1022 attenuated both serum free- and H(2) O(2) -induced damage, preserved mitochondrial membrane potential and Bcl-2 levels, inhibited mitochondrial cytochrome c release and the increase in cleaved caspase 9 and 3 levels, and enhanced the phosphorylation of protein kinase C and glycogen synthase kinase-3β. TVP1022 provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage resulting from I/R injuries. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Impaired Intestinal Mucosal Barrier upon Ischemia-Reperfusion: “Patching Holes in the Shield with a Simple Surgical Method”

PubMed Central

Rosero, Olivér; Ónody, Péter; Molnár, Dávid; Lotz, Gábor; Turóczi, Zsolt; Fülöp, András; Garbaisz, Dávid; Harsányi, László; Szijártó, Attila

2014-01-01

Mesenteric ischemia-reperfusion (IR) is associated with impairment of the gut barrier function and the initiation of a proinflammatory cascade with life-threatening results. Therefore methods directed to ameliorate IR injury are of great importance. We aimed at describing the effects of postconditioning (PC) on the alterations of the intestinal mucosal function and the inflammatory response upon mesenteric IR. Methods. Male Wistar rats were gavaged with green fluorescent protein-expressing E. coli suspensions. Animals were randomized into three groups (n = 15), sham-operated, IR-, and PC-groups, and underwent 60 minutes of superior mesenteric artery occlusion, followed by 6 hours of reperfusion. Postconditioning was performed at the onset of reperfusion. Blood and tissue samples were taken at the end of reperfusion, for histological, bacteriological, and plasma examinations. Results. The PC-group presented a more favorable claudin-2, claudin-3, claudin-4, and zonula occludens-1 membrane expression profile, and significantly lower rates of bacterial translocation to distant organs and plasma D-lactate levels compared to the IR-group. Histopathological lesions, plasma I-FABP, IL-6, and TNF-α levels were significantly lower in the PC-group compared to the IR-group. Conclusion. The use of postconditioning improved the integrity of the intestinal mucosal barrier upon mesenteric IR, and thus reduced the incidence of bacterial translocation and development of a systemic inflammatory response. PMID:24955347

Effect and mechanism of propofol on myocardial ischemia reperfusion injury in type 2 diabetic rats.

PubMed

Lin, Changfu; Sui, Haijing; Gu, Jie; Yang, Xue; Deng, Lin; Li, Wenzhi; Ding, Wengang; Li, Dongmei; Yang, Yingchun

2013-11-01

Propofol has been reported to have an inhibitory effect on ischemia/reperfusion (I/R) injury in various experimental models by reducing oxidative stress, protecting mitochondrial function and suppressing apoptosis. The aim of this study was to investigate the effect and mechanism of propofol on myocardial I/R injury in type 2 diabetic rats. A total of 24 streptozotocin (STZ)-induced diabetic rats were randomly divided into three equal groups as follows: the DI group with myocardial I/R, which was induced by occluding the left anterior descending coronary artery for 30min, followed by 2h of reperfusion; the DP group, which underwent I/R and propofol infusion at 6mg·kg(-1)·h(-1); and the DC group, which underwent sham operations without tightening of the coronary sutures. As a control, 24 healthy, age-matched, male Wistar rats were randomly divided into three equal groups: the CI, CP and CC groups. The injured cardiac tissues were removed for microscopic examination after reperfusion. The serum concentrations of nitric oxide (NO) and endothelin (ET-1); the expression of Bax, Bcl-2 and Caspase-3 within the cardiac structures; and the number of apoptotic myocardial cells were measured. Compared with the baseline levels before ischemia, the serum concentration of ET-1 after 2h of reperfusion was increased in the CI and DI groups, while the concentration of NO in these groups decreased after reperfusion. Compared with the I/R groups, propofol increased the content of NO and decreased the content of ET-1. Compared with the sham operation groups, I/R decreased the ratio of the anti-apoptotic protein Bcl-2 to the pro-apoptotic protein Bax, which resulted in an elevation of the index of apoptosis (AI). In contrast, compared with the I/R group, propofol increased the Bcl-2-to-Bax ratio and decreased the AI. I/R increased the expression of caspase-3 compared with the sham treatment groups, while treatment with propofol reduced caspase-3 expression relative to the I/R groups

Effect of Cuscuta chinensis on renal function in ischemia/reperfusion-induced acute renal failure rats.

PubMed

Shin, Sun; Lee, Yun Jung; Kim, Eun Ju; Lee, An Sook; Kang, Dae Gill; Lee, Ho Sub

2011-01-01

The kidneys play a central role in regulating water, ion composition and excretion of metabolic waste products in the urine. Cuscuta chinensis has been known as an important traditional Oriental medicine for the treatment of liver and kidney disorders. Thus, we studied whether an aqueous extract of Cuscuta chinensis (ACC) seeds has an effect on renal function parameters in ischemia/reperfusion-induced acute renal failure (ARF) rats. Administration of 250 mg/kg/day ACC showed that renal functional parameters including urinary excretion rate, osmolality, Na(+), K(+), Cl(-), creatinine clearance, solute-free water reabsorption were significantly recovered in ischemia/reperfusion-induced ARF. Periodic acid Schiff staining showed that administration of ACC improved tubular damage in ischemia/reperfusion-induced ARF. In immunoblot and immunohistological examinations, ischemia/reperfusion-induced ARF decreased the expressions of water channel AQP 2, 3 and sodium potassium pump Na,K-ATPase in the renal medulla. However, administration of ACC markedly incremented AQP 2, 3 and Na,K-ATPase expressions. Therefore, these data indicate that administration of ACC ameliorates regulation of the urine concentration and renal functions in rats with ischemia/reperfusion-induced ARF.

Pretreatment of parecoxib attenuates hepatic ischemia/reperfusion injury in rats.

PubMed

Zhang, Tao; Ma, Yi; Xu, Kang-Qing; Huang, Wen-Qi

2015-11-17

Previous studies showed that cyclooxygenase(COX) was involved in ischemia/reperfusion (I/R) injuries. Parecoxib, a selective inhibitor for COX -2, has been shown to have protective properties in reducing I/R injury in the heart, kidney and brain. The aim of this study was to investigate the effects of parecoxib on hepatic I/R and to explore the underlying mechanisms. Fifty-two Sprague-Dawley rats were randomly divided into three groups: the sham-operation (Sham) group, the hepatic ischemia/reperfusion (I/R) group, and the parecoxib pretreated I/R (I/R + Pare) group. Partial warm ischemia was produced in the left and middle hepatic lobes of Sprague-Dawley rats for 60 min, followed by 6 h of reperfusion. Rats in the I/R + Pare group received parecoxib (10 mg/kg) intraperitoneally twice a day for three consecutive days prior to ischemia. Blood and tissue samples from the groups were collected 6 h after reperfusion, and a survival study was performed. Pretreatment with parecoxib prior to I/R insult significantly reduced I/R-induced elevations of aminotransferases, and significantly improved the histological status of the liver. Parecoxib significantly suppressed inflammatory cascades, as demonstrated by attenuations in TNF-α and IL-6. Parecoxib significantly inhibited iNOS and nitrotyrosine expression after I/R and significantly attenuated I/R-induced apoptosis. The 7-day survival rate was increased by pre-administration of parecoxib. Administration of parecoxib prior to hepatic I/R attenuates hepatic injury through inhibition of inflammatory response and nitrosative stress.

Sevoflurane pretreatment enhance HIF-2α expression in mice after renal ischemia/reperfusion injury

PubMed Central

Zheng, Beijie; Zhan, Qionghui; Chen, Jue; Xu, Huan; He, Zhenzhou

2015-01-01

Ischemia/reperfusion (I/R) injury often occurs, which is one of the major causes of acute kidney injury, thus increasing in-hospital mortality. HIF-2α has a protective role against ischemia of the kidney. Renal ischemia/reperfusion under sevoflurane anesthesia resulted in drastic improvements in renal function. We hypothesized that underlying mechanism responsible for renal protection from sevoflurane pretreatment involves the upregulation of HIF-2α. Sevoflurane pretreatment were performed on WT and HIF-2α knockout mice before renal ischemia/reperfusion. Levels of blood urea nitrogen (BUN) and serum creatinine (Cr) were determined with a standard clinical automatic analyzer. The left kidneys were taken for morphological examination. Expression of HIF-2α in kidney tissue was examined by western blotting. In WT mice, group I/R injury had significantly higher BUN and Cr levels than group control, whereas group I/R + Sev had significantly lower BUN and Cr levels than group I/R injury. Renal HIF-2α expression levels were significantly higher in WT mice of group I/R + Sev than group control and group I/R. In HIF-2α-/- mice, group I/R + Sev showed much higher BUN and Cr levels and severer histological damage than group I/R and group control. Renal HIF-2α expression levels were significantly higher in WT mice of group I/R + Sev than group control and group I/R. Our findings suggested that HIF-2α might contribute to the beneficial effect of sevoflurane in renal ischemia/reperfusion injury. PMID:26722509

Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium

PubMed Central

Juhasz, Bela; Thirunavukkarasu, Mahesh; Pant, Rima; Zhan, Lijun; Penumathsa, Suresh Varma; Secor, Eric R.; Srivastava, Sapna; Raychaudhuri, Utpal; Menon, Venugopal P.; Otani, Hajime; Thrall, Roger S.; Maulik, Nilanjana

2008-01-01

Bromelain (Br), a proteolytic enzyme extracted from the stem of the pineapple, is known to possess anti-inflammatory activity and has been shown to reduce blood viscosity, prevent the aggregation of blood platelets, and improve ischemia-reperfusion (I/R) injury in a skeletal muscle model. We investigated the capacity of Br to limit myocardial injury in a global I/R model. Adult male Sprague-Dawley rats were divided into two groups: control (PBS) and Br at 10 mg/kg in PBS administered via intraperitoneal injection (twice/day) for 15 consecutive days. On day 16, the hearts were excised and subjected to 30 min of global ischemia followed by 2 h of reperfusion. Br treatment showed higher left ventricular functional recovery throughout reperfusion compared with the controls [maximum rate of rise in intraventricular pressure (dP/dtmax), 2,225 vs. 1,578 mmHg/s at 2 h reperfusion]. Aortic flow was also found to be increased in Br treatment when compared with that in untreated rats (11 vs. 1 ml). Furthermore, Br treatment reduced both the infarct size (34% vs. 43%) and the degree of apoptosis (28% vs. 37%) compared with the control animals. Western blot analysis showed an increased phosphorylation of both Akt and FOXO3A in the treatment group compared with the control. These results demonstrated for the first time that Br triggers an Akt-dependent survival pathway in the heart, revealing a novel mechanism of cardioprotective action and a potential therapeutic target against I/R injury. PMID:18192224

Long-term enteral arginine supplementation in rats with intestinal ischemia and reperfusion.

PubMed

Lee, Chien-Hsing; Hsiao, Chien-Chou; Hung, Ching-Yi; Chang, Yu-Jun; Lo, Hui-Chen

2012-06-01

The effects of short-term enteral arginine supplementation on intestinal ischemia-reperfusion (IR) injury have been widely studied, especially the ischemic preconditioning supplementation. The aim of this study was to investigate the effects of long-term intra-duodenal supplementation of arginine on intestinal morphology, arginine-associated amino acid metabolism, and inflammatory responses in rats with intestinal IR. Male Wistar rats with or without three hours of ileal ischemia underwent duodenal cannulation for continuous infusion of formula with 2% arginine or commercial protein powder for 7 d. The serological examinations, plasma amino acid and cytokine profiles, and intestinal morphology were assessed. Intestinal IR injury had significant impacts on the decreases in circulating red blood cells, hemoglobin, ileum mass, and villus height and crypt depth of the distal jejunum. In addition, arginine supplementation decreased serum cholesterol and increased plasma arginine concentrations. In rats with intestinal IR injury, arginine supplementation significantly decreased serum nitric oxide, plasma citrulline and ornithine, and the mucosal protein content of the ileum. These results suggest that long-term intra-duodenal arginine administration may not have observable benefits on intestinal morphology or inflammatory response in rats with intestinal ischemia and reperfusion injury. Therefore, the necessity of long-term arginine supplementation for patients with intestinal ischemia and reperfusion injury remains questionable and requires further investigation. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of Platelet-Rich Plasma (PRP) on a Model of Renal Ischemia-Reperfusion in Rats.

PubMed

Martín-Solé, Oriol; Rodó, Joan; García-Aparicio, Lluís; Blanch, Josep; Cusí, Victoria; Albert, Asteria

2016-01-01

Renal ischemia-reperfusion injury is a major cause of acute renal failure, causing renal cell death, a permanent decrease of renal blood flow, organ dysfunction and chronic kidney disease. Platelet-rich plasma (PRP) is an autologous product rich in growth factors, and therefore able to promote tissue regeneration and angiogenesis. This product has proven its efficacy in multiple studies, but has not yet been tested on kidney tissue. The aim of this work is to evaluate whether the application of PRP to rat kidneys undergoing ischemia-reperfusion reduces mid-term kidney damage. A total of 30 monorrenal Sprague-Dawley male rats underwent renal ischemia-reperfusion for 45 minutes. During ischemia, PRP (PRP Group, n = 15) or saline solution (SALINE Group, n = 15) was administered by subcapsular renal injection. Control kidneys were the contralateral organs removed immediately before the start of ischemia in the remaining kidneys. Survival, body weight, renal blood flow on Doppler ultrasound, kidney weight, kidney volume, blood biochemistry and histopathology were determined for all subjects and kidneys, as applicable. Correlations between these variables were searched for. The PRP Group showed significantly worse kidney blood flow (p = 0.045) and more histopathological damage (p<0.0001). Correlations were found between body weight, kidney volume, kidney weight, renal blood flow, histology, and serum levels of creatinine and urea. Our study provides the first evidence that treatment with PRP results in the deterioration of the kidney's response to ischemia-reperfusion injury.

Effects of Platelet-Rich Plasma (PRP) on a Model of Renal Ischemia-Reperfusion in Rats

PubMed Central

Martín-Solé, Oriol; Rodó, Joan; García-Aparicio, Lluís; Blanch, Josep; Cusí, Victoria; Albert, Asteria

2016-01-01

Renal ischemia-reperfusion injury is a major cause of acute renal failure, causing renal cell death, a permanent decrease of renal blood flow, organ dysfunction and chronic kidney disease. Platelet-rich plasma (PRP) is an autologous product rich in growth factors, and therefore able to promote tissue regeneration and angiogenesis. This product has proven its efficacy in multiple studies, but has not yet been tested on kidney tissue. The aim of this work is to evaluate whether the application of PRP to rat kidneys undergoing ischemia-reperfusion reduces mid-term kidney damage. A total of 30 monorrenal Sprague-Dawley male rats underwent renal ischemia-reperfusion for 45 minutes. During ischemia, PRP (PRP Group, n = 15) or saline solution (SALINE Group, n = 15) was administered by subcapsular renal injection. Control kidneys were the contralateral organs removed immediately before the start of ischemia in the remaining kidneys. Survival, body weight, renal blood flow on Doppler ultrasound, kidney weight, kidney volume, blood biochemistry and histopathology were determined for all subjects and kidneys, as applicable. Correlations between these variables were searched for. The PRP Group showed significantly worse kidney blood flow (p = 0.045) and more histopathological damage (p<0.0001). Correlations were found between body weight, kidney volume, kidney weight, renal blood flow, histology, and serum levels of creatinine and urea. Our study provides the first evidence that treatment with PRP results in the deterioration of the kidney’s response to ischemia-reperfusion injury. PMID:27551718

Antiarrhythmic effect of tamoxifen on the vulnerability induced by hyperthyroidism to heart ischemia/reperfusion damage.

PubMed

Pavón, Natalia; Hernández-Esquivel, Luz; Buelna-Chontal, Mabel; Chávez, Edmundo

2014-09-01

Hyperthyroidism, known to have deleterious effects on heart function, and is associated with an enhanced metabolic state, implying an increased production of reactive oxygen species. Tamoxifen is a selective antagonist of estrogen receptors. These receptors make the hyperthyroid heart more susceptible to ischemia/reperfusion. Tamoxifen is also well-known as an antioxidant. The aim of the present study was to explore the possible protective effect of tamoxifen on heart function in hyperthyroid rats. Rats were injected daily with 3,5,3'-triiodothyronine at 2mg/kg body weight during 5 days to induce hyperthyroidism. One group was treated with 10mg/kg tamoxifen and another was not. The protective effect of the drug on heart rhythm was analyzed after 5 min of coronary occlusion followed by 5 min reperfusion. In hyperthyroid rats not treated with tamoxifen, ECG tracings showed post-reperfusion arrhythmias, and heart mitochondria isolated from the ventricular free wall lost the ability to accumulate and retain matrix Ca(2+) and to form a high electric gradient. Both of these adverse effects were avoided with tamoxifen treatment. Hyperthyroidism-induced oxidative stress caused inhibition of cis-aconitase and disruption of mitochondrial DNA, effects which were also avoided by tamoxifen treatment. The current results support the idea that tamoxifen inhibits the hypersensitivity of hyperthyroid rat myocardium to reperfusion damage, probably because its antioxidant activity inhibits the mitochondrial permeability transition. Copyright © 2014 Elsevier Ltd. All rights reserved.

Education level and inequalities in stroke reperfusion therapy: observations in the Swedish stroke register.

PubMed

Stecksén, Anna; Glader, Eva-Lotta; Asplund, Kjell; Norrving, Bo; Eriksson, Marie

2014-09-01

Previous studies have revealed inequalities in stroke treatment based on demographics, hospital type, and region. We used the Swedish Stroke Register (Riksstroke) to test whether patient education level is associated with reperfusion (either or both of thrombolysis and thrombectomy) treatment. We included 85 885 patients with ischemic stroke aged 18 to 80 years registered in Riksstroke between 2003 and 2009. Education level was retrieved from Statistics Sweden, and thrombolysis, thrombectomy, patient, and hospital data were obtained from Riksstroke. We used multivariable logistic regression to analyze the association between reperfusion therapy and patient education. A total of 3649 (4.2%) of the patients received reperfusion therapy. University-educated patients were more likely to be treated (5.5%) than patients with secondary (4.6%) or primary education (3.6%; P<0.001). The inequality associated with education was still present after adjustment for patient characteristics; university education odds ratio, 1.14; 95% confidence interval, 1.03 to 1.26 and secondary education odds ratio, 1.08; 95% confidence interval, 1.00 to 1.17 compared with primary education. Higher hospital specialization level was also associated with higher reperfusion levels (P<0.001). In stratified multivariable analyses by hospital type, significant treatment differences by education level existed only among large nonuniversity hospitals (university education odds ratio, 1.20; 95% confidence interval, 1.04-1.40; secondary education odds ratio, 1.14; 95% confidence interval, 1.01-1.29). We demonstrated a social stratification in reperfusion, partly explained by patient characteristics and the local hospital specialization level. Further studies should address treatment delays, stroke knowledge, and means to improve reperfusion implementation in less specialized hospitals. © 2014 American Heart Association, Inc.

Intraperitoneal Administration of Silymarin Protects End Organs from Multivisceral Ischemia/Reperfusion Injury in a Rat Model

PubMed Central

Koçarslan, Aydemir; Koçarslan, Sezen; Aydin, Mehmet Salih; Gunay, Şamil; Karahan, Mahmut Alp; Taşkın, Abdullah; Üstunel, Murat; Aksoy, Nurten

2016-01-01

Objective To determine whether intraperitoneal silymarin administration has favorable effects on the heart, lungs, kidney, and liver and on oxidative stress in a rat model of supraceliac aorta ischemia/reperfusion injury. Methods Thirty male Wistar albino rats were divided equally into three groups: sham, control, and silymarin. The control and silymarin groups underwent supraceliac aortic occlusion for 45 min, followed by a 60 min period of reperfusion under terminal anesthesia. In the silymarin group, silymarin was administered intraperitoneally during ischemia at a dose of 200 mg/kg. Rats were euthanized using terminal anesthesia, and blood was collected from the inferior vena cava for total antioxidant capacity, total oxidative status, and oxidative stress index measurement. Lungs, heart, liver and kidney tissues were histologically examined. Results Ischemia/reperfusion injury significantly increased histopathological damage as well as the total oxidative status and oxidative stress index levels in the blood samples. The silymarin group incurred significantly lesser damage to the lungs, liver and kidneys than the control group, while no differences were observed in the myocardium. Furthermore, the silymarin group had significantly lower total oxidative status and oxidative stress index levels than the control group. Conclusion Intraperitoneal administration of silymarin reduces oxidative stress and protects the liver, kidney, and lungs from acute supraceliac abdominal aorta ischemia/reperfusion injury in the rat model. PMID:28076620

[Effect and mechanism of total flavonoids of bugloss on rats with myocardial ischemia and reperfusion injury].

PubMed

Xu, Xiao-Na; Niu, Zi-Ran; Wang, Shou-Bao; Chen, Yu-Cai; Gao, Li; Fang, Lian-Hu; Du, Guan-Hua

2014-06-01

This study is to investigate the effect of total flavonoids of Uygur medicine bugloss (BTF) on rats with myocardial ischemia/reperfusion injury, and to explore the mechanisms by which it acts. Left anterior descending (LAD) coronary artery in rats was occluded for 30 min followed by 4 h reperfusion. Meanwhile, BTF dissolved in saline was administered intraperitoneally at dosage of 10, 30 and 50 mg x kg(-1). Electrocardiograph, infarction index, serum myocardial enzymes and heart function were determined to evaluate the effect of BTF. Some other observations were carried out to explore whether inhibiting inflammation and apoptosis is involved in the mechanisms underlying BTF. Our results showed that in ischemia/reperfusion injured rats BTF could dose-dependently reduce myocardial infarction index and myocardial enzyme leakage, and enhance heart function, indicating that it possesses significant cardio protection. ELISA analysis showed that BTF could decrease the content of myocardial inflammatory cytokines such as IL-1beta, IL-6 and TNF-alpha. Western-blotting confirmed that BTF could increase the expression of anti-apoptotic protein Bcl-2 and reduce the expression of proapoptosis protein Bax. Further more, the phosphorylation level of PI3K and Akt was upregulated by BTF treatment. BTF can protect rat against myocardial ischemia/reperfusion injury. Anti-inflammation and inhibition of apoptosis through upregulating PI3K/Akt signal pathway may contribute to the protective effect of BTF.

Protective effect of tetraethyl pyrazine against focal cerebral ischemia/reperfusion injury in rats: therapeutic time window and its mechanism.

PubMed

Jia, Jie; Zhang, Xi; Hu, Yong-Shan; Wu, Yi; Wang, Qing-Zhi; Li, Na-Na; Wu, Cai-Qin; Yu, Hui-Xian; Guo, Qing-Chuan

2009-03-01

Tetramethyl pyrazine has been considered an effective agent in treating neurons ischemia/reperfusion injury, but the mechanism of its therapeutic effect remains unclear. This study was to explore the therapeutic time window and mechanism of tetramethyl pyrazine on temporary focal cerebral ischemia/reperfusion injury. Middle cerebral artery occlusion was conducted in male Sprague-Dawley rats and 20 mg/kg of tetramethyl pyrazine was intraperitoneally injected at different time points. At 72 h after reperfusion, all animals' neurologic deficit scores were evaluated. Cerebrums were removed and cerebral infarction volume was measured. The expression of thioredoxin and thioredoxin reductase mRNA was determined at 6 and 24 h after reperfusion. Cerebral infarction volume and neurological deficit scores were significantly decreased in the group with tetramethyl pyrazine treatment. The expression of thioredoxin-1/thioredoxin-2 and thioredoxin reductase-1/thioredoxin reductase-2 was significantly decreased in rats with ischemia/reperfusion injury, while it was increased by tetramethyl pyrazine administration. Treatment with tetramethyl pyrazine, within 4 h after reperfusion, protects the brain from ischemic reperfusion injury in rats. The neuroprotective mechanism of tetramethyl pyrazine treatment is, in part, mediated through the upregulation of thioredoxin transcription.

Cardioprotective properties of citicoline against hyperthyroidism-induced reperfusion damage in rat hearts.

PubMed

Hernández-Esquivel, Luz; Pavón, Natalia; Buelna-Chontal, Mabel; González-Pacheco, Héctor; Belmont, Javier; Chávez, Edmundo

2015-06-01

Hyperthyroidism represents an increased risk factor for cardiovascular morbidity, especially when the heart is subjected to an ischemia/reperfusion process. The aim of this study was to explore the possible protective effect of the nucleotide citicoline on the susceptibility of hyperthyroid rat hearts to undergo reperfusion-induced damage, which is associated with mitochondrial dysfunction. Hence, we analyzed the protective effect of citicoline on the electrical behavior and on the mitochondrial function in rat hearts. Hyperthyroidism was established after a daily i.p. injection of triiodothyronine (at 2 mg/kg of body weight) during 5 days. Thereafter, citicoline was administered i.p. (at 125 mg/kg of body weight) for 5 days. In hyperthyroid rat hearts, citicoline protected against reperfusion-induced ventricular arrhythmias. Moreover, citicoline maintained the accumulation of mitochondrial Ca(2+), allowing mitochondria to reach a high transmembrane electric gradient that protected against the release of cytochrome c. It also preserved the activity of the enzyme aconitase that inhibited the release of cytokines. The protection also included the inhibition of oxidative stress-induced mDNA disruption. We conclude that citicoline protects against the reperfusion damage that is found in the hyperthyroid myocardium. This effect might be due to its inhibitory action on the permeability transition in mitochondria.

Normal versus sickle red blood cells: hemodynamic and permeability characteristics in reperfusion lung injury.

PubMed

Haynes, J; Seibert, A; Shah, A; Taylor, A

1990-01-01

Decreased deformability and increased internal viscosity of the sickle red blood cell (SRBC) contribute to abnormal flow in the microcirculation. Since the lungs are commonly affected in sickle cell disease, we compared the hemodynamics of the normal human red blood cell (NRBC) with the SRBC in the pulmonary circulation. The SRBC has decreased antioxidant enzyme activities compared with the NRBC. Thus, using the capillary filtration coefficient (Kfc), we determined the ability of the NRBC and the SRBC to attenuate the increased permeability and resulting edema seen in the oxidant stress of reperfusion lung injury (RLI). We found that lungs perfused with a 5% SRBC perfusate had higher pulmonary arterial pressures (Ppa) and resistances than lungs perfused with a 5% NRBC perfusate. Lungs made ischemic and reperfused with a physiologic cell-free perfusate resulted in a significant increase (P less than .05) in Kfc compared with the preischemic Kfc (.45 +/- .06 to 1.4 +/- 22 mL.min-1.cm H2O.100 g-1). In lungs reperfused with 5% RBC-containing perfusates, the Kfc did not change from preischemic Kfc with NRBCs and decreased from the preischemic Kfc with SRBCs. These findings suggest that the SRBC causes physiologically significant increases in Ppa and resistances and the SRBC, like the NRBC, offers apparent protection in RLI.

Cardioprotective effect of resistance training and Crataegus oxyacantha extract on ischemia reperfusion-induced oxidative stress in diabetic rats.

PubMed

Ranjbar, Kamal; Zarrinkalam, Ebrahim; Salehi, Iraj; Komaki, Alireza; Fayazi, Bayan

2018-04-01

Discovering an effective approach to limit infarction size after ischemia-reperfusion has a clinical importance in diabetics. We investigated the anti-myocardial ischemia-reperfusion injury effect of resistance training and Crataegus oxyacantha extract on diabetic rats. To this end, 50 male Wistar rats were randomly divided into 5 groups: the sedentary control (SC), sedentary diabetic (SD), resistance trained diabetic (RD), diabetic plus C. oxyacantha extract treatment (CD) and resistance trained diabetic plus C. oxyacantha extract treatment (RCD) groups. Animals in trained groups were subjected to progressive resistance training program with the use of a ladder (5 days/week, for 10 weeks). C. oxyacantha extract rats were treated with 100 mg/kg body weight of the extract using a gavage every day for 10 weeks. After treatments, rats were subjected to ischemia via LAD artery ligation for 30 min followed by 90 min reperfusion. The heart was collected following the ischemia-reperfusion and analyzed for oxidative stress and ischemia-reperfusion injury. Compared to the SC group, LDH, CK-MB and infarction size in the SD group were significantly higher, whereas injury indices in the RCD group were significantly lower than those in the SD group. GPx and MPO levels after reperfusion increased and decreased, respectively in response to training and C. oxyacantha. These findings suggest that 10 weeks resistance training and C. oxyacantha can synergistically decrease ischemia-reperfusion injury, and this mechanism may be related to a reduction in oxidative stress which is normally associated with ischemia-reperfusion. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Ischemia-reperfusion injury of the cochlea: pharmacological strategies for cochlear protection and implications of glutamate and reactive oxygen species.

PubMed

Tabuchi, Keiji; Nishimura, Bungo; Tanaka, Shuho; Hayashi, Kentaro; Hirose, Yuki; Hara, Akira

2010-06-01

A large amount of energy produced by active aerobic metabolism is necessary for the cochlea to maintain its function. This makes the cochlea vulnerable to blockade of cochlear blood flow and interruption of the oxygen supply. Although certain forms of human idiopathic sudden sensorineural hearing loss reportedly arise from ischemic injury, the pathological mechanism of cochlear ischemia-reperfusion injury has not been fully elucidated. Recent animal studies have shed light on the mechanisms of cochlear ischemia-reperfusion injury. It will help in the understanding of the pathology of cochlear ischemia-reperfusion injury to classify this injury into ischemic injury and reperfusion injury. Excitotoxicity, mainly observed during the ischemic period, aggravates the injury of primary auditory neurons. On the other hand, oxidative damage induced by hydroxyl radicals and nitric oxide enhances cochlear reperfusion injury. This article briefly summarizes the generation mechanisms of cochlear ischemia-reperfusion injury and potential therapeutic targets that could be developed for the effective management of this injury type.

Honey improves spermatogenesis and hormone secretion in testicular ischaemia-reperfusion-induced injury in rats.

PubMed

Gholami, M; Abbaszadeh, A; Khanipour Khayat, Z; Anbari, K; Baharvand, P; Gharravi, A M

2018-02-01

This study was conducted to survey the protective effect of pre-treatment with Persian honey during post-ischaemia reperfusion on ischaemia-reperfusion (IR)-induced testis injury. Animals were divided into four groups of IR, honey + ischaemia- reperfusion (HIR), vitamin C + ischaemia- reperfusion (VIR) and carbohydrates + ischaemia- reperfusion (CIR). The testes were examined for spermatogenesis index. Detection of single- and double-stranded DNA breaks at the early stages of apoptosis was performed. Total serum concentration of FSH, LH and testosterone was measured using ELISA. All data were expressed as mean ± SD in each group, and significance was set at p ≤ .05. Spermatogenesis index was significant in the HIR group (p < .001). Serum levels of FSH and LH were significantly higher in the CIR and HIR groups. Serum levels of testosterone were significantly higher in VIR and HIR groups. Apoptotic cells in IR and CIR groups increased significantly statistically (p < .001), while in HIR and VIR groups, the number of apoptotic cells decreased and the positive cells of TUNEL staining were detected in spermatocytes and spermatid. The present study indicates that honey decreases the cellular damage and apoptosis during testicular I/R injury, with significant protective effects on reproductive hormone production. © 2017 Blackwell Verlag GmbH.

Obesity Alters Molecular and Functional Cardiac Responses to Ischemia-Reperfusion and Glucagon-Like Peptide-1 Receptor Agonism

PubMed Central

Sassoon, Daniel J; Goodwill, Adam G; Noblet, Jillian N; Conteh, Abass M; Herring, B. Paul; McClintick, Jeanette N; Tune, Johnathan D; Mather, Kieren J

2016-01-01

This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miR) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-min coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca2+ binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion. PMID:27234258

Assessment of global ischemic/reperfusion and Tacrolimus administration on CA1 region of hippocampus: gene expression profiles of BAX and BCL2 genes.

PubMed

Badr, R; Hashemi, M; Javadi, G; Movafagh, A; Mahdian, R

2016-01-01

It is well known that hippocampus has a pivotal role in learning, formation and consolidation of memory. Global cerebral ischemia causes severe damage to pyramidal neurons of the CA1 region and usually results in residual neurological deficits following a recovery from ischemia. Scientists investigate to find the molecular mechanism of apoptosis and to use this cell death for clinical treatment. In this investigation, we evaluated the molecular mechanism of FK-506 in apoptosis using gene expression quantification of BAX and BCL-2 genes in hippocampus following global ischemic/reperfusion. In the present experimental study, adult male Wistar rats were obtained and housed under standard conditions. Each experimental group consisted of five rats and was equally distributed in the normal control, ischemia/reperfusion, ischemia/reperfusion followed by FK-506. Global ischemia was induced for animals in ischemia and drug groups. In the drug group, moreover, two doses of FK-506 were injected as IV injection and intra-peritoneal (IP) injection after 48 h. Then, hippocampus tissue was removed. Consequently, RNA isolated, cDNA was synthesized and Real-Time PCR was performed. Finally, the obtained data was analyzed statistically (p<0.05). The quantitative results showed the BAX expression ratio increased approximately 3-times in ischemia/reperfusion (3.11 ± 0.28) group compared to the untreated (NR) and the drug group (p<0.001). The statistical analysis showed a significant difference for BCL-2 expression between the experimental groups (p<0.001). The mRNA level of BCL-2 decreased in the ischemia/reperfusion group, while it was without alteration in the other groups. The results showed that global cerebral ischemia/reperfusion induced BAX as pro-apoptotic gene and tacrolimus a neuroprotective drug inhibited BAX gene expression and induced BCL-2 gene expression as anti-apoptotic gene (Tab. 2, Fig. 3, Ref. 21).

Effect of sulfasalazine on renal ischemia/reperfusion injury in rats.

PubMed

Cámara-Lemarroy, Carlos Rodrigo; Guzmán-de la Garza, Francisco Javier; Alarcón-Galván, Gabriela; Cordero-Pérez, Paula; Fernández-Garza, Nancy Esthela

2009-01-01

Renal ischemia/reperfusion (I/R) occurs during shock and transplant procedures, greatly affecting outcome. A definitive treatment has not been found. One of the pathophysiological bases of renal I/R injury is the activation of the transcription factor nuclear factor-kappaB (NF-KappaB). We studied the effects of sulfasalazine (SFZ), a NF-kappaB inhibitor, over renal injury in a bilateral renal I/R model in rats. Ten male Wistar rats were subjected to bilateral renal I/R for 45 min followed by 24 h of reperfusion. Half of these received 100 mg/kg SFZ orally before the induction of I/R, while the others received only saline. Five rats served as sham-operated controls. At the end of the reperfusion period, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), P-selectin, tumor necrosis factor-alpha (TNF-alpha), intracellular adhesion molecule-1 (ICAM-1), and endothelin-1 (ET-1) concentrations were determined in serum, and renal samples were taken for histological evaluation. After renal I/R, AST, LDH, BUN, TNF-alpha, ICAM-1, and ET-1 serum levels were significantly increased, and tubules were severely damaged on histological analysis, compared to sham controls. SFZ treatment reduced the AST, LDH, BUN, TNF-alpha, and ET-1 elevations, as well as the tubular damage, induced by renal I/R. Serum ICAM-1 and P-selectin were unchanged. These results show that SFZ has a protective effect over renal IR injury. The modulation of adhesion molecules probably does not play a part in these effects, but TNF-alpha and ET-1 modulation could be partly responsible for the effects we observed.

Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury

PubMed Central

Wang, Feng; Zhang, Guangyuan; Lu, Zeyuan; Geurts, Aron M; Usa, Kristie; Jacob, Howard J; Cowley, Allen W; Wang, Niansong; Liang, Mingyu

2015-01-01

Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1+/− rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1+/− rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1+/− rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury. PMID:26108065

Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart.

PubMed

Mourouzis, I; Dimopoulos, A; Saranteas, T; Tsinarakis, N; Livadarou, E; Spanou, D; Kokkinos, A D; Xinaris, C; Pantos, C; Cokkinos, D V

2009-01-01

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (P<0.05). A different response to PC was observed in normal than in HYPO hearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (P<0.05), while in HYPO hearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.

Cardioprotective effects of BMS-180448, a prototype mitoK(ATP) channel opener, and the role of salvage kinases, in the rat model of global ischemia and reperfusion heart injury.

PubMed

Lee, Ju-Han; Jung, In-Sang; Lee, Sung-Hun; Yang, Min-Kyu; Hwang, Ji-Hye; Lee, Hak-Dong; Cho, Yu-Sun; Song, Min-Jin; Yi, Kyu-Yang; Yoo, Sung-Eun; Kwon, Suk-Hyung; Kim, Bokyung; Lee, Chang-Soo; Shin, Hwa-Sup

2007-05-01

To investigate the involvement of reperfusion-induced salvage kinases (RISK) as possible signaling molecules for the cardioprotective effects of BMS-180448, a prototype mitochondrial ATP-sensitive K+ (mitoK(ATP)) channel opener, we measured its cardioprotective effects in a rat model of ischemia/reperfusion (I/R) heart injury, together with western blotting analysis of five different signaling proteins. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, BMS-180448 (1, 3 and 10 microM) significantly increased reperfusion left ventricular developed pressure (LVDP) and 30-min reperfusion double product (heart rate x LVDP) in a concentration-dependent manner, while decreasing left ventricular end-diastolic pressure (LVEDP) throughout reperfusion period in a concentration-dependent manner. SDS-PAGE/western blotting analysis of left ventricle reperfused for 30 min revealed that BMS-180448 significantly decreased phospho-GSK3beta at high concentration, whereas it tended to increase slightly phospho-eNOS and phospho-p70S6K with concentration. However, BMS-180448 had no effect on phospho-Akt and phospho-Bad. These results suggest that the cardioprotective effects of BMS-180448 against I/R heart injury may result from direct activation of mitoK(ATP) channel in cardiomyocytes, with the minimal role of RISK pathway in the activation of this channel and the cardioprotective effects of BMS-180448.

Effects of Sildenafil and Tadalafil on Edema and Reactive Oxygen Species Production in an Experimental Model of Lung Ischemia-Reperfusion Injury.

PubMed

Guerra-Mora, J R; Perales-Caldera, E; Aguilar-León, D; Nava-Sanchez, C; Díaz-Cruz, A; Díaz-Martínez, N E; Santillán-Doherty, P; Torres-Villalobos, G; Bravo-Reyna, C C

Lung ischemia-reperfusion injury is characterized by formation of reactive oxygen species and cellular swelling leading to pulmonary edema and primary graft dysfunction. Phosphodiesterase 5 inhibitors could ameliorate lung ischemia-reperfusion injury by interfering in many molecular pathways. The aim of this work was to evaluate and compare the effects of sildenafil and tadalafil on edema and reactive oxygen species formation in an ex vivo nonhuman animal model of lung ischemia-reperfusion injury. Thirty-two Wistar rats were distributed, treated, perfused and the cardiopulmonary blocks were managed as follows: control group: immediate excision and reperfusion without pretreatment; ischemia reperfusion group: treatment with dimethylsulfoxide 0.9% and excision 1 hour later; sildenafil group: treatment with sildenafil (0.7 mg/kg) and excision 1 hour later; and tadalafil group: treatment with tadalafil (0.15 mg/kg) and excision 2 hours later. All cardiopulmonary blocks except control group were preserved for 8 hours and then reperfused. Pulmonary arterial pressure, pulmonary venous pressure, and capillary filtration coefficient were measured. Reactive oxygen species were measured. Edema was similar between control and sildenafil groups, but significantly greater in the ischemia-reperfusion (P ≤ .04) and tadalafil (P ≤ .003) groups compared with the sildenafil group. The malondialdehyde levels were significantly lower in the sildenafil (P ≤ .001) and tadalafil (P ≤ .001) groups than the ischemia-reperfusion group. Administration of sildenafil, but not tadalafil, decreased edema in lung ischemia-reperfusion injury. Both drugs decreased reactive oxygen species formation in a lung ischemia-reperfusion injury model. Copyright © 2017 Elsevier Inc. All rights reserved.

Coronary response to diadenosine tetraphosphate after ischemia-reperfusion in the isolated rat heart.

PubMed

García-Villalón, Angel Luis; Fernández, Nuria; Monge, Luis; Diéguez, Godofredo

2011-06-25

Diadenosine tetraphosphate (AP4A) is a vasoactive mediator that may be released from platelet granules and that may reach higher plasma concentrations during coronary ischemia-reperfusion. The objective of this study was to analyze its coronary effects in such conditions. To this, rat hearts were perfused in a Langendorff preparation and the coronary response to Ap4A (10(-7)-10(-5) M) was recorded. In control hearts, Ap4A produced concentration-dependent vasodilatation both at the basal coronary resting tone and after precontracting coronary vasculature with 11-dideoxy-1a,9a-epoxymethanoprostaglandin F2α (U46619), and this vasodilatation was reduced by reactive blue 2 (2×10(-6) M), glibenclamide (10(-5) M), H89 (10(-6) M), U73122 (5×10(-6) M) and endothelin-1 (10(-9) M), but not by L-NAME (10(-4) M), isatin (10(-4) M), GF109203x (5×10(-7) M), or wortmannin (5×10(-7) M). After ischemia-reperfusion, the vasodilatation to Ap4A diminished, both in hearts with basal or increased vascular tone, and in this case the relaxation to Ap4A was not modified by reactive blue 2, L-NAME, glibenclamide, isatin, H89, GF109203x or wortmannin, although it was reduced by U73122 and endothelin-1. UTP produced coronary relaxation that was also reduced after ischemia-reperfusion. These results suggest that the coronary relaxation to Ap4A is reduced after ischemia-reperfusion, and that this reduction may be due to impaired effects of KATP channels and to reduced response of purinergic P2Y receptors. Copyright © 2011 Elsevier B.V. All rights reserved.

Protective effect of Malva sylvestris L. extract in ischemia-reperfusion induced acute kidney and remote liver injury

PubMed Central

Najafi, Houshang; Mohamadi Yarijani, Zeynab; Changizi-Ashtiyani, Saeed; Mansouri, Kamran; Modarresi, Masoud; Madani, Seyed Hamid

2017-01-01

Mallow (Malva sylvestris L.) has had medicinal and therapeutic uses in addition to its oral consumption. The present study was conducted to examine the protective effect of Malva sylvestris L. extract on ischemia-reperfusion-induced kidney injury and remote organ injuries in the liver. Before ischemia-reperfusion, rats in the different groups received intraperitoneal normal saline or mallow extract at the doses of 200, 400 or 600 mg/kg of body weight. After 30-minutes of bilateral renal ischemia followed by 24-hours of reperfusion, tissue damage in the kidney and liver samples were determined through studying H&E-stained slides under a light microscope. The degree of leukocyte infiltration and tissue mRNA expressions of TNF- and ICAM-1 were then measured to examine the degree of renal inflammation. The renal tissue MDA and FRAP levels were measured for determining the amount of oxidative stress. Plasma concentrations of creatinine, urea, ALT and ALP were also measured. Ischemia-reperfusion led to a significant increase in plasma concentrations of creatinine, urea, ALT and ALP, and renal tissue MDA, and a significant decrease in renal tissue FRAP. The expression of pro-inflammatory factors in the kidney tissue, the level of leukocyte infiltration and the amount of tissue damage in the kidney and liver also increased. Pretreatment by mallow extract led to a significant improvement in all the variables measured. The 200- and 400-mg doses yielded better results in most parameters compared to the 600-mg dose. The findings showed that mallow extract protects the kidney against ischemia-reperfusion and reduces remote organ injury in the liver. PMID:29155898

Inhaled nitric oxide pretreatment but not posttreatment attenuates ischemia-reperfusion-induced pulmonary microvascular leak.

PubMed

Chetham, P M; Sefton, W D; Bridges, J P; Stevens, T; McMurtry, I F

1997-04-01

Ischemia-reperfusion (I/R) pulmonary edema probably reflects a leukocyte-dependent, oxidant-mediated mechanism. Nitric oxide (NO) attenuates leukocyte-endothelial cell interactions and I/R-induced microvascular leak. Cyclic adenosine monophosphate (cAMP) agonists reverse and prevent I/R-induced microvascular leak, but reversal by inhaled NO (INO) has not been tested. In addition, the role of soluble guanylyl cyclase (sGC) activation in the NO protection effect is unknown. Rat lungs perfused with salt solution were grouped as either I/R, I/R with INO (10 or 50 ppm) on reperfusion, or time control. Capillary filtration coefficients (Kfc) were estimated 25 min before ischemia (baseline) and after 30 and 75 min of reperfusion. Perfusate cell counts and lung homogenate myeloperoxidase activity were determined in selected groups. Additional groups were treated with either INO (50 ppm) or isoproterenol (ISO-10 microM) after 30 min of reperfusion. Guanylyl cyclase was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ-15 microM), and Kfc was estimated at baseline and after 30 min of reperfusion. (1) Inhaled NO attenuated I/R-induced increases in Kfc. (2) Cell counts were similar at baseline. After 75 min of reperfusion, lung neutrophil retention (myeloperoxidase activity) and decreased perfusate neutrophil counts were similar in all groups. (3) In contrast to ISO, INO did not reverse microvascular leak. (4) 8-bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP) prevented I/R-induced microvascular leak in ODQ-treated lungs, but INO was no longer effective. Inhaled NO attenuates I/R-induced pulmonary microvascular leak, which requires sGC activation and may involve a mechanism independent of inhibition of leukocyte-endothelial cell interactions. In addition, INO is ineffective in reversing I/R-induced microvascular leak.

Effects of simvastatin on cardiohemodynamic responses to ischemia-reperfusion in isolated rat hearts.

PubMed

Zheng, Xia; Hu, Shen-Jiang

2006-03-01

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has long been thought to exert its benefits by reducing cholesterol synthesis, and has been shown to significantly reduce cardiovascular events and mortality in patients with or without coronary artery disease. However, it is still unknown whether acute administration of simvastatin beneficially affects the cardiac function prior or during ischemia-reperfusion. The aim of this study is to evaluate the cardioprotective effect of acute simvastatin treatment on isolated rat hearts or isolated ischemia-reperfusion hearts. Hearts were isolated from male Sprague-Dawley rats and attached to a Langendorff apparatus. The isolated hearts with or without ischemia (15 min) and reperfusion (60 min) were perfused with different concentrations of simvastatin. The parameters of cardiac function (such as left ventricular developed pressure [LVDP], +dp/dt max, and -dp/dt max), heart rate, and coronary flow were recorded. Simvastatin (3-30 micromol/l) significantly increased LVDP, +dp/dt max, and -dp/dt max in isolated rat hearts perfused for 60 min. Heart rate was depressed by 30 micromol/l simvastatin and the coronary flow was increased by 10 and 30 micromol/l simvastatin. At a concentration of 100 micromol/l simvastatin, worsening of heart function and subsequent cardiac arrest occurred. Administration of simvastatin (3-30 micromol/l) significantly preserved cardiac function detected by LVDP, +dp/dt max, and -dp/dt max in the isolated ischemia/reperfused (15/60 min) rat hearts. Simvastatin also significantly decreased heart rate at 30 micromol/l, and increased coronary flow at 10 and 30 micromol/l in these rat hearts. However, the protective effect of simvastatin reverted to increased damage at 100 micromol/l. Only 3 micromol/l simvastatin pretreatment before 15/60 min ischemia-reperfusion altered LVDP, +dp/dt max, and -dp/dt max. Both heart rate and coronary flow were unaltered after simvastatin

Protective effects of notoginsenoside R1 on cerebral ischemia-reperfusion injury in rats.

PubMed

Zou, Shun; Zhang, Mingxiong; Feng, Limei; Zhou, Yuanfang; Li, Li; Ban, Lili

2017-12-01

The objective of this study was to investigate the protective effect of notoginsenoside R1 (NGR1) on cerebral ischemia-reperfusion injury (CIRI) in rats, and its molecular mechanism, to provide new insights into the diagnosis and treatment of CIRI. Sixty Sprague-Dawley rats were randomly divided into four groups including the sham-operation group (Sham), cerebral ischemia-reperfusion model group (CIR), NGR1 treatment group (NGR1), and nimodipine positive control group (NDC) with 15 rats each. Bilateral common carotid arteries occlusion was used to establish the rat CIRI model. The area of cerebral infarction at the end of reperfusion was calculated by triphenyl tetrazolium chloride staining. Apoptosis of hippocampal neurons in each group was detected by Annexin V/propidium iodide double staining. Hippocampal expression of brain-derived neurotrophic factor (BDNF) mRNA, and Bcl-2 and Bax protein at the end of reperfusion were measured by RT-qPCR and western blot analysis, respectively. Data were analyzed by SPSS software analysis to ensure statistical significance. At the end of reperfusion, the area of cerebral infarction in the NGR1 and NDC groups was significantly smaller than that of the CIR group. Apoptosis analysis showed that compared with the CIR group, the apoptosis rate of hippocampal neurons was significantly decreased in the NGR1 and NDC groups. RT-qPCR and western blot analysis showed that at the end of reperfusion, higher levels of BDNF mRNA and the anti-apoptotic factor, Bcl-2, and lower levels of the pro-apoptotic factor, Bax, in the hippocampus were found in the NGR1 and NDC groups compared with the CIR group. The protective effect of NGR1 on CIRI was significantly stronger than that of nimodipine. In conclusion, NGR1 can reduce the area of cerebral infarction, reduce apoptosis of hippocampal neurons, and protect rats from CIRI. Those effects were achieved by activating the expression of BDNF and Bcl-2, and by inhibiting the expression of Bax.

Adaptation to chronic continuous hypoxia potentiates Akt/HK2 anti-apoptotic pathway during brief myocardial ischemia/reperfusion insult.

PubMed

Kolar, David; Gresikova, Milada; Waskova-Arnostova, Petra; Elsnicova, Barbara; Kohutova, Jana; Hornikova, Daniela; Vebr, Pavel; Neckar, Jan; Blahova, Tereza; Kasparova, Dita; Novotny, Jiri; Kolar, Frantisek; Novakova, Olga; Zurmanova, Jitka M

2017-08-01

Adaptation to chronic hypoxia represents a potential cardioprotective intervention reducing the extent of acute ischemia/reperfusion (I/R) injury, which is a major cause of death worldwide. The main objective of this study was to investigate the anti-apoptotic Akt/hexokinase 2 (HK2) pathway in hypoxic hearts subjected to I/R insult. Hearts isolated from male Wistar rats exposed either to continuous normobaric hypoxia (CNH; 10% O 2 ) or to room air for 3 weeks were perfused according to Langendorff and subjected to 10 min of no-flow ischemia and 10 min of reperfusion. The hearts were collected either after ischemia or after reperfusion and used for protein analyses and quantitative fluorescence microscopy. The CNH resulted in increased levels of HK1 and HK2 proteins and the total HK activity after ischemia compared to corresponding normoxic group. Similarly, CNH hearts exhibited increased ischemic level of Akt protein phosphorylated on Ser 473 . The CNH also strengthened the interaction of HK2 with mitochondria and prevented downregulation of mitochondrial creatine kinase after reperfusion. The Bax/Bcl-2 ratio was significantly lower after I/R in CNH hearts than in normoxic ones, suggesting a lower probability of apoptosis. In conclusion, the Akt/HK2 pathway is likely to play a role in the development of a cardioprotective phenotype of CNH by preventing the detachment of HK2 from mitochondria at reperfusion period and decreases the Bax/Bcl-2 ratio during I/R insult, thereby lowering the probability of apoptosis activation in the mitochondrial compartment.

Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Jae-Sung, E-mail: Jae.Kim@surgery.ufl.edu; Wang, Jin-Hee, E-mail: jin-hee.wang@surgery.ufl.edu; Biel, Thomas G., E-mail: Thomas.Biel@surgery.ufl.edu

Onset of the mitochondrial permeability transition (MPT) plays a causative role in ischemia/reperfusion (I/R) injury. Current therapeutic strategies for reducing reperfusion injury remain disappointing. Autophagy is a lysosome-mediated, catabolic process that timely eliminates abnormal or damaged cellular constituents and organelles such as dysfunctional mitochondria. I/R induces calcium overloading and calpain activation, leading to degradation of key autophagy-related proteins (Atg). Carbamazepine (CBZ), an FDA-approved anticonvulsant drug, has recently been reported to increase autophagy. We investigated the effects of CBZ on hepatic I/R injury. Hepatocytes and livers from male C57BL/6 mice were subjected to simulated in vitro, as well as in vivomore » I/R, respectively. Cell death, intracellular calcium, calpain activity, changes in autophagy-related proteins (Atg), autophagic flux, MPT and mitochondrial membrane potential after I/R were analyzed in the presence and absence of 20 μM CBZ. CBZ significantly increased hepatocyte viability after reperfusion. Confocal microscopy revealed that CBZ prevented calcium overloading, the onset of the MPT and mitochondrial depolarization. Immunoblotting and fluorometric analysis showed that CBZ blocked calpain activation, depletion of Atg7 and Beclin-1 and loss of autophagic flux after reperfusion. Intravital multiphoton imaging of anesthetized mice demonstrated that CBZ substantially reversed autophagic defects and mitochondrial dysfunction after I/R in vivo. In conclusion, CBZ prevents calcium overloading and calpain activation, which, in turn, suppresses Atg7 and Beclin-1 depletion, defective autophagy, onset of the MPT and cell death after I/R. - Highlights: • A mechanism of carbamazepine (CBZ)-induced cytoprotection in livers is proposed. • Impaired autophagy is a key event contributing to lethal reperfusion injury. • The importance of autophagy is extended and confirmed in an in vivo model. • CBZ is a

Anti-inflammatory effects of vinpocetine on the functional expression of nuclear factor-kappa B and tumor necrosis factor-alpha in a rat model of cerebral ischemia-reperfusion injury.

PubMed

Wang, Hongxin; Zhang, Kan; Zhao, Lan; Tang, Jiangwei; Gao, Luyan; Wei, Zhongping

2014-04-30

The restoration of blood flow to the brain after ischemic stroke prevents further, extensive damage but can result in reperfusion injury. The inflammation response is one of many factors involved in cerebral ischemia-reperfusion injury. This study investigated the use of vinpocetine, a drug used to treat cognitive impairment, to explore its effects on inflammation in a rat model of cerebral ischemia-reperfusion. Wistar rats were randomly assigned to a control group, (n=40) a cerebral ischemia-reperfusion group (n=52) and a vinpocetine cerebral ischemia-reperfusion group (n=52). A model of middle cerebral artery occlusion was induced for 2h followed by reperfusion and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining 6h, 24h, 3 days, and 7 days after reperfusion. The dry-wet weight method was used to measure brain water content and evaluate the extent of brain edema. Immunohistochemistry and in-situ hybridization were used to detect the expression of NF-κB and TNF-α. The NF-κB levels in ischemic brain tissue increased 6h after reperfusion and the TNF-α levels increased at 24h, both reached their peaks at day 3 then decreased gradually, but remained above the controls at day 7. Vinpocetine decreased the levels of NF-κB and TNF-α 24h and 3 days after reperfusion. NF-κB and TNF-α is associated with changes in brain edema and infarct volume. Vinpocetine decreases the expression of NF-κB and TNF-α and inhibits the inflammatory response after cerebral ischemia-reperfusion. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Vitamin E attenuates myocardial ischemia-reperfusion injury in murine AIDS.

PubMed

Chen, Yinhong; Davis-Gorman, Grace; Watson, Ronald Ross; McDonagh, Paul F

2002-01-01

The incidence of myocardial infarction in patients who have the aquired immunodeficiency syndrome (AIDS) is increasing. However, no effective therapeutic agents have been discovered to reduce myocardial ischemia-reperfusion (I/R) injury in pathologies associated with AIDS. The aim of this study was to determine if infarct size is increased in murine AIDS after I/R injury and if I/R injury could be attenuated with vitamin E supplementation. Three groups of mice were studied: control, murine AIDS, and murine AIDS with vitamin E supplementation. Anesthetized mice were subjected to 30 min of left anterior descending coronary artery occlusion and 120 min of reperfusion. The hearts in mice that had murine AIDS had a larger infarct size compared to controls after I/R injury. Vitamin E supplementation significantly reduced infarct size and inhibited polymorphonuclear neutrophil (PMN) CD11b expression (p < 0.05). However, vitamin E supplementation did not affect PMN reactive oxygen species (ROS) production and platelet CD62p expression. These results suggest that the reduction of myocardial I/R injury with vitamin E supplementation may be the result of the inhibition of PMN CD11b expression. Vitamin E may be a promising prophylactic agent for the reduction of the severity of myocardial I/R injury in patients who have AIDS.

Hepatic ischemia/reperfusion injury is diminished by atorvastatin in Wistar rats.

PubMed

Cámara-Lemarroy, Carlos Rodrigo; Guzmán-de la Garza, Francisco Javier; Alarcón-Galván, Gabriela; Cordero-Pérez, Paula; Muñoz-Espinosa, Linda; Torres-González, Liliana; Fernández-Garza, Nancy Esthela

2014-04-01

Temporal occlusion of the hepatoduodenal ligament (HDL) is often used during liver surgeries in order to reduce blood loss, resulting in ischemia/reperfusion injury (I/R). The aim of the study was to investigate the effects of atorvastatin (ATOR) on hepatic I/R injury and on serum levels of tumor necrosis factor-alpha (TNF-α), endothelin-1 (ET-1), antithrombin III (ATIII) and intracellular adhesion molecule-1 (ICAM-1). Liver ischemia was induced in Wistar rats by clamping the HDL for 60 min, followed by either 60 or 180 min reperfusion. Rats received either vehicle or 10 mg/kg ATOR before hepatic I/R. Control group received sham surgery. Livers were examined for histological damage and serum AST, ALT, TNF-α, ET-1, ATIII and ICAM-1 concentrations were measured. After I/R, AST and ALT were significantly elevated, ATIII levels were significantly depleted, both TNF-α and ICAM-1 levels increased and ET-1 was significantly elevated (at 180 min). ATOR pretreatment attenuated these alterations and diminished histological injury scores. Our results show that ATOR protects the liver from I/R injury. Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.

The effects of tramadol on hepatic ischemia/reperfusion injury in rats

PubMed Central

Mahmoud, Mona F.; Gamal, Samar; Shaheen, Mohamed A.; El-Fayoumi, Hassan M.

2016-01-01

Objectives: Tramadol is a centrally acting synthetic analgesic. It has a cardioprotective effect against myocardial ischemia-reperfusion (I/R) injury in isolated rat heart. We hypothesized that tramadol may exert a similar protective effect on hepatic I/R injury. Hence, the current investigation was designed to study the possible protective effects of tramadol on experimentally-induced hepatic I/R injury in rats. Materials and Methods: Tramadol was administered 30 min before ischemia following which the rats were subjected to 45 min of ischemia followed by 1 h of reperfusion. Results: Tramadol attenuated hepatic injury induced by I/R as evidenced by the reduction of transaminases, structural changes, and apoptotic cell death. It decreased the level of inflammatory markers such as tumor necrosis factor-alpha (TNF-α), TNF-α/interleukin-10 (IL-10) ratio, and nuclear factor-κB gene expression. It also increased the anti-inflammatory cytokine, IL-10 levels in hepatic tissues. Furthermore, it reduced oxidative stress parameters except manganese superoxide dismutase activity. Conclusion: The results suggest that tramadol has hepatoprotective effects against hepatic I/R injury via anti-inflammatory, antiapoptotic, and antioxidant effects. PMID:27298497

Sex Differences in Timeliness of Reperfusion in Young Patients With ST-Segment-Elevation Myocardial Infarction by Initial Electrocardiographic Characteristics.

PubMed

Gupta, Aakriti; Barrabes, Jose A; Strait, Kelly; Bueno, Hector; Porta-Sánchez, Andreu; Acosta-Vélez, J Gabriel; Lidón, Rosa-Maria; Spatz, Erica; Geda, Mary; Dreyer, Rachel P; Lorenze, Nancy; Lichtman, Judith; D'Onofrio, Gail; Krumholz, Harlan M

2018-03-07

Young women with ST-segment-elevation myocardial infarction experience reperfusion delays more frequently than men. Our aim was to determine the electrocardiographic correlates of delay in reperfusion in young patients with ST-segment-elevation myocardial infarction. We examined sex differences in initial electrocardiographic characteristics among 1359 patients with ST-segment-elevation myocardial infarction in a prospective, observational, cohort study (2008-2012) of 3501 patients with acute myocardial infarction, 18 to 55 years of age, as part of the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study at 103 US and 24 Spanish hospitals enrolling in a 2:1 ratio for women/men. We created a multivariable logistic regression model to assess the relationship between reperfusion delay (door-to-balloon time >90 or >120 minutes for transfer or door-to-needle time >30 minutes) and electrocardiographic characteristics, adjusting for sex, sociodemographic characteristics, and clinical characteristics at presentation. In our study (834 women and 525 men), women were more likely to exceed reperfusion time guidelines than men (42.4% versus 31.5%; P <0.01). In multivariable analyses, female sex persisted as an important factor in exceeding reperfusion guidelines after adjusting for electrocardiographic characteristics (odds ratio, 1.57; 95% CI, 1.15-2.15). Positive voltage criteria for left ventricular hypertrophy and absence of a prehospital ECG were positive predictors of reperfusion delay; and ST elevation in lateral leads was an inverse predictor of reperfusion delay. Sex disparities in timeliness to reperfusion in young patients with ST-segment-elevation myocardial infarction persisted, despite adjusting for initial electrocardiographic characteristics. Left ventricular hypertrophy by voltage criteria and absence of prehospital ECG are strongly positively correlated and ST elevation in lateral leads is negatively correlated with

Fasciotomy Reduces Compartment Pressures and Improves Recovery in a Porcine Model of Extremity Vascular Injury and Ischemia/Reperfusion

DTIC Science & Technology

2012-10-01

the study. Ill. ~Ut’i.Jt.t.;l I 1:111V1~ Vascular injury, Extremity\\ Ischemia-rcperfusion, Therapeutic reperfusion, Statin \\ Recovery\\ Neuromuscular...Health Sciences, Bethesda, Maryland Keywords: Vascular injury, Extremity, Ischemia-reperfusion, Therapeutic reperfusion, Statin , Recovery...compartment pressure (pɘ.05) which were directly related to degree of muscle degeneration (pɘ.05) and inversely related to nerve recovery (p<.05

Effects of propofol, midazolam and thiopental sodium on outcome and amino acids accumulation in focal cerebral ischemia-reperfusion in rats.

PubMed

Chen, Lianhua; Gong, Qinyan; Xiao, Changsi

2003-02-01

To investigate the effects of propofol, midazolam and thiopental sodium on outcomes and amino acid accumulation in focal cerebral ischemia-reperfusion in rats. Male Sprague Dawley (SD) rats were scheduled to undergo 3-hour middle cerebral artery occlusion by intraluminal suture and 24-hour reperfusion. Neurologic outcomes were scored on a 0-5 grading scale. Infarct volume was shown with triphenyltetrazolium chloride staining and measured by an image analysis system. Concentrations of various amino acids (aspartate, glutamate, glycine, taurine, and gama-aminobutyric acid) were measured after 3 hours of reperfusion using high performance liquid chromatography. Propofol, midazolam and thiopental sodium were given intraperitoneally at the beginning of reperfusion. Both propofol and midazolam attenuated neurological deficits and reduced infarct and edema volumes. Propofol showed better neurological protection than midazolam while thiopental sodium did not exhibit any protective effect. Both propofol and midazolam decreased excitatory amino acids accumulation, while propofol increased gama-aminobutyric acid accumulation in ischemic areas in reperfusion. Propofol and midazolam, but not thiopental sodium, may provide protective effects against reperfusion induced injury in rats subjected to focal cerebral ischemia. This neurological protection may be due to the acceleration of excitatory amino acids elimination in reperfusion.

Aerosolized PGE1, PGI2 and nitroprusside protect against vascular leakage in lung ischaemia-reperfusion.

PubMed

Schütte, H; Löckinger, A; Seeger, W; Grimminger, F

2001-07-01

High permeability oedema is an important feature in lung injury secondary to ischaemia-reperfusion. This study investigated the influence of aerosolized prostaglandin E1 (PGE1), prostaglandin I2 (PCI2) and the nitric oxide (NO)-donor, sodium nitroprusside (SNP) on microvascular barrier function in pulmonary ischaemia-reperfusion. Buffer-perfused rabbit lungs were exposed to 180 or 210 min of warm ischaemia while maintaining anoxic ventilation and a positive intravascular pressure. Reperfusion provoked a transient, mostly precapillary elevation of vascular resistance, followed by a severe increase of the capillary filtration coefficient (Kfc) versus nonischaemic controls (3.17+/-0.34 versus 0.85+/-0.05 cm3 x s(-1) cmH2O(-1) x g(-1) x 10(-4) after 30 min of reperfusion), and progressive oedema formation. Short-term aerosolization of SNP, PGE1 or PGI2 at the beginning of ischaemia largely suppressed the Kfc increase (1.36+/-0.22, 1.32+/-0.23 and 1.32+/-0.22 cm3 x s(-1) x cmH2O(-1) x g(-1) x 10(-4), respectively) and oedema formation. In contrast, application prior to reperfusion was much less effective, with some reduction of Kfc increase by PGI2 and SNP and no effect of PGE, (1.79+/-0.31, 2.2+/-0.53 and 3.2+/-0.05 cm3 x s(-1) x cmH2O(-1) x g(-1) x 10(-4), respectively). Haemodynamics, including microvascular pressure, were only marginally affected by the chosen doses of aerosolized vasodilators. It is concluded that short-term aerosolization of prostaglandin E1, prostaglandin I2 and sodium nitroprusside at the onset of ischaemia is highly effective in maintaining endothelial barrier properties in pulmonary ischaemia-reperfusion. This effect is apparently attributable to nonvasodilatory mechanisms exerted by these agents. Alveolar deposition of prostaglandins and/or nitric oxide donors by the aerosol technique may offer pulmonary protection in ischaemia-reperfusion injury.

Ischemia-reperfusion of human skeletal muscle during aortoiliac surgery: effects of acetylcarnitine.

PubMed

Adembri, C; Domenici, L L; Formigli, L; Brunelleschi, S; Ferrari, E; Novelli, G P

1994-10-01

Our previous study on human skeletal muscle undergoing ischemia and reperfusion has revealed that granulocytes, which infiltrate the muscle tissue in large numbers, play an important role in mediating fibre injuries by producing superoxide anion (O2-) which is responsible for membrane lipid peroxidation. In the current study, five patients undergoing aortic reconstructive surgery were given acetyl-carnitine (2 mg/kg i.v. plus 1 mg/kg/min for 30 min) prior to the induction of ischemia. Muscle biopsies and blood samples were examined: a) after anaesthesia; b) at the end of ischemia; and c) 30 min after reperfusion, with the aim of elucidating whether acetylcarnitine could prevent the infiltration and/or the activation of granulocytes and eventually skeletal muscle injuries. During ischemia and reperfusion complement activation recruited numerous granulocytes into the muscle tissue, but, contrary to the untreated samples, the ability for O2(-)-generation of these cells remained at low levels and was comparable to that of ischemia even when molecular O2 was reintroduced to the tissue. Accordingly, the morphological changes of the postischemic muscle fibers were substantially reduced when compared to the untreated samples; in fact, the mitochondrial swelling was only moderate and the intramitochondrial dense bodies were small and scarce. The current findings support a positive role of acetyl-carnitine in ameliorating the ischemia-reperfusion (I-R)-induced damage of human skeletal muscle.

Time course evaluation of myocardial perfusion after reperfusion therapy by 99mTc-tetrofosmin SPECT in patients with acute myocardial infarction.

PubMed

Tanaka, R; Nakamura, T

2001-09-01

BMIPP image were very close (r = 0.963, r = 0.981, and r = 0.975, respectively). Gated TF SPECT revealed that the left ventricular ejection fraction was not significantly different (P = not significant) between 1 and 20 d after reperfusion, but regional wall motion was significantly different after reperfusion (P < 0.05). These results suggest that the interval between reperfusion therapy and TF SPECT should be 7 d to evaluate the salvage effect and that TF delayed and BMIPP images are both useful in estimation of risk area.

Protective effect of agmatine on a reperfusion model after transient cerebral ischemia: Temporal evolution on perfusion MR imaging and histopathologic findings.

PubMed

Kim, D J; Kim, D I; Lee, S K; Suh, S H; Lee, Y J; Kim, J; Chung, T S; Lee, J E

2006-04-01

The goal of thrombolytic therapy in patients with acute ischemic stroke is early recanalization, but this may result in delayed reperfusion injury. The purpose of this study was to evaluate the neuroprotective effect of agmatine in a transient ischemic cat model by using MR perfusion imaging and histopathologic analyses. One-hour temporary occlusion of the left middle cerebral artery of cats was performed in the control ischemia group (n = 10), and 100 mg/kg of agmatine was intravenously injected immediately after recanalization in the agmatine-treated group (n = 15). MR imaging was performed at 1, 24, and 48 hours after recanalization, and the perfusion patterns were investigated. Terminal-deoxynucleotidyl transferase mediated nick and end-labeling (TUNEL) and hematoxylin-eosin (H&E) stainings were performed at the corresponding sections. In the control ischemia group, the number of TUNEL-positive cells was significantly increased in the areas with reperfusion hyperemia (P < .05). In the agmatine-treated group, no significant increase in the number of TUNEL-positive cells was noted in the areas of reperfusion hyperemia. The difference in the number of TUNEL-positive cells between the control ischemia and agmatine-treated group in the areas of reperfusion hyperemia was significant (P < .05). The total number of TUNEL-positive cells and the area of severe ischemic neuronal damage on H&E stain were also significantly attenuated in the agmatine-treated cats compared with the control ischemia cats (P < .05). Our results suggest that agmatine has neuroprotective effects against reperfusion injury and ischemia.

Astaxanthin Protects Against Retinal Damage: Evidence from In Vivo and In Vitro Retinal Ischemia and Reperfusion Models.

PubMed

Otsuka, Tomohiro; Shimazawa, Masamitsu; Inoue, Yuki; Nakano, Yusuke; Ojino, Kazuki; Izawa, Hiroshi; Tsuruma, Kazuhiro; Ishibashi, Takashi; Hara, Hideaki

2016-11-01

Astaxanthin exhibits various pharmacological activities, including anti-oxidative, anti-tumor, and anti-inflammatory effects, and is thought to exert a neuroprotective effect via these mechanisms. The purpose of this study was to investigate the protective effects of astaxanthin on neuronal cell death using a retinal ischemia/reperfusion model. In vivo, retinal ischemia was induced by 5 h unilateral ligation of the pterygopalatine artery (PPA) and the external carotid artery (ECA) in ddY mice. Astaxanthin (100 mg/kg) was administered orally 1 h before induction of ischemia, immediately after reperfusion, at 6 or 12 h after reperfusion, and twice daily for the following 4 days. Histological analysis and an electroretinogram (ERG) were performed 5 days after ischemia/reperfusion. In vitro, cell death was induced in the RGC-5 (retinal precursor cells) by oxygen-glucose deprivation (OGD), and the rates of cell death and production of intracellular reactive oxygen species (ROS) were measured using nuclear staining and a ROS reactive reagent, CM-H 2 DCFDA. Histological studies revealed that astaxanthin significantly reduced retinal ischemic damage and ERG reduction. In in vitro studies, astaxanthin inhibited cell death and ROS production in a concentration-dependent manner. Collectively, these results indicate that astaxanthin inhibits ischemia-induced retinal cell death via its antioxidant effect. Hence, astaxanthin might be effective in treating retinal ischemic pathologies.

Impaired intestinal mucosal barrier upon ischemia-reperfusion: "patching holes in the shield with a simple surgical method".

PubMed

Rosero, Olivér; Ónody, Péter; Kovács, Tibor; Molnár, Dávid; Lotz, Gábor; Tóth, Szilárd; Turóczi, Zsolt; Fülöp, András; Garbaisz, Dávid; Harsányi, László; Szijártó, Attila

2014-01-01

Mesenteric ischemia-reperfusion (IR) is associated with impairment of the gut barrier function and the initiation of a proinflammatory cascade with life-threatening results. Therefore methods directed to ameliorate IR injury are of great importance. We aimed at describing the effects of postconditioning (PC) on the alterations of the intestinal mucosal function and the inflammatory response upon mesenteric IR. Male Wistar rats were gavaged with green fluorescent protein-expressing E. coli suspensions. Animals were randomized into three groups (n = 15), sham-operated, IR-, and PC-groups, and underwent 60 minutes of superior mesenteric artery occlusion, followed by 6 hours of reperfusion. Postconditioning was performed at the onset of reperfusion. Blood and tissue samples were taken at the end of reperfusion, for histological, bacteriological, and plasma examinations. The PC-group presented a more favorable claudin-2, claudin-3, claudin-4, and zonula occludens-1 membrane expression profile, and significantly lower rates of bacterial translocation to distant organs and plasma D-lactate levels compared to the IR-group. Histopathological lesions, plasma I-FABP, IL-6, and TNF- α levels were significantly lower in the PC-group compared to the IR-group. The use of postconditioning improved the integrity of the intestinal mucosal barrier upon mesenteric IR, and thus reduced the incidence of bacterial translocation and development of a systemic inflammatory response.

Progressive thermopreconditioning attenuates rat cardiac ischemia/reperfusion injury by mitochondria-mediated antioxidant and antiapoptotic mechanisms.

PubMed

Chien, Chen-Yen; Chien, Chiang-Ting; Wang, Shoei-Shen

2014-08-01

Progressive thermal preconditioning (PTP) provides vascular protection with less hemodynamic fluctuations, endoplasmic reticulum (ER), and oxidative stress compared with whole body hyperthermia. We suggest PTP might efficiently diminish cardiac ischemia/reperfusion-induced apoptosis and autophagy injury. A total of 67 male Wistar rats were divided into a non-PTP control group, 24 or 72 hours after a single cycle or 3 consecutive cycles of PTP in a 42°C water bath (1-24, 1-72, 3-24, and 3-72 groups). We measured the cardiac O2(-) amount in vivo in response to left anterior descending coronary artery ligation for 2 hours and reperfusion for 3 hours. Cardiac function and injury were determined by microcirculation, electrocardiography, and infarct size. The PTP-induced protective effects on nicotinamide adenine dinucleotide phosphate oxidase gp91-mediated oxidative stress, ER stress, and apoptosis- and autophagy-related mechanisms were examined using Western blot and immunohistochemistry. Coronary arterial ischemia/reperfusion depressed cardiac microcirculation, induced ST-segment elevation and increased infarct size in non-PTP and PTP rats. Ischemia/reperfusion enhanced the cardiac O2(-) levels by enhanced nicotinamide adenine dinucleotide phosphate oxidase gp91 expression, cytosolic cytochrome C release, and decreased mitochondrial Bcl-2 expression. Cardiac injury activated ER stress-78-kDa glucose-regulated protein expression, increased the Bax/Bcl-2 ratio, cleaved caspase 3 expression and poly-(ADP-ribose)-polymerase fragments, leading to apoptosis formation, and promoted LC3-II expression, resulting in autophagy formation. PTP treatment elevated heat shock protein 70, heat shock protein 32, Bcl-2, Bcl-xL, and manganese superoxide dismutase in the rat heart, especially in the 3-72 group. PTP treatment significantly restored cardiac microcirculation, decreased oxidative stress, ER stress, apoptosis, autophagy, and infarct size. PTP significantly reduced cardiac

Prophylactic Ozone Administration Reduces Intestinal Mucosa Injury Induced by Intestinal Ischemia-Reperfusion in the Rat

PubMed Central

Onal, Ozkan; Yetisir, Fahri; Sarer, A. Ebru Salman; Zeybek, N. Dilara; Onal, C. Oztug; Yurekli, Banu; Celik, H. Tugrul; Sirma, Ayse; Kılıc, Mehmet

2015-01-01

Objectives. Intestinal ischemia-reperfusion injury is associated with mucosal damage and has a high rate of mortality. Various beneficial effects of ozone have been shown. The aim of the present study was to show the effects of ozone in ischemia reperfusion model in intestine. Material and Method. Twenty eight Wistar rats were randomized into four groups with seven rats in each group. Control group was administered serum physiologic (SF) intraperitoneally (ip) for five days. Ozone group was administered 1 mg/kg ozone ip for five days. Ischemia Reperfusion (IR) group underwent superior mesenteric artery occlusion for one hour and then reperfusion for two hours. Ozone + IR group was administered 1 mg/kg ozone ip for five days and at sixth day IR model was applied. Rats were anesthetized with ketamine∖xyzlazine and their intracardiac blood was drawn completely and they were sacrificed. Intestinal tissue samples were examined under light microscope. Levels of superoxide dismutase (SOD), catalase (CAT), glutathioneperoxidase (GSH-Px), malondyaldehide (MDA), and protein carbonyl (PCO) were analyzed in tissue samples. Total oxidant status (TOS), and total antioxidant capacity (TAC) were analyzed in blood samples. Data were evaluated statistically by Kruskal Wallis test. Results. In the ozone administered group, degree of intestinal injury was not different from the control group. IR caused an increase in intestinal injury score. The intestinal epithelium maintained its integrity and decrease in intestinal injury score was detected in Ozone + IR group. SOD, GSH-Px, and CAT values were high in ozone group and low in IR. TOS parameter was highest in the IR group and the TAC parameter was highest in the ozone group and lowest in the IR group. Conclusion. In the present study, IR model caused an increase in intestinal injury.In the present study, ozone administration had an effect improving IR associated tissue injury. In the present study, ozone therapy prevented

Mucosal injury induced by ischemia and reperfusion in the piglet intestine: Influences of age and feeding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crissinger, K.D.; Granger, D.N.

1989-10-01

The pathogenesis of neonatal necrotizing enterocolitis is unknown, but enteral alimentation, infectious agents, and mesenteric ischemia have been frequently invoked as primary initiators of the disease. To define the vulnerability of the intestinal mucosa to ischemia and reperfusion in the developing piglet, we evaluated changes in mucosal permeability using plasma-to-lumen clearance of chromium 51-labeled ethylenediaminetetraacetic acid in the ileum of anesthetized 1-day-, 3-day-, 2-wk-, and 1-mo-old piglets as a function of (a) duration of intestinal ischemia (20, 40, or 60 min of total superior mesenteric artery occlusion), (b) feeding status (fasted or nursed), and (c) composition of luminal perfusate (balancedmore » salt solution vs. predigested cow milk-based formula). Baseline chromium 51-labeled ethylenediaminetetraacetic acid clearance was not significantly altered by ischemia, irrespective of duration, or feeding in all age groups. However, clearances were significantly elevated during reperfusion after 1 h of total intestinal ischemia in all age groups, whether fasted or fed. Reperfusion-induced increases in clearance did not differ among age groups when the bowel lumen was perfused with a balanced salt solution. However, luminal perfusion with formula resulted in higher clearances in 1-day-old piglets compared with all older animals. Thus, the neonatal intestine appears to be more vulnerable to mucosal injury induced by ischemia and reperfusion in the presence of formula than the intestine of older animals.« less

Protective effects of vitamin E against myocardial ischemia/reperfusion injury in rats.

PubMed

Saleh, Nermine K; Saleh, Hanan A

2010-02-01

To clarify the cardioprotective effects of a short course of vitamin E treatment (vit E) as compared with a nitric oxide donor, nitroglycerin (GTN) against ischemia-reperfusion induced heart injury in rats. This randomized control study was conducted in the Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt from 1st June to 31 August 2009. This work was undertaken on 28 female Wistar rats weighing 150- 200 gm. Rats were allocated into 4 groups; control group (non-treated), GTN-treated group (rats received GTN intraperitoneally 25 minutes before sacrifice, in a dose of 120 ug/kg body weight), vit E-treated group (rat received vit E by oral tubal feeding 16-20 hours before sacrifice, in a dose of 250 mg/rat), and vit E and GTN-treated group (rats received vit E and GTN as in both GTN-treated group and vit E -treated group). After sacrifice, the hearts were excised and perfused in a Langendorff preparation and subjected to 30 minutes global ischemia and reperfused for 30 minutes. Following reperfusion, heart tissues were used for assessment of malondialdehyde (MDA) and nicotinamide adenine dinucleotide (NAD)+, and for histological examination. Vitamin E treatment resulted in an enhanced post-ischemic recovery of systolic function in vit E-treated groups (vit E-treated group, and vit E and GTN-treated group) compared to the control group. Post-ischemic recovery of coronary flow was enhanced in the vit E-treated group compared to the GTN-treated group. Post ischemic tissue degeneration indicators: MDA, and NAD+ indicated a cardioprotective effect of vit E. Histological study revealed marked improvement of myocytes and mitochondrial structure in the vit E-treated group as compared with the control group. Preconditioning with vit E treatment afforded substantial recovery of post-ischemic contractile, and vascular functions compared to GTN treatment, the mechanism might involve less opening of mitochondrial permeability transition during

Reperfusion injury intensifies the adaptive human T cell alloresponse in a human-mouse chimeric artery model.

PubMed

Yi, Tai; Fogal, Birgit; Hao, Zhengrong; Tobiasova, Zuzana; Wang, Chen; Rao, Deepak A; Al-Lamki, Rafia S; Kirkiles-Smith, Nancy C; Kulkarni, Sanjay; Bradley, John R; Bothwell, Alfred L M; Sessa, William C; Tellides, George; Pober, Jordan S

2012-02-01

Perioperative nonimmune injuries to an allograft can decrease graft survival. We have developed a model for studying this process using human materials. Human artery segments were transplanted as infrarenal aortic interposition grafts into an immunodeficient mouse host, allowed to "heal in" for 30 days, and then retransplanted into a second mouse host. To induce a reperfusion injury, the healed-in artery segments were incubated for 3 hours under hypoxic conditions ex vivo before retransplantation. To induce immunologic rejection, the animals receiving the retransplanted artery segment were adoptively transferred with human peripheral blood mononuclear cells or purified T cells from a donor allogeneic to the artery 1 week before surgery. To compare rejection of injured versus healthy tissues, these manipulations were combined. Results were analyzed ex vivo by histology, morphometry, immunohistochemistry, and mRNA quantitation or in vivo by ultrasound. Our results showed that reperfusion injury, which otherwise heals with minimal sequelae, intensifies the degree of allogeneic T cell-mediated injury to human artery segments. We developed a new human-mouse chimeric model demonstrating interactions of reperfusion injury and alloimmunity using human cells and tissues that may be adapted to study other forms of nonimmune injury and other types of adaptive immune responses.

Chronic heat improves mechanical and metabolic response of trained rat heart on ischemia and reperfusion.

PubMed

Levy, E; Hasin, Y; Navon, G; Horowitz, M

1997-05-01

Cardiac mechanics and metabolic performance were studied in isolated perfused hearts of rats subjected to a combined chronic stress of heat acclimation and swimming training (EXAC) or swimming training alone (EX). Diastolic (DP) and systolic pressures (SP), coronary flow (CF), and oxygen consumption were measured during normoperfusion (80 mmHg), and the appearance of ischemic contracture (IC), DP, and SP were measured during progressive graded ischemia, total ischemia (TI), and reperfusion insults. ATP, phosphocreatine, and intracellular pH were measured during TI and reperfusion with 31P nuclear magnetic resonance spectroscopy. During normoperfusion, SP and cardiac efficiency (derived from rate-pressure product-oxygen consumption relationships) were the highest in the 2-mo EXAC hearts (P < 0.0001). During progressive graded ischemia, the development of IC (percentage of total hearts) was similar in both EXAC and EX hearts; the only significant difference was confined to the 1- vs. 2-mo groups. The onset of IC was delayed in the EXAC hearts and, on reperfusion, recovery, particularly of DP, was significantly improved in the latter. After TI, EXAC hearts retained 30% of the ATP pool and there was a delayed decline in intracellular pH. On reperfusion, these hearts also displayed improved ATP and phosphocreatine recovery, the 2-mo EXAC heart demonstrating significantly faster high-energy phosphate salvage, improved diastolic function, and pulse pressure recovery. The data attest to the beneficial effects of heat acclimation on cardiac mechanics of trained rats during normoperfusion and cardiac protection on ischemia and reperfusion. Possibly, energy sparing, lesser acidosis, and shorter duration of IC on ischemia and improved energy salvage on reperfusion contribute synergistically to this potent beneficial effect.

Protective effect of sevoflurane on myocardial ischemia-reperfusion injury in rat hearts and its impact on HIF-1α and caspase-3 expression.

PubMed

Zhou, Tao; Guo, Shanliang; Wang, Shaolin; Li, Qiong; Zhang, Mingsheng

2017-11-01

This study was designed to investigate possible protective effects of sevoflurane on myocardial ischemia-reperfusion injury (MIRI) and its impact on expression of HIF-1α and caspase-3 in rats, so as to provide new insights for the treatment of MIRI. Forty SD rats were randomly divided into four groups (n=10) including Sham operation (Sham), ischemia-reperfusion (IR), sevoflurane preconditioning group (Sevo-Pre) and sevoflurane post-conditioning (Sevo-Post) groups. Perfusion was performed using ex vivo heart perfusion. The baseline values of cardiac function were recorded in each group at the end of balanced perfusion and after 60 min of reperfusion. Myocardial infarct size (MIS) was calculated at the end of perfusion using TTC staining. Levels of HIF-1α and caspase-3 protein and HIF-1α (western blotting) and Bcl-2 mRNA (RT-qPCR) were detected at the end of reperfusion. Our results showed no significant differences in cardiac function between the groups at the end of the balanced perfusion. After reperfusion for 60 min, however, the cardiac functions of the Sevo-Pre and Sevo-Post groups were significantly better than those in the IR group, and the MIS at the end of reperfusion was significantly decreased. Western blotting and RT-qPCR showed that expression of HIF-1α protein was significantly increased, expression of caspase-3 protein was significantly decreased and expression of HIF-1α and Bcl-2 mRNA were significantly increased in Sevo-Pre and Sevo-Post groups compared with the levels in the IR group at the end of reperfusion. There were no significant differences in experimental results between Sevo-Pre and Sevo-Post groups. Our data support the idea that sevoflurane can improve MIRI in rats by improving cardiac function and reducing MIS. This protective effect seems to be achieved by activation of HIF-1α and inhibition of caspase-3.

Locations of ectopic beats coincide with spatial gradients of NADH in a regional model of low-flow reperfusion.

PubMed

Kay, Matthew; Swift, Luther; Martell, Brian; Arutunyan, Ara; Sarvazyan, Narine

2008-05-01

We studied the origins of ectopic beats during low-flow reperfusion after acute regional ischemia in excised rat hearts. The left anterior descending coronary artery was cannulated. Perfusate was delivered to the cannula using an high-performance liquid chromatography pump. This provided not only precise control of flow rate but also avoided mechanical artifacts associated with vessel occlusion and deocclusion. Optical mapping of epicardial transmembrane potential served to identify activation wavefronts. Imaging of NADH fluorescence was used to quantify local ischemia. Our experiments suggest that low-flow reperfusion of ischemic myocardium leads to a highly heterogeneous ischemic substrate and that the degree of ischemia between adjacent patches of tissue changes in time. In contrast to transient ectopic activity observed during full-flow reperfusion, persistent ectopic arrhythmias were observed during low-flow reperfusion. The origins of ectopic beats were traceable to areas of high spatial gradients of changes in NADH fluorescence caused by low-flow reperfusion.

Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

PubMed Central

Suh, Sang Won; Gum, Elizabeth T.; Hamby, Aaron M.; Chan, Pak H.; Swanson, Raymond A.

2007-01-01

Hypoglycemic coma and brain injury are potential complications of insulin therapy. Certain neurons in the hippocampus and cerebral cortex are uniquely vulnerable to hypoglycemic cell death, and oxidative stress is a key event in this cell death process. Here we show that hypoglycemia-induced oxidative stress and neuronal death are attributable primarily to the activation of neuronal NADPH oxidase during glucose reperfusion. Superoxide production and neuronal death were blocked by the NADPH oxidase inhibitor apocynin in both cell culture and in vivo models of insulin-induced hypoglycemia. Superoxide production and neuronal death were also blocked in studies using mice or cultured neurons deficient in the p47phox subunit of NADPH oxidase. Chelation of zinc with calcium disodium EDTA blocked both the assembly of the neuronal NADPH oxidase complex and superoxide production. Inhibition of the hexose monophosphate shunt, which utilizes glucose to regenerate NADPH, also prevented superoxide formation and neuronal death, suggesting a mechanism linking glucose reperfusion to superoxide formation. Moreover, the degree of superoxide production and neuronal death increased with increasing glucose concentrations during the reperfusion period. These results suggest that high blood glucose concentrations following hypoglycemic coma can initiate neuronal death by a mechanism involving extracellular zinc release and activation of neuronal NADPH oxidase. PMID:17404617

Edaravone enhances the viability of ischemia/reperfusion flaps.

PubMed

Zhang, Dong-Yi; Kang, Shen-Song; Zhang, Zheng-Wen; Wu, Rui

2017-02-01

The purpose of the experiment was to study the efficacy of edaravone in enhancing flap viability after ischemia/reperfusion (IR) and its mechanism. Forty-eight adult male SD rats were randomly divided into 3 groups: control group (n=16), IR group (n=16), and edaravone-treated IR group (n=16). An island flap at left lower abdomen (6.0 cm×3.0 cm in size), fed by the superficial epigastric artery and vein, was created in each rat of all the three groups. The arterial blood flow of flaps in IR group and edaravone-treated IR group was blocked for 10 h, and then the blood perfusion was restored. From 15 min before reperfusion, rats in the edaravone-treated IR group were intraperitoneally injected with edaravone (10 mg/kg), once every 12 h, for 3 days. Rats in the IR group and control group were intraperitoneally injected with saline, with the same method and frequency as the rats in the edaravone-treated IR group. In IR group and edaravone-treated IR group, samples of flaps were harvested after reperfusion of the flaps for 24 h. In the control group, samples of flaps were harvested 34 h after creation of the flaps. The content of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) were determined, and changes in organizational structure and infiltration of inflammatory cells were observed by hematoxylin-eosin (HE) staining, apoptotic cells of vascular wall were marked by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and the apoptotic rate of cells in vascular wall was calculated. The ultrastructural changes of vascular endothelial cells were observed by transmission electron microscopy (TEM). Seven days after the operation, we calculated the flap viability of each group, and marked vessels of flaps by immunohistochemical staining for calculating the average number of subcutaneous vessels. The results showed that the content of MDA, the number of multicore inflammatory cells and apoptotic rate of cells in vascular wall

Neuroprotective effect of pretreatment with ganoderma lucidum in cerebral ischemia/reperfusion injury in rat hippocampus.

PubMed

Zhang, Wangxin; Zhang, Quiling; Deng, Wen; Li, Yalu; Xing, Guoqing; Shi, Xinjun; Du, Yifeng

2014-08-01

Ganoderma lucidum is a traditional Chinese medicine, which has been shown to have both anti-oxidative and anti-inflammatory effects, and noticeably decreases both the infarct area and neuronal apoptosis of the ischemic cortex. This study aimed to investigate the protective effects and mechanisms of pretreatment with ganoderma lucidum (by intragastric administration) in cerebral ischemia/reperfusion injury in rats. Our results showed that pretreatment with ganoderma lucidum for 3 and 7 days reduced neuronal loss in the hippocampus, diminished the content of malondialdehyde in the hippocampus and serum, decreased the levels of tumor necrosis factor-α and interleukin-8 in the hippocampus, and increased the activity of superoxide dismutase in the hippocampus and serum. These results suggest that pretreatment with ganoderma lucidum was protective against cerebral ischemia/reperfusion injury through its anti-oxidative and anti-inflammatory actions.

Neuroprotective effect of pretreatment with ganoderma lucidum in cerebral ischemia/reperfusion injury in rat hippocampus

PubMed Central

Zhang, Wangxin; Zhang, Quiling; Deng, Wen; Li, Yalu; Xing, Guoqing; Shi, Xinjun; Du, Yifeng

2014-01-01

Ganoderma lucidum is a traditional Chinese medicine, which has been shown to have both anti-oxidative and anti-inflammatory effects, and noticeably decreases both the infarct area and neuronal apoptosis of the ischemic cortex. This study aimed to investigate the protective effects and mechanisms of pretreatment with ganoderma lucidum (by intragastric administration) in cerebral ischemia/reperfusion injury in rats. Our results showed that pretreatment with ganoderma lucidum for 3 and 7 days reduced neuronal loss in the hippocampus, diminished the content of malondialdehyde in the hippocampus and serum, decreased the levels of tumor necrosis factor-α and interleukin-8 in the hippocampus, and increased the activity of superoxide dismutase in the hippocampus and serum. These results suggest that pretreatment with ganoderma lucidum was protective against cerebral ischemia/reperfusion injury through its anti-oxidative and anti-inflammatory actions. PMID:25317156

The Cardioprotective Effects of Citric Acid and L-Malic Acid on Myocardial Ischemia/Reperfusion Injury

PubMed Central

Tang, Xilan; Liu, Jianxun; Dong, Wei; Li, Peng; Li, Lei; Lin, Chengren; Zheng, Yongqiu; Hou, Jincai; Li, Dan

2013-01-01

Organic acids in Chinese herbs, the long-neglected components, have been reported to possess antioxidant, anti-inflammatory, and antiplatelet aggregation activities; thus they may have potentially protective effect on ischemic heart disease. Therefore, this study aims to investigate the protective effects of two organic acids, that is, citric acid and L-malic acid, which are the main components of Fructus Choerospondiatis, on myocardial ischemia/reperfusion injury and the underlying mechanisms. In in vivo rat model of myocardial ischemia/reperfusion injury, we found that treatments with citric acid and L-malic acid significantly reduced myocardial infarct size, serum levels of TNF-α, and platelet aggregation. In vitro experiments revealed that both citric acid and L-malic acid significantly reduced LDH release, decreased apoptotic rate, downregulated the expression of cleaved caspase-3, and upregulated the expression of phosphorylated Akt in primary neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation injury. These results suggest that both citric acid and L-malic acid have protective effects on myocardial ischemia/reperfusion injury; the underlying mechanism may be related to their anti-inflammatory, antiplatelet aggregation and direct cardiomyocyte protective effects. These results also demonstrate that organic acids, besides flavonoids, may also be the major active ingredient of Fructus Choerospondiatis responsible for its cardioprotective effects and should be attached great importance in the therapy of ischemic heart disease. PMID:23737849

Remote Ischemic Postconditioning (RIPC) of the Upper Arm Results in Protection from Cardiac Ischemia-Reperfusion Injury Following Primary Percutaneous Coronary Intervention (PCI) for Acute ST-Segment Elevation Myocardial Infarction (STEMI)

PubMed Central

Cao, Bangming; Wang, Haipeng; Zhang, Chi; Xia, Ming

2018-01-01

Background The aim of this study was to evaluate the role of remote ischemic postconditioning (RIPC) of the upper arm on protection from cardiac ischemia-reperfusion injury following primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). Material/Methods Eighty patients with STEMI were randomized into two groups: primary PCI (N=44) and primary PCI+RIPC (N=36). RIPC consisted of four cycles of 5 minutes of occlusion and five minutes of reperfusion by cuff inflation and deflation of the upper arm, commencing within one minute of the first PCI balloon dilatation. Peripheral venous blood samples were collected before PCI and at 0.5, 8, 24, 48, and 72 hours after PCI. Levels of creatine kinase-MB (CK-MB), serum creatinine (Cr), nitric oxide (NO), and stromal cell-derived factor-1α (SDF-1α) were measured. The rates of acute kidney injury (AKI) and the estimated glomerular filtration rate (eGFR) were calculated. Results Patients in the primary PCI+RIPC group, compared with the primary PCI group, had significantly lower peak CK-MB concentrations (P<0.01), a significantly increased left ventricular ejection fraction (LVEF) (P=0.01), a significantly lower rate of AKI (P<0.01) a significantly increased eGFR (P<0.01), and decreased area under the curve (AUC) of CK-MB, NO and SDF-1α. Conclusions RIPC of the upper arm following primary PCI in patients with acute STEMI might provide cardiac and renal protection from ischemia-reperfusion injury via the actions of SDF-1α, and NO. PMID:29456238

Remote Ischemic Postconditioning (RIPC) of the Upper Arm Results in Protection from Cardiac Ischemia-Reperfusion Injury Following Primary Percutaneous Coronary Intervention (PCI) for Acute ST-Segment Elevation Myocardial Infarction (STEMI).

PubMed

Cao, Bangming; Wang, Haipeng; Zhang, Chi; Xia, Ming; Yang, Xiangjun

2018-02-19

BACKGROUND The aim of this study was to evaluate the role of remote ischemic postconditioning (RIPC) of the upper arm on protection from cardiac ischemia-reperfusion injury following primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). MATERIAL AND METHODS Eighty patients with STEMI were randomized into two groups: primary PCI (N=44) and primary PCI+RIPC (N=36). RIPC consisted of four cycles of 5 minutes of occlusion and five minutes of reperfusion by cuff inflation and deflation of the upper arm, commencing within one minute of the first PCI balloon dilatation. Peripheral venous blood samples were collected before PCI and at 0.5, 8, 24, 48, and 72 hours after PCI. Levels of creatine kinase-MB (CK-MB), serum creatinine (Cr), nitric oxide (NO), and stromal cell-derived factor-1α (SDF-1α) were measured. The rates of acute kidney injury (AKI) and the estimated glomerular filtration rate (eGFR) were calculated. RESULTS Patients in the primary PCI+RIPC group, compared with the primary PCI group, had significantly lower peak CK-MB concentrations (P<0.01), a significantly increased left ventricular ejection fraction (LVEF) (P=0.01), a significantly lower rate of AKI (P<0.01) a significantly increased eGFR (P<0.01), and decreased area under the curve (AUC) of CK-MB, NO and SDF-1α. CONCLUSIONS RIPC of the upper arm following primary PCI in patients with acute STEMI might provide cardiac and renal protection from ischemia-reperfusion injury via the actions of SDF-1α, and NO.

Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

PubMed Central

Soljancic, Andrea; Ruiz, Arnaldo Lopez; Chandrashekar, Kiran; Maranon, Rodrigo; Liu, Ruisheng; Juncos, Luis A.

2013-01-01

Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease, in general. In the present study, we tested the hypothesis that I/R of the kidney reduces serum testosterone, and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 h after reperfusion that remained at 24 h. Acute infusion of testosterone 3 h after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 h, prevented the reduction in outer medullary blood flow, and attenuated the increase in intrarenal TNF-α and the decrease in intrarenal VEGF at 48 h. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 h than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney, whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol. PMID:23552495

Carbamylated erythropoietin protects the kidneys from ischemia-reperfusion injury without stimulating erythropoiesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Imamura, Ryoichi; Isaka, Yoshitaka; Ichimaru, Naotsugu

Several studies have shown that erythropoietin (EPO) can protect the kidneys from ischemia-reperfusion injury and can raise the hemoglobin (Hb) concentration. Recently, the EPO molecule modified by carbamylation (CEPO) has been identified and was demonstrated to be able to protect several organs without increasing the Hb concentration. We hypothesized that treatment with CEPO would protect the kidneys from tubular apoptosis and inhibit subsequent tubulointerstitial injury without erythropoiesis. The therapeutic effect of CEPO was evaluated using a rat ischemia-reperfusion injury model. Saline-treated kidneys exhibited increased tubular apoptosis with interstitial expression of {alpha}-smooth muscle actin ({alpha}-SMA), while EPO treatment inhibited tubular apoptosismore » and {alpha}-SMA expression to some extent. On the other hand, CEPO-treated kidneys showed minimal tubular apoptosis with limited expression of {alpha}-SMA. Moreover, CEPO significantly promoted tubular epithelial cell proliferation without erythropoiesis. In conclusion, we identified a new therapeutic approach using CEPO to protect kidneys from ischemia-reperfusion injury.« less

[Clinical aspects of reperfusion arrhythmia following intravenous thrombolysis in acute myocardial infarct].

PubMed

Kettner, W; Klein, E; Schulz, W; Götze, C

1987-05-15

In accordance with the majority of the reports in the literature reperfusion arrhythmias were observed in more than 30% of the patients with acute myocardial infarction (n = 25) under or immediately after a highly dosed short-term infusion with streptokinase. With reference to indirect signs the recanalisation rate was assumed with 75%. Only one third of the reperfusion arrhythmias had haemodynamically significant characteristics and required an influence. Though in literature from animal experimental findings directive conclusions for the therapy are to be derived, the procedure in practice is still vastly empirical. In the ventricular tachycardia lidocaine, procainamide and ajmalin may be recommended. In ineffectiveness or particularly threatening situations the electrotherapy (cardioversion, DC-shock) is to be preferred. The concept inaugurated by Corr and Witkowski apply alpha-adrenoreceptor blockers has not yet entered the clinical practice. Possible problems in the treatment of reperfusion arrhythmias in the prehospital phase should at present still be a reason not to antedate the thrombolytic therapy into this phase.

The protective effect of diosmin on hepatic ischemia reperfusion injury: an experimental study

PubMed Central

Tanrikulu, Yusuf; Şahin, Mefaret; Kismet, Kemal; Kilicoglu, Sibel Serin; Devrim, Erdinc; Tanrikulu, Ceren Sen; Erdemli, Esra; Erel, Serap; Bayraktar, Kenan; Akkus, Mehmet Ali

2013-01-01

Liver ischemia reperfusion injury (IRI) is an important pathologic process leading to bodily systemic effects and liver injury. Our study aimed to investigate the protective effects of diosmin, a phlebotrophic drug with antioxidant and anti-inflammatory effects, in a liver IRI model. Forty rats were divided into 4 groups. Sham group, control group (ischemia-reperfusion), intraoperative treatment group, and preoperative treatment group. Ischemia reperfusion model was formed by clamping hepatic pedicle for a 60 minute of ischemia followed by liver reperfusion for another 90 minutes. Superoxide dismutase (SOD) and catalase (CAT) were measured as antioaxidant enzymes in the liver tissues, and malondialdehyde (MDA) as oxidative stress marker, xanthine oxidase (XO) as an oxidant enzyme and glutathione peroxidase (GSH-Px) as antioaxidant enzyme were measured in the liver tissues and the plasma samples. Hepatic function tests were lower in treatment groups than control group (p<0.001 for ALT and AST). Plasma XO and MDA levels were lower in treatment groups than control group, but plasma GSH-Px levels were higher (p<0.05 for all). Tissue MDA levels were lower in treatment groups than control group, but tissue GSH-Px, SOD, CAT and XO levels were higher (p<0.05 for MDA and p<0.001 for others). Samples in control group histopathologically showed morphologic abnormalities specific to ischemia reperfusion. It has been found that both preoperative and intraoperative diosmin treatment decreases cellular damage and protects cells from toxic effects in liver IRI. As a conclusion, diosmin may be used as a protective agent against IRI in elective and emergent liver surgical operations. PMID:24289756

Melatonin attenuates lung ischaemia-reperfusion injury via inhibition of oxidative stress and inflammation.

PubMed

Wang, Ming-Liang; Wei, Chun-Hua; Wang, Wen-Dong; Wang, Jia-Shun; Zhang, Jun; Wang, Jian-Jun

2018-05-01

Lung ischaemia-reperfusion injury is a complex pathophysiological process due to the production of reactive oxygen species and the generation of inflammatory reaction. We investigated the protective effects and the corresponding mechanism of melatonin (MT), a potent free-radical scavenger, on lung injury induced by ischaemia-reperfusion in a mouse model. Adult male C57BL/6J mice (n = 30) were randomly and equally allocated into 5 groups: sham controls, IR, IR + 10 mg/kg MT, IR + 20 mg/kg MT and IR + 30 mg/kg MT. Lung ischaemia-reperfusion injury was induced by thoracotomy followed by clamping of the left hilum for 1 h and subsequent reperfusion for 2 h. Histological scoring analysis showed that lung parenchymal damage was ameliorated in the melatonin pretreatment groups when compared with the IR group, with the IR + 20 mg/kg MT group showing the strongest effect among the melatonin pretreatment groups. Wet-to-dry weight ratio, detection of malondialdehyde, protein expressions of inflammatory factors (tumour necrosis factor-α, interleukin-1β, NF-κB and IKK-γ) and apoptotic factors (cleaved caspase-3 and Bax/Bcl-2), as well as TUNEL assay showed changes similar to those of the lung injury scores in all groups. In contrast, the examination of superoxide dismutase showed a pattern contrary to that of the lung injury score in all groups. In addition, immunohistochemistry staining showed that the expressions of the antioxidants glutathione peroxidase and glutathione reductase were increased in the melatonin pretreatment groups. This study demonstrated that melatonin pretreatment attenuated lung ischaemia-reperfusion injury via inhibition of oxidative stress, inflammation and apoptosis.

Ischaemia-reperfusion injury in orthotopic mouse lung transplants - a scanning electron microscopy study.

PubMed

Draenert, Alice; Marquardt, Klaus; Inci, Ilhan; Soltermann, Alex; Weder, Walter; Jungraithmayr, Wolfgang

2011-02-01

Lung ischaemia-reperfusion (I/R) injury remains a major cause of graft failure in lung transplantation (Tx). With the implementation of orthotopic lung Tx in mice, a physiological model on the base of a perfused and ventilated graft became available for the investigation of I/R injury. Using the scanning electron microscopy (SEM) technique, we here present an analysis of early and late morphological changes of pulmonary I/R injury. Syngeneic lungs were orthotopically transplanted between C57BL/6 mice. Grafts were exposed to 2 h of cold ischaemia. Transplants and right lungs were examined by SEM with corresponding haematoxylin-eosin histology 30 min and 4 h after reperfusion. Thirty minutes after reperfusion, the alveolar surface of transplants showed a discontinued lining of surfactant, while the lining of the non-transplanted lung was normal. Within the graft, leucocytes displayed an irregular surface with development of pseudopodia, and microvilli were detected on the membrane of pneumocytes. At 4 h after reperfusion, leucocytes significantly increased in numbers within the alveolar space. Also, the number of microvilli on pneumocytes increased significantly. Similar to these, the endothelium of vessels increasingly developed microvilli from 30 min towards 4 h after reperfusion. The airways of transplanted grafts showed mild changes with thickening of the bronchial epithelium and a destruction of kinocilia. Taken together, SEM detects pathological events of I/R that are previously not described in normal histology. These findings may influence the interpretation of studies investigating the I/R injury in the mouse model of lung Tx. © 2011 The Authors. International Journal of Experimental Pathology © 2011 International Journal of Experimental Pathology.

Critical role of PI3-kinase/Akt activation in the PARP inhibitor induced heart function recovery during ischemia-reperfusion.

PubMed

Kovacs, Krisztina; Toth, Ambrus; Deres, Peter; Kalai, Tamas; Hideg, Kalman; Gallyas, Ferenc; Sumegi, Balazs

2006-02-14

Poly(ADP-ribose) polymerase (PARP) inhibitors protect hearts from ischemia-reperfusion (IR)-induced damages by limiting nicotinamide adenine dinucleotide (NAD+) and ATP depletion, and by other, not yet elucidated mechanisms. Our preliminary data suggested that PARP catalyzed ADP-ribosylations may affect signaling pathways in cardiomyocytes. To clarify this possibility, we studied the effect of a well-characterized (4-hydroxyquinazoline) and a novel (carboxaminobenzimidazol-derivative) PARP inhibitor on the activation of phosphatidylinositol-3-kinase (PI3-kinase)/Akt pathway in Langendorff-perfused hearts. PARP inhibitors promoted the restoration of myocardial energy metabolism (assessed by 31P nuclear magnetic resonance spectroscopy) and cardiac function compared to untreated hearts. PARP inhibitors also attenuated the infarct size and reduced the IR-induced lipid peroxidation, protein oxidation and total peroxide concentration. Moreover, PARP inhibitors facilitated Akt phosphorylation and activation, as well as the phosphorylation of its downstream target glycogen synthase kinase-3beta (GSK-3beta) in normoxia and, more robustly, during IR. Blocking PI3-kinase by wortmannin or LY294002 reduced the PARP inhibitor-elicited robust Akt and GSK-3beta phosphorylation upon ischemia-reperfusion, and significantly diminished the recovery of ATP and creatine phosphate showing the importance of Akt activation in the recovery of energy metabolism. In addition, inhibition of PI3-kinase/Akt pathway decreased the protective effect of PARP inhibitors on infarct size and the recovery of heart functions. All these data suggest that contrary to the original view, which considered preservation of NAD+ and consequently ATP pools as the exclusive underlying mechanism for the cytoprotective effect of PARP inhibitors, the activation of PI3-kinase/Akt pathway and related processes are at least equally important in the cardioprotective effects of PARP inhibitors during ischemia-reperfusion.

Hydrogen Gas Ameliorates Hepatic Reperfusion Injury After Prolonged Cold Preservation in Isolated Perfused Rat Liver.

PubMed

Shimada, Shingo; Wakayama, Kenji; Fukai, Moto; Shimamura, Tsuyoshi; Ishikawa, Takahisa; Fukumori, Daisuke; Shibata, Maki; Yamashita, Kenichiro; Kimura, Taichi; Todo, Satoru; Ohsawa, Ikuroh; Taketomi, Akinobu

2016-12-01

Hydrogen gas reduces ischemia and reperfusion injury (IRI) in the liver and other organs. However, the precise mechanism remains elusive. We investigated whether hydrogen gas ameliorated hepatic I/R injury after cold preservation. Rat liver was subjected to 48-h cold storage in University of Wisconsin solution. The graft was reperfused with oxygenated buffer with or without hydrogen at 37° for 90 min on an isolated perfusion apparatus, comprising the H 2 (+) and H 2 (-) groups, respectively. In the control group (CT), grafts were reperfused immediately without preservation. Graft function, injury, and circulatory status were assessed throughout the perfusion. Tissue samples at the end of perfusion were collected to determine histopathology, oxidative stress, and apoptosis. In the H 2 (-) group, IRI was indicated by a higher aspartate aminotransferase (AST), alanine aminotransferase (ALT) leakage, portal resistance, 8-hydroxy-2-deoxyguanosine-positive cell rate, apoptotic index, and endothelial endothelin-1 expression, together with reduced bile production, oxygen consumption, and GSH/GSSG ratio (vs. CT). In the H 2 (+) group, these harmful changes were significantly suppressed [vs. H 2 (-)]. Hydrogen gas reduced hepatic reperfusion injury after prolonged cold preservation via the maintenance of portal flow, by protecting mitochondrial function during the early phase of reperfusion, and via the suppression of oxidative stress and inflammatory cascades thereafter. Copyright © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Lack of chlorpromazine effect on skeletal muscle metabolism after ischemia and a short reperfusion period.

PubMed

Piccinato, Carlos E; Salles Roselino, José E; Massuda, Carlos A; Cherri, Jesualdo

2004-01-01

The great resistance of muscle to ischemia was used to study blood flow-dependent phenomena produced by anesthetic drugs in this condition. A short reperfusion period was used in order to favor metabolic changes indicative of an effect of chlorpromazine (CPZ) on blood flow. Gracilis muscles of dogs were submitted to 5 h of ischemia and 30 min of reperfusion. CPZ-treated animals were injected I.V. (2 mg/kg) 10 min before the beginning of ischemia. Biopsies provided the material for tissue measurements. Lactate content and pH were determined in blood samples collected from a muscle efferent vein. In both the CPZ-treated and nontreated groups, ischemia induced a decline in muscle glycogen content, with a corresponding increase in muscle lactate and a decrease in mitochondrial respiratory control ratio. After 30 min of reperfusion, tissue levels of lactate did not attain preischemic values but showed a clear decline in the two experimental groups, evidencing the reversible state of the muscle. All other metabolic parameters remained unchanged. Mitochondrial respiratory control remained functional during ischemia and reperfusion. Blood pH displayed similar changes in both groups. There was no metabolic indication that the drug affected blood flow during early reperfusion and/or of a greater sensitivity of muscle endothelial cells to anesthetic drugs. Copyright 2004 Wiley-Liss, Inc.

Osthole ameliorates renal ischemia-reperfusion injury in rats.

PubMed

Zheng, Yi; Lu, Min; Ma, Lulin; Zhang, Shudong; Qiu, Min; Wang, Yunpeng

2013-07-01

Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. The pathogenetic mechanisms underlying I/R injury involve oxidative stress and apoptosis. Osthole, a natural coumarin derivative, has been reported to possess antioxidant and antiapoptotic activities. This study aimed to investigate the potential effects of osthole on renal I/R injury in an in vivo rat model. 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 54 rats to three groups (18 rats/group): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intraperitoneally with osthole (40 mg/kg) or vehicle (40 mg/kg) 30 min before renal ischemia. We harvested serum and kidneys at 1, 6, and 24 h after reperfusion. Renal function and histological changes were assessed. We also determined markers of oxidative stress and cell apoptosis in kidneys. Osthole treatment significantly attenuated renal dysfunction and histologic damage induced by I/R injury. The I/R-induced elevation in kidney malondialdehyde level decreased, whereas reduced kidney superoxide dismutase and catalase activities were markedly increased. Moreover, osthole-treated rats had a dramatic decrease in apoptotic tubular cells, along with a decrease in caspase-3 and an increase in the Bcl-2/Bax ratio. Osthole treatment protects murine kidney from renal I/R injury by suppressing oxidative stress and cell apoptosis. Thus, osthole may represent a novel practical strategy to prevent renal I/R injury. Copyright © 2013 Elsevier Inc. All rights reserved.

Leptin attenuates cerebral ischemia/reperfusion injury partially by CGRP expression.

PubMed

Zhang, Jin-ying; Yan, Guang-tao; Liao, Jie; Deng, Zi-hui; Xue, Hui; Wang, Lu-huan; Zhang, Kai

2011-12-05

Ischemic stroke is a medical emergency triggered by a rapid reduction in blood supply to localized portions of the brain, usually because of thrombosis or embolism, which leads to neuronal dysfunction and death in the affected brain areas. Leptin is generally considered to be a strong and quick stress mediator after injuries. However, whether and how peripherally administered leptin performs neuroprotective potency in cerebral stroke has not been fully investigated. It has been reported that CGRP(8-37), an antagonist of the CGRP receptor, could reverse the protective effect of leptin on rats with CIP (caerulein-induced pancreatitis). However, the question remains: are leptin and CGRP associated in cerebral ischemia/reperfusion injury? The present study attempted to evaluate the relationship between CGRP expression and leptin neuroprotective effects (1mg/kg in 200 μL normal saline, i.p.) on focal cerebral ischemia/reperfusion injury in mice and the protective effect of leptin (500 μg/L) on neurons during hypoxia/reoxygenation injury. Peripheral administration of leptin alleviated injury-evoked brain damage by promoting CGRP expression, improving regional cerebral blood flow, and reducing local infarct volume and neurological deficits. Furthermore, leptin also promoted bcl-2 expression and suppressed caspase-3 in vivo and vitro after injury. Administration of CGRP(8-37) (4 × 10(-8)mol/L) partly abolished the beneficial effects of leptin, and restored the normal expression levels of bcl-2 and caspase-3 in neurons, which indicated that leptin-induced protection of neurons was correlated with release of CGRP. These results indicate that the neuroprotective effect of leptin against cerebral ischemia/reperfusion injury may be strongly relevant to the increase of CGRP expression. Copyright © 2011 Elsevier B.V. All rights reserved.

Preconditioning by inhaled nitric oxide prevents hyperoxic and ischemia/reperfusion injury in rat lungs.

PubMed

Waldow, Thomas; Witt, Wolfgang; Ulmer, André; Janke, Andreas; Alexiou, Konstantin; Matschke, Klaus

2008-01-01

Since the generation of nitric oxide (NO) is an essential step in the trigger phase of ischemic preconditioning, short-term inhalation of NO before ischemia should ameliorate ischemia/reperfusion (I/R) injury of the lung. We tested this hypothesis in high oxygen (>99%) ventilated rats in order to additionally evaluate compatibility of NO and exposure to hyperoxia. Male adult Sprague-Dawley rats inhaled NO (15 ppm, 10 min) before the left lung hilum was clamped for 1 h, and the reperfusion phase was observed for 4 h (NO group). Animals in the I/R group underwent the same treatment, but without NO inhalation. A third group without I/R served as time-matched controls. Animals in the I/R group showed severe I/R injury in terms of arterial pO2 (apO2), which was reduced to 22% of surgical controls (SCs) at time point 30 min reperfusion, and increased endothelial permeability (Evans blue procedure). The pretreatment with NO attenuated these effects. The pO2 after 4 h reperfusion was still 3.0-fold higher in the NO group compared to I/R. In contrast, the I/R- and hyperoxia-induced invasion of leukocytes, as determined by measuring myeloperoxidase (MPO) activity, was not affected by NO. These data were correlated with the activity of major cellular signaling pathways by measuring the phosphorylation at activating and inhibitory sites of extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, protein kinase B (AKT), and glycogen synthase kinase 3beta (GSK-3beta), and by determination of cGMP in plasma and lung tissue. Inhalation of NO partly prevented the loss of activation by I/R and hyperoxic ventilation of ERK, JNK, and AKT, and it reduced the I/R-induced activation of GSK-3beta. The level of cGMP in plasma and lung tissue was increased in the NO group after 4 h reperfusion. In conclusion, application of inhaled NO in the preconditioning mode prevented I/R injury in the rat lung without interfering effects of hyperoxic ventilation. The effects of

A TSPO ligand prevents mitochondrial sterol accumulation and dysfunction during myocardial ischemia-reperfusion in hypercholesterolemic rats.

PubMed

Musman, Julien; Paradis, Stéphanie; Panel, Mathieu; Pons, Sandrine; Barau, Caroline; Caccia, Claudio; Leoni, Valerio; Ghaleh, Bijan; Morin, Didier

2017-10-15

A major cause of cell death during myocardial ischemia-reperfusion is mitochondrial dysfunction. We previously showed that the reperfusion of an ischemic myocardium was associated with an accumulation of cholesterol into mitochondria and a concomitant strong generation of auto-oxidized oxysterols. The inhibition of mitochondrial accumulation of cholesterol abolished the formation of oxysterols and prevented mitochondrial injury at reperfusion. The aim of this study was to investigate the impact of hypercholesterolemia on sterol and oxysterol accumulation in rat cardiac cytosols and mitochondria and to analyse the effect of the translocator protein ligand 4'-chlorodiazepam on this accumulation and mitochondrial function. Hypercholesterolemic ZDF fa/fa rats or normocholesterolemic lean rats were submitted to 30min of coronary artery occlusion followed by 15min reperfusion where cardiac cytosols and mitochondria were isolated. Hypercholesterolemia increased the cellular cardiac concentrations of cholesterol, cholesterol precursors and oxysterols both in cytosol and mitochondria in non-ischemic conditions. It also amplified the accumulation of all these compounds in cardiac cells and the alteration of mitochondrial function with ischemia-reperfusion. Administration of 4'-chlorodiazepam to ZDF fa/fa rats had no effect on the enhancement of sterols and oxysterols observed in the cytosols but inhibited cholesterol transfer to the mitochondria. It also alleviated the mitochondrial accumulation of all the investigated sterols and oxysterols. This was associated with a restoration of oxidative phosphorylation and a prevention of mitochondrial transition pore opening. The inhibition of cholesterol accumulation with TSPO ligands represents an interesting strategy to protect the mitochondria during ischemia-reperfusion in hypercholesterolemic conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

Fate of Neutrophils during the Recovery Phase of Ischemia/Reperfusion Induced Acute Kidney Injury

PubMed Central

2017-01-01

Effective clearance of inflammatory cells is required for resolution of inflammation. Here, we show in vivo evidence that apoptosis and reverse transendothelial migration (rTEM) are important mechanisms in eliminating neutrophils and facilitating recovery following ischemia/reperfusion injury (IRI) of the kidney. The clearance of neutrophils was delayed in the Bax knockout (KO)BM → wild-type (WT) chimera in which bone marrow derived cells are partially resistant to apoptosis, compared to WTBM → WT mice. These mice also showed delayed functional, histological recovery, increased tissue cytokines, and accelerated fibrosis. The circulating intercellular adhesion molecule-1 (ICAM-1)+ Gr-1+ neutrophils displaying rTEM phenotype increased during the recovery phase and blockade of junctional adhesion molecule-C (JAM-C), a negative regulator of rTEM, resulted in an increase in circulating ICAM-1+ neutrophils, faster resolution of inflammation and recovery. The presence of Tamm-Horsfall protein (THP) in circulating ICAM-1+ neutrophils could suggest that they are derived from injured kidneys. In conclusion, we suggest that apoptosis and rTEM are critically involved in the clearance mechanisms of neutrophils during the recovery phase of IRI. PMID:28875605

Reduced inflammatory response and increased microcirculatory disturbances during hepatic ischemia-reperfusion injury in steatotic livers of ob/ob mice

PubMed Central

Hasegawa, Tadashi; Ito, Yoshiya; Wijeweera, Jayanthika; Liu, Jie; Malle, Ernst; Farhood, Anwar; McCuskey, Robert S.; Jaeschke, Hartmut

2016-01-01

Steatosis is a major risk factor for complications after liver surgery. Since neutrophil cytotoxicity is critical for ischemia-reperfusion injury in normal livers, the aim of the present study was to evaluate whether an exaggerated inflammatory response could cause the increased injury in steatotic livers. In C57Bl/6 mice, 60 min of warm hepatic ischemia triggered a gradual increase in hepatic neutrophil accumulation during reperfusion with peak levels of 100-fold over baseline at 12 h of reperfusion. Neutrophil extravasation and a specific neutrophil-induced oxidant stress (immunostaining for hypochlorous acid-modified epitopes) started at 6 h of reperfusion and peaked at 12–24 h. Ob/ob mice, which had a severe macrovesicular steatosis, suffered significantly higher injury (alanine transaminase activity: 18,000 ± 2,100 U/l; 65% necrosis) compared with lean littermates (alanine transaminase activity: 4,900 ± 720 U/l; 24% necrosis) at 6 h of reperfusion. However, 62% fewer neutrophils accumulated in steatotic livers. This correlated with an attenuated increase in mRNA levels of several proinflammatory genes in ob/ob mice during reperfusion. In contrast, sham-operated ob/ob mice had a 50% reduction in liver blood flow and 35% fewer functional sinusoids compared with lean littermates. These deficiencies in liver blood flow and the microcirculation were further aggravated only in ob/ob mice during reperfusion. The attenuated inflammatory response and reduced neutrophil-induced oxidant stress observed in steatotic livers during reperfusion cannot be responsible for the dramatically increased injury in ob/ob mice. In contrast, the aggravated injury appears to be mediated by ischemic necrosis due to massive impairment of blood and oxygen supply in the steatotic livers. PMID:17307725

Vitexin exerts cardioprotective effect on chronic myocardial ischemia/reperfusion injury in rats via inhibiting myocardial apoptosis and lipid peroxidation

PubMed Central

Che, Xia; Wang, Xin; Zhang, Junyan; Peng, Chengfeng; Zhen, Yilan; Shao, Xu; Zhang, Gongliang; Dong, Liuyi

2016-01-01

Purpose: The aim of this study was to explore the cardioprotective effect of vitexin on chronic myocardial ischemia/reperfusion injury in rats and potential mechanisms. Methods: A chronic myocardial ischemia/reperfusion injury model was established by ligating left anterior descending coronary for 60 minutes, and followed by reperfusion for 14 days. After 2 weeks ischemia/reperfusion, cardiac function was measured to assess myocardial injury. The level of ST segment was recorded in different periods by electrocardiograph. The change of left ventricular function and myocardial reaction degree of fibrosis of heart was investigated by hematoxylin and eosin (HE) staining and Sirius red staining. Endothelium-dependent relaxations due to acetylcholine were observed in isolated rat thoracic aortic ring preparation. The blood samples were collected to measure the levels of MDA, the activities of SOD and NADPH in serum. Epac1, Rap1, Bax and Bcl-2 were examined by using Western Blotting. Results: Vitexin exerted significant protective effect on chronic myocardial ischemia/reperfusion injury, improved obviously left ventricular diastolic function and reduced myocardial reactive fibrosis degree in rats of myocardial ischemia. Medium and high-dose vitexin groups presented a significant decrease in Bax, Epac1 and Rap1 production and increase in Bcl-2 compared to the I/R group. It may be related to preventing myocardial cells from apoptosis, improving myocardial diastolic function and inhibiting lipid peroxidation. Conclusions: Vitexin is a cardioprotective herb, which may be a promising useful complementary and alternative medicine for patients with coronary heart disease. PMID:27648122

Increased coronary blood flow and cardiac contractile efficiency with intraaortic balloon counterpulsation in a porcine model of myocardial ischemia-reperfusion injury.

PubMed

Gelsomino, Sandro; Lucà, Fabiana; Renzulli, Attilio; Rubino, Antonino S; Romano, Salvatore Mario; van der Veen, Frederik H; Carella, Rocco; Maessen, Joseph G; Gensini, Gian Franco; Lorusso, Roberto

2011-01-01

The evaluation of the impact of intraaortic balloon pump (IABP) on postischemic coronary perfusion and myocardial contractile impairment has been so far limited to early reperfusion phase. Therefore, we analyzed the 24-hour effects of IABP on coronary blood flow (CBF) and left ventricular performance in an animal model of acute myocardial ischemia-reperfusion injury. Healthy swine (n = 20) underwent 120-minute ligation of the left anterior descending coronary artery followed by 24 hours of reperfusion. We randomly assigned the animals to have IABP placed in the descending aorta 5 minutes after reperfusion onset (n = 10) or to undergo no implantation (n = 10). We measured CBF, coronary resistance, cardiac cycle efficiency (CCE), and maximal pressure/time ratio before ischemia was induced and at 30 minutes and 1, 6, 12, and 24 hours after reperfusion began. During diastole, CBF was significantly increased in IABP compared with baseline and controls at all time points (all p < 0.001). This was also true during systole in IABP only for the first hour after reperfusion began. Additionally, both CCE and pressure/time ratio were significantly increased in IABP compared with baseline at 30 minutes and 1 hour after reperfusion began (p < 0.001). IABP was associated with enhanced CBF and cardiac efficiency in a model of acute ischemic-reperfusion injury.

Hydrogen, a potential safeguard for graft-versus-host disease and graft ischemia-reperfusion injury?

PubMed Central

Yuan, Lijuan; Shen, Jianliang

2016-01-01

Post-transplant complications such as graft-versus-host disease and graft ischemia-reperfusion injury are crucial challenges in transplantation. Hydrogen can act as a potential antioxidant, playing a preventive role against post-transplant complications in animal models of multiple organ transplantation. Herein, the authors review the current literature regarding the effects of hydrogen on graft ischemia-reperfusion injury and graft-versus-host disease. Existing data on the effects of hydrogen on ischemia-reperfusion injury related to organ transplantation are specifically reviewed and coupled with further suggestions for future work. The reviewed studies showed that hydrogen (inhaled or dissolved in saline) improved the outcomes of organ transplantation by decreasing oxidative stress and inflammation at both the transplanted organ and the systemic levels. In conclusion, a substantial body of experimental evidence suggests that hydrogen can significantly alleviate transplantation-related ischemia-reperfusion injury and have a therapeutic effect on graft-versus-host disease, mainly via inhibition of inflammatory cytokine secretion and reduction of oxidative stress through several underlying mechanisms. Further animal experiments and preliminary human clinical trials will lay the foundation for hydrogen use as a drug in the clinic. PMID:27652837

Hypoxic Air Inhalation and Ischemia Interventions Both Elicit Preconditioning Which Attenuate Subsequent Cellular Stress In vivo Following Blood Flow Occlusion and Reperfusion.

PubMed

Barrington, James H; Chrismas, Bryna C R; Gibson, Oliver R; Tuttle, James; Pegrum, J; Govilkar, S; Kabir, Chindu; Giannakakis, N; Rayan, F; Okasheh, Z; Sanaullah, A; Ng Man Sun, S; Pearce, Oliver; Taylor, Lee

2017-01-01

protocol. This was seen independent of changes in systemic oxidative stress, which likely explains the absence of change in Hsp32 mRNA transcripts within leukocytes and the gastrocnemius. Both the established IPC and novel HPC interventions facilitate a priming of the skeletal muscle, but not leukocyte, Hsp system prior to femoral blood flow occlusion. This response demonstrates a localized tissue specific adaptation which may ameliorate reperfusion stress.

Hypoxic Air Inhalation and Ischemia Interventions Both Elicit Preconditioning Which Attenuate Subsequent Cellular Stress In vivo Following Blood Flow Occlusion and Reperfusion

PubMed Central

Barrington, James H.; Chrismas, Bryna C. R.; Gibson, Oliver R.; Tuttle, James; Pegrum, J.; Govilkar, S.; Kabir, Chindu; Giannakakis, N.; Rayan, F.; Okasheh, Z.; Sanaullah, A.; Ng Man Sun, S; Pearce, Oliver; Taylor, Lee

2017-01-01

protocol. This was seen independent of changes in systemic oxidative stress, which likely explains the absence of change in Hsp32 mRNA transcripts within leukocytes and the gastrocnemius. Both the established IPC and novel HPC interventions facilitate a priming of the skeletal muscle, but not leukocyte, Hsp system prior to femoral blood flow occlusion. This response demonstrates a localized tissue specific adaptation which may ameliorate reperfusion stress. PMID:28824456

The effects of tramadol on hepatic ischemia/reperfusion injury in rats.

PubMed

Mahmoud, Mona F; Gamal, Samar; Shaheen, Mohamed A; El-Fayoumi, Hassan M

2016-01-01

Tramadol is a centrally acting synthetic analgesic. It has a cardioprotective effect against myocardial ischemia-reperfusion (I/R) injury in isolated rat heart. We hypothesized that tramadol may exert a similar protective effect on hepatic I/R injury. Hence, the current investigation was designed to study the possible protective effects of tramadol on experimentally-induced hepatic I/R injury in rats. Tramadol was administered 30 min before ischemia following which the rats were subjected to 45 min of ischemia followed by 1 h of reperfusion. Tramadol attenuated hepatic injury induced by I/R as evidenced by the reduction of transaminases, structural changes, and apoptotic cell death. It decreased the level of inflammatory markers such as tumor necrosis factor-alpha (TNF-α), TNF-α/interleukin-10 (IL-10) ratio, and nuclear factor-κB gene expression. It also increased the anti-inflammatory cytokine, IL-10 levels in hepatic tissues. Furthermore, it reduced oxidative stress parameters except manganese superoxide dismutase activity. The results suggest that tramadol has hepatoprotective effects against hepatic I/R injury via anti-inflammatory, antiapoptotic, and antioxidant effects.

The protective effect of dexmedetomidine in a rat ex vivo lung model of ischemia-reperfusion injury.

PubMed

Zhou, Yan; Zhou, Xinqiao; Zhou, Wenjuan; Pang, Qingfeng; Wang, Zhiping

2018-01-01

To investigate the effect of dexmedetomidine (Dex) in a rat ex vivo lung model of ischemia-reperfusion injury. An IL-2 ex vivo lung perfusion system was used to establish a rat ex vivo lung model of ischemia-reperfusion injury. Drugs were added to the perfusion solution for reperfusion. Lung injury was assessed by histopathological changes, airway pressure (Res), lung compliance (Compl), perfusion flow (Flow), pulmonary venous oxygen partial pressure (PaO2), and lung wet/dry (W/D) weight ratio. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), 78 kDa glucose-regulated protein (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) were measured, respectively. The introduction of Dex attenuated the post-ischemia-reperfusion lung damage and MDA level, improved lung histology, W/D ratio, lung injury scores and SOD activity. Decreased mRNA and protein levels of GRP78 and CHOP compared with the IR group were observed after Dex treatment. The effect of Dex was dosage-dependence and a high dose of Dex (10 nM) was shown to confer the strongest protective effect against lung damage (P<0.05). Yohimbine, an α2 receptor antagonist, significantly reversed the protective effect of Dex in lung tissues (P<0.05). Dex reduced ischemia-reperfusion injury in rat ex vivo lungs.

Ischaemia-reperfusion injury in orthotopic mouse lung transplants – a scanning electron microscopy study

PubMed Central

Draenert, Alice; Marquardt, Klaus; Inci, Ilhan; Soltermann, Alex; Weder, Walter; Jungraithmayr, Wolfgang

2011-01-01

Lung ischaemia-reperfusion (I/R) injury remains a major cause of graft failure in lung transplantation (Tx). With the implementation of orthotopic lung Tx in mice, a physiological model on the base of a perfused and ventilated graft became available for the investigation of I/R injury. Using the scanning electron microscopy (SEM) technique, we here present an analysis of early and late morphological changes of pulmonary I/R injury. Syngeneic lungs were orthotopically transplanted between C57BL/6 mice. Grafts were exposed to 2 h of cold ischaemia. Transplants and right lungs were examined by SEM with corresponding haematoxylin–eosin histology 30 min and 4 h after reperfusion. Thirty minutes after reperfusion, the alveolar surface of transplants showed a discontinued lining of surfactant, while the lining of the non-transplanted lung was normal. Within the graft, leucocytes displayed an irregular surface with development of pseudopodia, and microvilli were detected on the membrane of pneumocytes. At 4 h after reperfusion, leucocytes significantly increased in numbers within the alveolar space. Also, the number of microvilli on pneumocytes increased significantly. Similar to these, the endothelium of vessels increasingly developed microvilli from 30 min towards 4 h after reperfusion. The airways of transplanted grafts showed mild changes with thickening of the bronchial epithelium and a destruction of kinocilia. Taken together, SEM detects pathological events of I/R that are previously not described in normal histology. These findings may influence the interpretation of studies investigating the I/R injury in the mouse model of lung Tx. PMID:21272104

Activation of peroxisome proliferator-activated receptor-alpha protects the heart from ischemia/reperfusion injury.

PubMed

Yue, Tian-li; Bao, Weike; Jucker, Beat M; Gu, Juan-li; Romanic, Anne M; Brown, Peter J; Cui, Jianqi; Thudium, Douglas T; Boyce, Rogely; Burns-Kurtis, Cynthia L; Mirabile, Rosanna C; Aravindhan, Karpagam; Ohlstein, Eliot H

2003-11-11

Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is expressed in the heart and regulates genes involved in myocardial fatty acid oxidation (FAO). The role of PPAR-alpha in acute ischemia/reperfusion myocardial injury remains unclear. The coronary arteries of male mice were ligated for 30 minutes. After reperfusion for 24 hours, ischemic and infarct sizes were determined. A highly selective and potent PPAR-alpha agonist, GW7647, was administered by mouth for 2 days, and the third dose was given 1 hour before ischemia. GW7647 at 1 and 3 mg x kg(-1) x d(-1) reduced infarct size by 28% and 35%, respectively (P<0.01), and myocardial contractile dysfunction was also improved. Cardioprotection by GW7647 was completely abolished in PPAR-alpha-null mice. Ischemia/reperfusion downregulated mRNA expression of cardiac PPAR-alpha and FAO enzyme genes, decreased myocardial FAO enzyme activity and in vivo cardiac fat oxidation, and increased serum levels of free fatty acids. All of these changes were reversed by GW7647. Moreover, GW7647 attenuated ischemia/reperfusion-induced release of multiple proinflammatory cytokines and inhibited neutrophil accumulation and myocardial expression of matrix metalloproteinases-9 and -2. Furthermore, GW7647 inhibited nuclear factor-kappaB activation in the heart, accompanied by enhanced levels of inhibitor-kappaBalpha. Activation of PPAR-alpha protected the heart from reperfusion injury. This cardioprotection might be mediated through metabolic and antiinflammatory mechanisms. This novel effect of the PPAR-alpha agonist could provide an added benefit to patients treated with PPAR-alpha activators for dyslipidemia.

Early markers of reperfusion injury after liver transplantation: association with primary dysfunction.

PubMed

Bruns, Helge; Heil, Jan; Schultze, Daniel; Al Saeedi, Mohammed; Schemmer, Peter

2015-06-01

In patients with end-stage liver disease, liver transplantation is the only available curative treatment. Although the outcome and quality of life in the patients have improved over the past decades, primary dys- or nonfunction (PDF/PNF) can occur. Early detection of PDF and PNF is crucial and could lead to individual therapies. This study was designed to identify early markers of reperfusion injury and PDF in liver biopsies taken during the first hour after reperfusion. Biopsies from donor livers were prospectively taken as a routine during the first hour after reperfusion. Recipient data, transaminases and outcome were routinely monitored. In total, 10 biopsy specimens taken from patients with 90-day mortality and PDF, and patients with long-term survival but without PDF were used for DNA microarrays. Markers that were significantly up- or down-regulated in the microarray were verified using quantitative real-time PCR. Age, indications and labMELD score were similar in both groups. Peak-transaminases during the first week after transplantation were significantly different in the two groups. In total, 20 differentially regulated markers that correlated to PDF were identified using microarray analysis and verified with quantitative real-time PCR. The markers identified in this study could predict PDF at a very early time point and might point to interventions that ameliorate reperfusion injury and thus prevent PDF. Identification of patients and organs at risk might lead to individualized therapies and could ultimately improve outcome.

Resistance to Reperfusion Injury Following Short Term Postischemic Administration of Natural Honey in Globally Ischemic Isolated Rat Heart

PubMed Central

Vaez, Haleh; Samadzadeh, Mehrban; Zahednezhad, Fahimeh; Najafi, Moslem

2012-01-01

Purpose: Results of our previous study revealed that preischemic perfusion of honey before zero flow global ischemia had cardioprotective effects in rat. The present study investigated potential resistance to reperfusion injury following short term postischemic administration of natural honey in globally ischemic isolated rat heart. Methods: Male Wistar rats were divided into five groups (n=10-13). The rat hearts were isolated, mounted on a Langendorff apparatus, allowed to equilibrate for 30 min then subjected to 30 min global ischemia. In the control group, the hearts were reperfused with drug free normal Krebs-Henseleit (K/H) solution before ischemia and during 120 min reperfusion. In the treatment groups, reperfusion was initiated with K/H solution containing different concentration of honey (0.25, 0.5, 1 and 2%) for 15 min and was resumed until the end of 120 min with normal K/H solution. Results: In the control group, VEBs number was 784±199, while in honey concentration of 0.25, 0.5, 1 and 2%, it decreased to 83±23 (P<0.001), 138±48 (P<0.01), 142±37 (P<0.001) and 157±40 (P<0.01), respectively. Number and duration of VT and time spent in reversible VF were also reduced by honey. In the control group, the infarct size was 54.1±7.8%, however; honey (0.25, 0.5, 1 and 2%) markedly lowered the value to 12.4±2.4, 12.7±3.3, 11.3±2.6 and 7.9±1.7 (P<0.001), respectively. Conclusion: Postischemic administration of natural honey in global ischemia showed protective effects against ischemia/reperfusion (I/R) injuries in isolated rat heart. Antioxidant and radical scavenging activity, lipoperoxidation inhibition, reduction of necrotized tissue, presence of rich energy sources, various type of vitamins, minerals and enzymes and formation of NO-contain metabolites may probably involve in those cardioprotective effects. PMID:24312792

Correlation between liver cell necrosis and circulating alanine aminotransferase after ischaemia/reperfusion injuries in the rat liver.

PubMed

Knudsen, Anders R; Andersen, Kasper J; Hamilton-Dutoit, Stephen; Nyengaard, Jens R; Mortensen, Frank V

2016-04-01

Circulating liver enzymes such as alanine transaminase are often used as markers of hepatocellular damage. Ischaemia/reperfusion (I/R) injury is an inevitable consequence of prolonged liver ischaemia. The aim of this study was to examine the correlation between liver enzymes and volume of liver cell necrosis after ischaemia/reperfusion injuries, using design-unbiased stereological methods. Forty-seven male Wistar rats were subjected to 1 h of partial liver ischaemia, followed by either 4 or 24 h of reperfusion. Within each group, one-third of animals were subjected to ischaemic preconditioning and one-third to ischaemic postconditioning. At the end of reperfusion, blood and liver samples were collected for analysis. The volume of necrotic liver tissue was subsequently correlated to circulating markers of I/R injury. Correlation between histological findings and circulating markers was performed using Pearson's correlation coefficient. Alanine transferase peaked after 4 h of reperfusion; however, at this time-point, only mild necrosis was observed, with a Pearson's correlation coefficient of 0.663 (P = 0.001). After 24 h of reperfusion, alanine aminotransferase was found to be highly correlated to the degree of hepatocellular necrosis R = 0.836 (P = 0.000). Furthermore, alkaline phosphatase (R = 0.806) and α-2-macroglobulin (R = 0.655) levels were also correlated with the degree of necrosis. We show for the first time that there is a close correlation between the volume of hepatocellular necrosis and alanine aminotransferase levels in a model of I/R injury. This is especially apparent after 24 h of reperfusion. Similarly, increased levels of alkaline phosphatase and α-2-macroglobulin are correlated to the volume of liver necrosis. © 2016 The Authors. International Journal of Experimental Pathology © 2016 International Journal of Experimental Pathology.

The Effects of Two Anesthetics, Propofol and Sevoflurane, on Liver Ischemia/Reperfusion Injury.

PubMed

Xu, Zhijie; Yu, Jingui; Wu, Jianbo; Qi, Feng; Wang, Huanliang; Wang, Zhigang; Wang, Zhou

2016-01-01

Propofol and sevoflurane are widely used in clinical anesthesia, and both have been reported to exert a protective effect in organ ischemia/reperfusion (IR). This study aims to investigate and compare the effects of propofol and sevoflurane on liver ischemia/reperfusion and the precise molecular mechanism. Rats were randomized into four groups: the sham group, I/R group, propofol treatment group (infused with 1% propofol at 500 μg· kg-1· min-1), and sevoflurane treatment group (infused with 3% (2 L/min) sevoflurane). The liver ischemia/reperfusion model was used to evaluate the hepatoprotective effect on ischemic injury. Liver enzyme leakage, liver cytokines and histopathological examination were used to evaluate the extent of hepatic ischemia/reperfusion injury. Oxidative stress was investigated by evaluating the levels of Malondialdehyde(MDA), Superoxide Dismutase(SOD) and NO. The terminal dexynucleotidyl transferase(TdT)-mediated dUTP nick end labeling (TUNEL) assay and western blot were applied to detect apoptosis in the ischemic liver tissue and its mechanism. Both propofol and sevoflurane attenuated the extent of hepatic ischemia/reperfusion injury which is evident from the hisopathological studies and alterations in liver enzymes such as AST and LDH by inhibiting Nuclear factor kappa B (NFx03BA;B) activation and subsequent alterations in inflammatory cytokines interleukin-1(IL-1), interleukin-6(IL-6), tumor necrosis factor-alpha (TNF-α) and increased IL10 release. Propofol exhibited a similar protective effect and a lower IL-1 release, while sevoflurane decreased TNF-α leakage more significantly. Meanwhile, oxidative stress was attenuated by reduced MDA and NO and elevated SOD release. The expression of antiapoptotic protein Bcl-2 and Bcl-xl were enhanced while that of apoptotic protein Bax and Bak were reduced by both propofol and sevoflurane to regulate hepatic apoptosis. In addition, propofol downregulated the phosphorylation of AKT and Bad protein

Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT.

PubMed

Jubair, Shaiban; Li, Jianping; Dehlin, Heather M; Manteufel, Edward J; Goldspink, Paul H; Levick, Scott P; Janicki, Joseph S

2015-08-15

Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT. Copyright © 2015 the American Physiological Society.

Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT

PubMed Central

Jubair, Shaiban; Li, Jianping; Dehlin, Heather M.; Manteufel, Edward J.; Goldspink, Paul H.; Levick, Scott P.

2015-01-01

Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT. PMID:26071541

Effect of dietary palm olein oil on oxidative stress associated with ischemic-reperfusion injury in isolated rat heart

PubMed Central

Narang, Deepak; Sood, Subeena; Thomas, Mathew Kadali; Dinda, Amit Kumar; Maulik, Subir Kumar

2004-01-01

Background Palm olein oil (PO), obtained from refining of palm oil is rich in monounsaturated fatty acid and antioxidant vitamins and is widely used as oil in diet in many parts of the world including India. Palm oil has been reported to have beneficial effects in oxidative stress associated with hypertension and arterial thrombosis. Oxidative stress plays a major role in the etiopathology of myocardial ischemic-reperfusion injury (IRI) which is a common sequel of ischemic heart disease. Antioxidants have potent therapeutic effects on both ischemic heart disease and ischemic-reperfusion injury. Information on the effect of PO on ischemic-reperfusion injury is, however, lacking. In the present study, the effect of dietary palm olein oil on oxidative stress associated with IRI was investigated in an isolated rat heart model. Wistar rats (150–200 gm) of either sex were divided into three different groups (n = 16). Rats were fed with palm olein oil supplemented commercial rat diet, in two different doses [5% v / w (PO 5) and 10% v / w (PO 10) of diet] for 30 days. Control rats (C) were fed with normal diet. After 30 days, half the rats from each group were subjected to in vitro myocardial IRI (20 min of global ischemia, followed by 40 min of reperfusion). Hearts from all the groups were then processed for biochemical and histopathological studies. One way ANOVA followed by Bonferroni test was applied to test for significance and values are expressed as mean ± SE (p < 0.05). Results There was a significant increase in myocardial catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities with no significant change in myocardial thiobarbituric acid reactive substances (TBARS) only in group PO 5 as compared to group C. There was no light microscopic evidence of tissue injury. A significant rise in myocardial TBARS and depletion of myocardial endogenous antioxidants (SOD, CAT and GPx) along with significant myocyte injury was observed in

Neuroprotective effect of curcumin on spinal cord in rabbit model with ischemia/reperfusion.

PubMed

Liu, Zhi-Qiang; Xing, Shan-Shan; Zhang, Wei

2013-03-01

Ischemic/reperfusion (I/R) injury of the spinal cord is a serious complication that can result from thoracoabdominal aortic surgery. To investigate the neuroprotective effect of curcumin against I/R injury in a rabbit model. A total of 36 rabbits were randomly divided into three groups: sham, I/R, and curcumin-treated group. Rabbits were subject to 30-min aortic occlusion to induce transient spinal cord ischemia. Neurological function was observed after reperfusion and spinal cord segment (L3-L5) was collected for histopathological evaluation. Malondialdehyde (MDA) and total superoxide dismutase (SOD) activity were also assayed. Rabbits in I/R group were induced to paraplegia. While after 48-hour treatment, compared with I/R group, curcumin significantly improved neurological function, reduced cell apoptosis and MDA levels as well as increased SOD activity (P < 0.05). The results suggest that curcumin, at least in an animal model, can attenuate transient spinal cord ischemic injury potentially via reducing oxidative damage, which may provide a novel approach in the treatment of spinal cord ischemic injury.

Down-regulated Na+/K+-ATPase activity in ischemic penumbra after focal cerebral ischemia/reperfusion in rats

PubMed Central

Huang, Hao; Chen, Yang-Mei; Zhu, Fei; Tang, Shi-Ting; Xiao, Ji-Dong; Li, Lv-Li; Lin, Xin-Jing

2015-01-01

This study was aimed to examine whether the Na+/K+ adenosine triphosphatase (Na+/K+-ATPase) activity in ischemic penumbra is associated with the pathogenesis of ischemia/reperfusion-induced brain injury. An experimental model of cerebral ischemia/reperfusion was made by transient middle cerebral artery occlusion (tMCAO) in rats and the changes of Na+/K+-ATPase activity in the ischemic penumbra was examined by Enzyme Assay Kit. Extensive infarction was observed in the frontal and parietal cortical and subcortical areas at 6 h, 24 h, 48 h, 3 d and 7 d after tMCAO. Enzyme Assay analyses revealed the activity of Na+/K+-ATPase was decreased in the ischemic penumbra of model rats after focal cerebral ischemia/reperfusion compared with sham-operated rats, and reduced to its minimum at 48 h, while the infarct volume was enlarged gradually. In addition, accompanied by increased brain water content, apoptosis-related bcl-2 and Bax proteins, apoptotic index and neurologic deficits Longa scores, but fluctuated the ratio of bcl-2/Bax. Correlation analysis showed that the infarct volume, apoptotic index, neurologic deficits Longa scores and brain water content were negatively related with Na+/K+-ATPase activity, while the ratio of bcl-2/Bax was positively related with Na+/K+-ATPase activity. Our results suggest that down-regulated Na+/K+-ATPase activity in ischemic penumbra might be involved in the pathogenesis of cerebral ischemia/reperfusion injury presumably through the imbalance ratio of bcl-2/Bax and neuronal apoptosis, and identify novel target for neuroprotective therapeutic intervention in cerebral ischemic disease. PMID:26722460

Delayed expression of cytokines after reperfused myocardial infarction: possible trigger for cardiac dysfunction and ventricular remodeling.

PubMed

Moro, Cécile; Jouan, Marie-Gabrielle; Rakotovao, Andry; Toufektsian, Marie-Claire; Ormezzano, Olivier; Nagy, Norbert; Tosaki, Arpad; de Leiris, Joël; Boucher, François

2007-11-01

Previous studies have shown that 1 wk after permanent coronary artery ligation in rats, some cellular mechanisms involving TNF-alpha occur and contribute to the development of cardiac dysfunction and subsequent heart failure. The aim of the present study was to determine whether similar phenomena also occur after ischemia-reperfusion and whether cytokines other than TNF-alpha can also be involved. Anesthetized male Wistar rats were subjected to 1 h coronary occlusion followed by reperfusion. Cardiac geometry and function were assessed by echocardiography at days 5, 7, 8, and 10 postligation. Before death, heart function was assessed in vivo under basal conditions, as well as after volume overload. Finally, hearts were frozen for histoenzymologic assessment of infarct size and remodeling. The profile of cardiac cytokines was determined by ELISA and ChemiArray on heart tissue extracts. As expected, ischemia-reperfusion induced a progressive remodeling of the heart, characterized by left ventricular free-wall thinning and cavity dilation. Heart function was also decreased in ischemic rats during the first week after surgery. Interestingly, a transient and marked increase in TNF-alpha, IL-1beta, IL-6, cytokine-induced neutrophil chemoattractant (CINC) 2, CINC3, and macrophage inflammatory protein-3alpha was also observed in the myocardium of myocardial ischemia (MI) animals at day 8, whereas the expression of anti-inflammatory interleukins IL-4 and IL-10 remained unchanged. These results suggest that overexpression of proinflammatory cytokines occurring during the first week after ischemia-reperfusion may play a role in the adaptative process in the myocardium and contribute to early dysfunction and remodeling.

Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo

PubMed Central

Guo, Yiru; Stein, Adam B.; Wu, Wen-Jian; Tan, Wei; Zhu, Xiaoping; Li, Qian-Hong; Dawn, Buddhadeb; Motterlini, Roberto; Bolli, Roberto

2011-01-01

Although carbon monoxide (CO) has traditionally been viewed as a toxic gas, increasing evidence suggests that it plays an important homeostatic and cytoprotective role. Its therapeutic use, however, is limited by the side effects associated with CO inhalation. Recently, transition metal carbonyls have been shown to be a safe and effective means of transporting and releasing CO groups in vivo. The goal of the present study was to test whether a water-soluble CO-releasing molecule, tricarbonylchloro (glycinato) ruthenium (II) (CORM-3), reduces infarct size in vivo when given in a clinically relevant manner, i.e., at the time of reperfusion. Mice were subjected to a 30-min coronary artery occlusion followed by 24 h of reperfusion and were given either CORM-3 (3.54 mg/kg as a 60-min intravenous infusion starting 5 min before reperfusion) or equivalent doses of inactive CORM-3, which does not release CO. CORM-3 had no effect on arterial blood pressure or heart rate. The region at risk did not differ in control and treated mice (44.5 ± 3.5% vs. 36.5 ± 1.6% of the left ventricle, respectively). However, infarct size was significantly smaller in treated mice [25.8 ± 4.9% of the region at risk (n = 13) vs. 47.7 ± 3.8% (n = 14), P < 0.05]. CORM-3 did not increase carboxyhemoglobin levels in the blood. These results suggest that a novel class of drugs, CO-releasing molecules, can be useful to limit myocardial ischemia-reperfusion injury in vivo. PMID:14704226

Injectable caltrop fruit saponin protects against ischemia-reperfusion injury in rat brain.

PubMed

Yan, Ling-Geng; Lu, Yin; Zheng, Shi-Zhong; Wang, Ai-Yun; Li, Meng-Qiu; Ruan, Jun-Shan; Zhang, Lei

2011-01-01

The present study aimed to investigate the protective effects of injectable caltrop fruit saponin preparation (ICFSP) on ischemia-reperfusion injury in rat brain. Rats were injected with ICFSP and then subjected to cerebral ischemia-reperfusion injury induced by middle cerebral artery occlusion. Then the neurological deficit score was evaluated by Bederson's method. The infarct size was assessed by TTC staining. The content of malondialdehyde (MDA) and nitric oxide (NO), and the activity of superoxide dismutase (SOD) in rat cerebrum were measured with kits, and the content of 6 K prostaglandin F1α (6-K-PGF 1α), thromboxane B2 (TXB2) and endothelin (ET) in blood plasma was measured by radioimmunoassay. The results demonstrated that ICFSP led to a decrease in infarct size (p < 0.01), neurological deficit score (p < 0.05) and plasma content of TXB2 and ET (p < 0.05), and an increase of the plasma level of 6-K-PGF 1α (p < 0.05) and SOD activity in cerebrum, where the MDA and NO content were decreased. The treatment improved forelimb function. ICFSP showed a similar potency compared to that of Ligustrazine hydrochloride parenteral solution (LHPS) and nimodipine (Nim). We concluded that ICFSP protects the brain damage caused by ischemia-reperfusion injury in rats, and this may be closely related to the regulation of reactive oxygen species (MDA and SOD activity) and NO levels in the rat cerebrum, as well as vasoactive factors in the plasma (6-K-PGF 1α, TXB2 and ET).

Attenuation of intestinal ischemia-reperfusion-injury by β-alanine: a potentially glycine-receptor mediated effect.

PubMed

Brencher, Lisa; Verhaegh, Rabea; Kirsch, Michael

2017-05-01

Acute mesenteric ischemia is often caused by embolization of the mesenteric arterial circulation. Coherent intestinal injury due to ischemia and following reperfusion get visible on macroscopic and histologic level. In previous studies, application of glycine caused an ameliorated intestinal damage after ischemia-reperfusion in rats. Because we speculated that glycine acted here as a signal molecule, we investigated whether the glycine-receptor agonist β-alanine evokes the same beneficial effect in intestinal ischemia-reperfusion. β-alanine (10, 30, and 100 mg/kg) was administered intravenously. Ischemia/reperfusion of the small intestine was initiated by occluding and reopening the superior mesenteric artery in rats. After 90 min of ischemia and 120 min of reperfusion, the intestine was analyzed with regard to macroscopic and histologic tissue damage, the activity of the saccharase, and accumulation of macrophages. In addition, systemic parameters and metabolic ones (e.g., acid-base balance, electrolytes, and blood glucose) were measured at certain points in time. All three dosages of β-alanine did not change systemic parameters but prevent from hyponatremia during the period of reperfusion. Most importantly, application of 100-mg β-alanine clearly diminished intestinal tissue damage, getting visible on macroscopic and histologic level. In addition, I/R-mediated decrease of saccharase activity and accumulation of macrophages in the small intestine were ameliorated. The present study demonstrated that β-alanine was a potent agent to ameliorate I/R-induced injury of the small intestine. Due to its diminishing effect on the accumulation of macrophages, β-alanine is strongly expected to mediate its beneficial effect via glycine receptors. Copyright © 2017 Elsevier Inc. All rights reserved.

Sildenafil Attenuates Hepatocellular Injury after Liver Ischemia Reperfusion in Rats: A Preliminary Study

PubMed Central

Savvanis, Spyridon; Nastos, Constantinos; Tasoulis, Marios-Konstantinos; Papoutsidakis, Nikolaos; Demonakou, Maria; Karmaniolou, Iosifina; Arkadopoulos, Nikolaos; Smyrniotis, Vassilios; Theodoraki, Kassiani

2014-01-01

We evaluated the role of sildenafil in a rat liver ischemia-reperfusion model. Forty male rats were randomly allocated in four groups. The sham group underwent midline laparotomy only. In the sildenafil group, sildenafil was administered intraperitoneally 60 minutes before sham laparotomy. In the ischemia-reperfusion (I/R) group, rats were subjected to 45 minutes of hepatic ischemia followed by 120 minutes of reperfusion, while in the sild+I/R group rats were subjected to a similar pattern of I/R after the administration of sildenafil, 60 minutes before ischemia. Two hours after reperfusion, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured and histopathological examination of the lobes subjected to ischemia as well as TUNEL staining for apoptotic bodies was performed. Additionally, myeloperoxidase (MPO) activity and the expression of intercellular adhesion molecule-1 (ICAM-1) were analyzed. Serum markers of hepatocellular injury were significantly lower in the sild+I/R group, which also exhibited lower severity of histopathological lesions and fewer apoptotic bodies, as compared to the I/R group. The I/R group showed significantly higher MPO activity and higher expression of ICAM-1, as compared to the sild+I/R group. Use of sildenafil as a preconditioning agent in a rat model of liver I/R exerted a protective effect. PMID:24999378

Bcl-2 protects tubular epithelial cells from ischemia reperfusion injury by inhibiting apoptosis.

PubMed

Suzuki, Chigure; Isaka, Yoshitaka; Shimizu, Shigeomi; Tsujimoto, Yoshihide; Takabatake, Yoshitsugu; Ito, Takahito; Takahara, Shiro; Imai, Enyu

2008-01-01

Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of graft dysfunction in kidney transplantation subjected to ischemia. The mechanism that triggers inflammation and renal injury after ischemia remains to be elucidated; however, cellular stress may induce apoptosis during the first hours and days after transplantation, which might play a crucial role in early graft dysfunction. Bcl-2 is known to inhibit apoptosis induced by the etiological factors promoting ischemia and reperfusion injury. Accordingly, we hypothesized that an augmentation of the antiapoptotic factor Bcl-2 may thus protect tubular epithelial cells by inhibiting apoptosis, thereby ameliorating the subsequent tubulointerstitial injury. We examined the effects of Bcl-2 overexpression on ischemia-reperfusion (I/R) injury using Bcl-2 transgenic mice (Bcl-2 TG) and their wild-type littermates (WT). To investigate the effects of I/R injury, the left renal artery and vein were clamped for 45 min, followed by reperfusion for 0-96 h. Bcl-2 TG exhibited decreased active caspase protein in the tubular cells, which led to a reduction in TUNEL-positive apoptotic cells. Consequently, interstitial fibrosis and phenotypic changes were ameliorated in Bcl-2 TG. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R, and subsequent interstitial injury by inhibiting tubular apoptosis.

Spontaneous Reperfusion after In Situ Thromboembolic Stroke in Mice

PubMed Central

Cho, Tae-Hee; Bolbos, Radu; Langlois, Jean-Baptiste; Hermitte, Laure; Wiart, Marlène; Berthezène, Yves; Nighoghossian, Norbert

2012-01-01

Injection of thrombin into the middle cerebral artery (MCA) of mice has been proposed as a new model of thromboembolic stroke. The present study used sequential multiparametric Magnetic Resonance Imaging (MRI), including Magnetic Resonance Angiography (MRA), Diffusion-Weighted Imaging (DWI) and Perfusion-Weighted Imaging (PWI), to document MCA occlusion, PWI-DWI mismatch, and lesion development. In the first experiment, complete MCA occlusion and reproducible hypoperfusion were obtained in 85% of animals during the first hour after stroke onset. In the second experiment, 80% of animals showed partial to complete reperfusion during a three-hour follow-up. Spontaneous reperfusion thus contributed to the variability in ischemic volume in this model. The study confirmed the value of the model for evaluating new thrombolytic treatments, but calls for extended MRI follow-up at the acute stage in therapeutic studies. PMID:23166825

[Transfection of hBcl-2 gene protects the liver against ischemia/reperfusion injury in rats during liver transplantation].

PubMed

Liu, Ji-tong; Liu, Jing-shi; Jiang, Jin-yu; Zhou, Li-xue; Liang, Gang; Li, Yan-chun

2010-12-01

To study the effect of hBcl-2 gene transfer on rat liver against ischemia-reperfusion injury, and explore the feasibility of this approach to reduce ischemia-reperfusion injury in liver transplantation. We constructed the replication-deficient recombinant adenoviruses Adv-EGFP and Adv-Bcl-2 and transfected them into 293 cells and packaged into adenovirus particles for amplification and purification. The empty plasmid vector virus was constructed similarly. Male SD rats were randomized into Adv-Bcl-2-transfected group, Adv-EGFP-transfected group, ischemia-reperfusion group, and sham-operated group, and liver allograft transplantation model was established by sleeve method. In the transfected groups, the recombinant viruses were administered by perfusion through the portal vein, and the ischemia-reperfusion and sham-operated groups received no treatment. Real-time quantitative PCR and Western blotting were used to detect the mRNA and protein expressions of bcl-2 in the liver tissue of each group, and at 0, 60 and 180 min after reperfusion, serum AST, LDH, and MDA levels were measured. Histological changes of the liver cells were evaluated by HE staining. Bcl-2 mRNA and protein expressions in Adv-Bcl-2-transfected group, as compared with those in Adv-EGFP-transfected group and control group, were significantly increased (P<0.01); the serum levels of AST, LDH and MDA in Adv-Bcl-2-transfected group were significantly lower than those of Adv-EGFP-transfected group and ischemia-reperfusion group (P<0.05 or 0.01). Compared with the sham-operated group, Adv-Bcl-2 treatment group showed lessened edema and vacuolar degeneration of the liver cells without patches or spots of necrosis. In ischemia-reperfusion and Adv-EGFP group, HE staining revealed hepatic lobular destruction and extensive liver cell swelling, enlargement, vacuolar degeneration, edema and occasional focal necrosis. Adv-Bcl-2 transfection can induce the expression of bcl-2 gene to reduce ischemia-reperfusion

Reperfusion is a more accurate predictor of follow-up infarct volume than recanalization: a proof of concept using CT in acute ischemic stroke patients.

PubMed

Soares, Bruno P; Tong, Elizabeth; Hom, Jason; Cheng, Su-Chun; Bredno, Joerg; Boussel, Loic; Smith, Wade S; Wintermark, Max

2010-01-01

The purpose of this study was to compare recanalization and reperfusion in terms of their predictive value for imaging outcomes (follow-up infarct volume, infarct growth, salvaged penumbra) and clinical outcome in acute ischemic stroke patients. Twenty-two patients admitted within 6 hours of stroke onset were retrospectively included in this study. These patients underwent a first stroke CT protocol including CT-angiography (CTA) and perfusion-CT (PCT) on admission, and similar imaging after treatment, typically around 24 hours, to assess recanalization and reperfusion. Recanalization was assessed by comparing arterial patency on admission and posttreatment CTAs; reperfusion, by comparing the volumes of CBV, CBF, and MTT abnormality on admission and posttreatment PCTs. Collateral flow was graded on the admission CTA. Follow-up infarct volume was measured on the discharge noncontrast CT. The groups of patients with reperfusion, no reperfusion, recanalization, and no recanalization were compared in terms of imaging and clinical outcomes. Reperfusion (using an MTT reperfusion index >75%) was a more accurate predictor of follow-up infarct volume than recanalization. Collateral flow and recanalization were not accurate predictors of follow-up infarct volume. An interaction term was found between reperfusion and the volume of the admission penumbra >50 mL. Our study provides evidence that reperfusion is a more accurate predictor of follow-up infarct volume in acute ischemic stroke patients than recanalization. We recommend an MTT reperfusion index >75% to assess therapy efficacy in future acute ischemic stroke trials that use perfusion-CT.

Compartmentalization of Inflammatory Response Following Gut Ischemia Reperfusion.

PubMed

Collange, O; Charles, A-L; Lavaux, T; Noll, E; Bouitbir, J; Zoll, J; Chakfé, N; Mertes, M; Geny, B

2015-01-01

Gut ischemia reperfusion (IR) is thought to trigger systemic inflammation, multiple organ failure, and death. The aim of this study was to investigate inflammatory responses in blood and in two target organs after gut IR. This was a controlled animal study. Adult male Wistar rats were randomized into two groups of eight rats: control group and gut IR group (60 minutes of superior mesenteric artery occlusion followed by 60 minutes of reperfusion). Lactate and four cytokines (tumor necrosis factor-a, interleukin [IL]-1b, IL-6, and IL-10) were measured in mesenteric and systemic blood. The relative gene expression of these cytokines was determined by real time polymerase chain reaction in the gut, liver, and lung. Gut IR significantly increased lactate levels in mesenteric (0.9 ± 0.4 vs. 3.7 ± 1.8 mmol/L; p < .001) and in systemic blood (1.3 ± 0.2 vs. 4.0 ± 0.3 mmol/L; p < .001). Gut IR also increased the levels of four cytokines in mesenteric and systemic blood. IL-6 and IL-10 were the main circulating cytokines; there were no significant differences between mesenteric and systemic cytokine levels. IL-10 was upregulated mainly in the lung,suggesting that this organ could play a major role during gut reperfusion. The predominance of IL-10 over other cytokines in plasma and the dissimilar organ responses,especially of the lung, might be a basis for the design of therapies, for example lung protective ventilation strategies, to limit the deleterious effects of the inflammatory cascade. A multi-organ protective approach might involve gut directed therapies, protective ventilation, hemodynamic optimization, and hydric balance.

Neuroprotective effect of Feronia limonia on ischemia reperfusion induced brain injury in rats

PubMed Central

Rakhunde, Purushottam B.; Saher, Sana; Ali, Syed Ayaz

2014-01-01

Objectives: Brain stroke is a leading cause of death without effective treatment. Feronia limonia have potent antioxidant activity and can be proved as neuroprotective against ischemia-reperfusion induced brain injury. Materials and Methods: We studied the effect of methanolic extract of F. limonia fruit (250 mg/kg, 500 mg/kg body weight, p.o.) and Vitamin E as reference standard drug on 30 min induced ischemia, followed by reperfusion by testing the neurobehavioral tests such as neurodeficit score, rota rod test, hanging wire test, beam walk test and elevated plus maze. The biochemical parameters, which were measured in animals brain were catalase, superoxide dismutase (SOD), malondialdehyde and nitric oxide in control and treated rats. Results: The methanolic extract of F. limonia fruit (250 mg/kg, 500 mg/kg body weight, p.o.) treated groups showed a statistically significant improvement in the neurobehavioral parameters such as motor performance (neurological status, significant increase in grasping ability, forelimb strength improvement in balance and co-ordination). The biochemical parameters in the brains of rats showed a significant reduction in the total nitrite (P < 0.01) and lipid peroxidation (P < 0.01), also a significant enhanced activity of enzymatic antioxidants such as catalase (P < 0.01) and SOD (P < 0.05). Conclusion: These observations suggest the neuroprotective and antioxidant activity of F. limonia and Vitamin E on ischemia reperfusion induced brain injury and may require further evaluation. PMID:25538333

Estradiol worsens the syndrome of ischemia-reperfusion injury in an experimental lung transplantation model.

PubMed

Santana-Rodríguez, Norberto; Clavo, Bernardino; Llontop, Pedro; López, Ana; García-Castellano, José Manuel; Machín, Rubén P; Ponce, Miguel A; Fiuza, María D; García-Herrera, Ricardo; Brito, Yanira; Yordi, Nagib Atallah; Chirino, Ricardo

2011-06-01

Ischemia-reperfusion injury (IRI) is a common complication after lung transplantation. There is evidence that reactive oxygen species are involved in its pathogenesis. We designed an experimental study to evaluate whether the administration of antioxidants to lung transplantation recipients protects against IRI and early acute rejection (AR). Twenty-five rats received left lung transplants after 6 h of ischemia. Fifty minutes before the reperfusion, groups of five rats received a single dose of desferrioxamine (20 mg/kg), estradiol (25 mg/kg), or melatonin (10 mg/kg). The animals were killed 48 h after surgery and the postoperative outcome, IRI, and AR were evaluated. The frequency of severe injury and of moderate-to-severe edema was higher in animals treated with estradiol than in the control group (P = 0.022 and P = 0.026, respectively). No significant changes in the degree of IRI or AR were observed in the groups treated with desferrioxamine or melatonin. In our study, treatment with the antioxidants melatonin or desferrioxamine before reperfusion had no effects on IRI damage or on AR frequency or severity. However, treatment with estradiol resulted in a worse postoperative outcome and in severe edema. Therefore, despite the antioxidant capacity of estradiol, it is recommended that an evaluation of these adverse effects of estradiol in human lung transplant recipients be performed.

The novel guanylhydrazone CPSI-2364 ameliorates ischemia reperfusion injury after experimental small bowel transplantation.

PubMed

Websky, Martin von; Fujishiro, Jun; Ohsawa, Ichiro; Praktiknjo, Michael; Wehner, Sven; Abu-Elmagd, Kareem; Kitamura, Koji; Kalff, Joerg C; Schaefer, Nico; Pech, Thomas

2013-06-15

Resident macrophages within the tunica muscularis are known to play a crucial role in initiating severe inflammation in response to ischemia reperfusion injury after intestinal transplantation contributing to graft dysmotility, bacterial translocation, and possibly, acute rejection. The p38 mitogen-activated protein kinase is a key player in the signaling of proinflammatory cytokine synthesis in macrophages. Therefore, we investigated the effects of CPSI-2364, an apparent macrophage-specific inhibitor of the p38 mitogen-activated protein kinase pathway in an isogenic intestinal rat transplantation model. Recipient and donor animals were treated perioperatively with CPSI-2364 (1 mg/kg, intravenously) or vehicle solution. Nontransplanted animals served as control. Animals were killed 30 min, 3 hr, and 18 hr after reperfusion. CPSI-2364 treatment resulted in significantly less leukocyte infiltration and significantly improved graft motor function (18 hr). Messenger RNA expression of proinflammatory cytokines (interleukin 6) and kinetic active mediators (NO) was reduced by CPSI-2364 in the early phase after transplantation. Histologic evaluation revealed the protective effects of CPSI-2364 treatment by a significantly less destruction of mucosal integrity at all time points. Perioperative treatment with CPSI-2364 improves graft motor function through impaired inflammatory responses to ischemia reperfusion injury by inhibition of proinflammatory cytokines and suppression of nitric oxide production in macrophages. CPSI-2364 presents as a promising complementary pharmacological approach preventing postoperative dysmotility for clinical intestinal transplantation.

A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia-reperfusion injury in mice.

PubMed

Atochin, Dmitriy N; Schepetkin, Igor A; Khlebnikov, Andrei I; Seledtsov, Victor I; Swanson, Helen; Quinn, Mark T; Huang, Paul L

2016-04-08

The c-Jun N-terminal kinase (JNK) has been shown to be an important regulator of neuronal cell death. Previously, we synthesized the sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one (IQ-1S) and demonstrated that it was a high-affinity inhibitor of the JNK family. In the present work, we found that IQ-1S could release nitric oxide (NO) during its enzymatic metabolism by liver microsomes. Moreover, serum nitrite/nitrate concentration in mice increased after intraperitoneal injection of IQ-1S. Because of these dual actions as JNK inhibitor and NO-donor, the therapeutic potential of IQ-1S was evaluated in an animal stroke model. We subjected wild-type C57BL6 mice to focal ischemia (30min) with subsequent reperfusion (48h). Mice were treated with IQ-1S (25mg/kg) suspended in 10% solutol or with vehicle alone 30min before and 24h after middle cerebral artery (MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30min of MCAO provoked by a filament and during the first 30min of subsequent reperfusion. In mice treated with IQ-1S, ischemic and reperfusion values of CBF were not different from vehicle-treated mice. However, IQ-1S treated mice demonstrated markedly reduced neurological deficit and infarct volumes as compared with vehicle-treated mice after 48h of reperfusion. Our results indicate that the novel JNK inhibitor releases NO during its oxidoreductive bioconversion and improves stroke outcome in a mouse model of cerebral reperfusion. We conclude that IQ-1S is a promising dual functional agent for the treatment of cerebral ischemia and reperfusion injury. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A Novel Dual NO-donating Oxime and c-Jun N-terminal Kinase Inhibitor Protects Against Cerebral Ischemia–Reperfusion Injury in Mice

PubMed Central

Atochin, Dmitriy N.; Schepetkin, Igor A.; Khlebnikov, Andrei I.; Seledtsov, Victor I.; Swanson, Helen; Quinn, Mark T.; Huang, Paul L.

2017-01-01

The c-Jun N-terminal kinase (JNK) has been shown to be an important regulator of neuronal cell death. Previously, we synthesized the sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one (IQ-1S) and demonstrated that it was a high-affinity inhibitor of the JNK family. In the present work, we found that IQ-1S could release nitric oxide (NO) during its enzymatic metabolism by liver microsomes. Moreover, serum nitrite/nitrate concentration in mice increased after intraperitoneal injection of IQ-1S. Because of these dual actions as JNK inhibitor and NO-donor, the therapeutic potential of IQ-1S was evaluated in an animal stroke model. We subjected wild-type C57BL6 mice to focal ischemia (30 minutes) with subsequent reperfusion (48 hours). Mice were treated with IQ-1S (25 mg/kg) suspended in 10% solutol or with vehicle alone 30 minutes before and 24 hours after middle cerebral artery MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30 minutes of MCAO provoked by a filament and during the first 30 minutes of subsequent reperfusion. In mice treated with IQ-1S, ischemic and reperfusion values of CBF were not different from vehicle-treated mice. However, IQ-1S treated mice demonstrated markedly reduced neurological deficit and infarct volumes as compared with vehicle-treated mice after 48 hours of reperfusion. Our results indicate that the novel JNK inhibitor releases NO during its oxidoreductive bioconversion and improves stroke outcome in a mouse model of cerebral reperfusion. We conclude that IQ-1S is a promising dual functional agent for the treatment of cerebral ischemia and reperfusion injury. PMID:26923672

Differences in the effects of Na+-H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts.

PubMed

Hotta, Yoshihiro; Nishimaki, Haruaki; Takeo, Tomohiro; Itoh, Gen; Yajima, Michio; Otsuka-Murakami, Hidetsugu; Ishikawa, Naohisa; Kawai, Norio; Huang, Lei; Yamada, Kazuto; Yamamoto, Setsuko; Matsui, Kazuki; Ohashi, Naohito

2004-10-25

The protective effects of the Na+-H+ exchange (NHE) inhibitors SM-198110 (2-[[(aminoiminomethyl) amino] carbonyl]-4-chloro-1H-indole-1-propanesulfonic acid monohydrate) and SM-197378 (N-(aminoiminomethyl)-1-methyl-7-(sulfooxy)-4-(trifluoromethyl)-1H-indole-2-carboxamide monohydrate) were investigated in perfused Langendorff guinea-pig hearts subjected to ischemia (40 min) and reperfusion (40 min). The recovery of left ventricular developed pressure (LVDP) from ischemia by reperfusion was 39.0% in the control, while in the hearts pretreated with SM-198110 or SM-197378 (10(-7) M), it was about 100%. The ATP level, monitored simultaneously by (31)P-nuclear magnetic resonance spectrometry, was already higher than the control value at the end of the ischemic period, and the elevation in Na+ or Ca2+ fluorometric signals induced during ischemia was suppressed. In post-treated hearts, the LVDP recovery rate was significantly higher with SM-198110 than with SM-197378. By in vitro electron paramagnetic resonance spectrometry, SM-197378 was found to directly quench the active oxygen radical, whereas SM-198110 had no effect. Numbers of apoptotic cardiomyocytes after ischemia (1 h) followed by reperfusion (5 h) were significantly lower in SM-197378-treated than in SM-198110-treated hearts, consistent with the level of activity of caspase-3. These results suggest that the antioxidant effects of NHE inhibitors have an important role in apoptosis during ischemia-reperfusion, but apoptosis is not a major manifestation of cardiac function during postischemic recovery, and that NHE-sensitive mechanisms of reperfusion injury promote both necrotic and apoptotic processes death.

POST-REPERFUSION LIVER BIOPSY AND ITS VALUE IN PREDICTING MORTALITY AND GRAFT DYSFUNCTION AFTER LIVER TRANSPLANTATION.

PubMed

Zanchet, Marcos Vinícius; Silva, Larissa Luvison Gomes da; Matias, Jorge Eduardo Fouto; Coelho, Júlio Cezar Uili

2016-01-01

The outcome of the patients after liver transplant is complex and to characterize the risk for complications is not always easy. In this context, the hepatic post-reperfusion biopsy is capable of portraying alterations of prognostic importance. To compare the results of liver transplantation, correlating the different histologic features of the hepatic post-reperfusion biopsy with graft dysfunction, primary non-function and patient survival in the first year after transplantation. From the 377 transplants performed from 1996 to 2008, 164 patients were selected. Medical records were reviewed and the following clinical outcomes were registered: mortality in 1, 3, 6 and 12 months, graft dysfunction in varied degrees and primary graft non-function. The post-reperfusion biopsies had been examined by a blinded pathologist for the outcomes. The following histological variables had been evaluated: ischemic alterations, congestion, steatosis, neutrophilic exudate, monomorphonuclear infiltrate and necrosis. The variables associated with increased mortality were: steatosis (p=0.02209), monomorphonuclear infiltrate (p=0.03935) and necrosis (p<0.00001). The neutrophilic exudate reduced mortality in this study (p=0.00659). The primary non-function showed significant association (p<0.05) with the necrosis, steatosis and the monomorphonuclear infiltrate. Post-reperfusion biopsy is useful tool to foresee complications after liver transplant. A evolução dos pacientes após transplante hepático é complexa e caracterizar o risco para complicações nem sempre é fácil. Nesse contexto, a biópsia hepática pós-reperfusão é capaz de retratar alterações de importância prognóstica. Avaliar os resultados no primeiro ano após transplante hepático, correlacionando as alterações histológicas à biópsia hepática pós-reperfusão com a sobrevida, a disfunção e o não-funcionamento primário do enxerto. Dos 377 transplantes ocorridos de 1996 a 2008, 164 pacientes foram

Modulation of the oxidative stress by metformin in the cerebrum of rats exposed to global cerebral ischemia and ischemia/reperfusion.

PubMed

Abd-Elsameea, A A; Moustaf, A A; Mohamed, A M

2014-08-01

Oxidative stress plays a major role in the pathogenesis of ischemic and reperfusion injury to many organs, including the brain. Chronic metformin treatment is associated with a lower risk of stroke in clinical populations. The aim of the present study was to investigate the effect of metformin on the oxidative stress induced in experimental model of incomplete global cerebral ischemia and ischemia/reperfusion in adult male Wistar rats. Metformin was administered to rats orally by gavage 500 mg/kg once daily for one week before induction of cerebral ischemia (rats were subjected to 30 min of ischemia before decapitation) and ischemia/reperfusion (rats were subjected to 30 min of ischemia then 60 minutes of reperfusion before decapitation). The selected parameters for oxidative stress were the activities of the antioxidant enzymes: glutathione peroxidase (GSHPx), superoxide dismutase (SOD), and catalase as well as malondialdehyde (MDA) levels. Metformin reduced the elevated activites of GSHPx, SOD and catalase as well as MDA levels in cerebrum of rats exposed to ischemia and ischemia/reperfusion injures. Metformin improved the oxidative stress induced by ischemia and ischemia/reperfusion injuries. This may be a mechanism that explains the cerebroprotective effect of the drug.

[Effects of xenon preconditioning against ischemia/reperfusion injury and oxidative stress in immature heart].

PubMed

Li, Qian; Lian, Chun-Wei; Fang, Li-Qun; Liu, Bin; Yang, Bo

2014-09-01

To investigate whether xenon preconditioning (PC) could protect immature myocardium against ischemia-reperfusion (I/R) injury in a dose-dependent manner and clarify the role of xenon PC on oxidative stress. Forty-eight isolated perfused immature rabbit hearts were randomly divided into four groups (n = 12): The sham group had the hearts perfused continuously for 300 min. In I/R group, the hearts were subjected to 60 min perfusion followed by 60 min ischemia and 180 min reperfusion. In 1 minimum alveolar concentration (MAC) and 0.5 MAC xenon PC groups, the hearts were preconditioned with 1 MAC or 0.5 MAC xenon respectively, following 60 min ischemia and 180 min reperfusion. The cardiac function, myocardial infarct size, mitochondrial structure, superoxide dismutase (SOD) activity and malondialdehyde (MDA) level in each group were determined after reperfusion. Compared with I/R group, both 1 MAC and 0. 5 MAC xenon preconditioning significantly improved cardiac function (P < 0.01), reduced myocardial infarct size (P < 0.01) and mitochondrial damage, increased SOD activity and decreased MDA level (P < 0.01). There were no differences between 1 MAC group and 0.5 MAC xenon group (P > 0.05). Xenon preconditioning at 0. 5 and 1 MAC produce similar cardioprotective effects against I/R injury in isolated perfused immature heart.

Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery

PubMed Central

Chen, Han-sen; Chen, Xi; Li, Wen-ting; Shen, Jian-gang

2018-01-01

Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO−), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment. PMID:29595191

Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide.

PubMed

Toyoda, Tomomi; Tosaka, Shinya; Tosaka, Reiko; Maekawa, Takuji; Cho, Sungsam; Eguchi, Susumu; Nakashima, Masahiro; Sumikawa, Koji

2014-01-01

Ischemic postconditioning (PostC) protects the liver against ischemia-reperfusion (IR) injury. Milrinone, a phosphodiesterase 3 inhibitor, has been reported to exhibit preconditioning properties against hepatic IR injury; however, its PostC properties remain unknown. This study investigated whether milrinone has PostC properties against hepatic IR injury and the roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS). Male Wistar rats were separated into six groups: (1) group S: animals that underwent sham operation without ischemia, (2) group C: ischemia followed by reperfusion with no other intervention, (3) group M: milrinone administered immediately after reperfusion, (4) group MW: wortmannin, a PI3K inhibitor, injected before milrinone administration, (5) group MN: l-NAME, a NOS inhibitor, injected before milrinone administration, and (6) group MD, milrinone administered 30 min after reperfusion. Except for group S, all groups underwent 1 h of warm ischemia of median and left lateral lobes, followed by 5 h of reperfusion. Biochemical liver function analysis and histologic examination were performed. Serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, histologic damage scores, and apoptotic rate in group M were significantly lower than those in group C. The inhibition of PI3K or NOS prevented this protective effect. Milrinone administered 30 min after reperfusion did not show obvious protective effects. Milrinone-induced PostC protects against hepatic IR injury when it is administered immediately after reperfusion, and PI3K and NOS may play an important role in this protective effect. Copyright © 2014 Elsevier Inc. All rights reserved.

Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery.

PubMed

Chen, Han-Sen; Chen, Xi; Li, Wen-Ting; Shen, Jian-Gang

2018-05-01

Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO - ), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.

Increase in coronary blood flow by intra-aortic balloon counterpulsation in a porcine model of myocardial reperfusion.

PubMed

Bonios, Michael J; Pierrakos, Charalampos N; Argiriou, Michael; Dalianis, Argirios; Terrovitis, John V; Dolou, Paraskevi; Drakos, Stavros G; Koudoumas, Dimitrios; Charitos, Christos E; Anastasiou-Nana, Maria I

2010-02-04

Studies of the IABP have reported variable effects on coronary blood flow (CBF). The purpose of the present study was to measure the changes in coronary blood flow induced by intra-aortic balloon pump (IABP) counterpulsation in normal and reperfused porcine myocardium. A 30-ml IABP was placed in the descending aorta of 6 open-chest pigs. Each pig underwent occlusion of the mid-left anterior descending (LAD) coronary artery for 1 h, followed by reperfusion for 2 h. The effects of IABP support on systolic aortic pressure (SAP) and aortic end-diastolic pressure were recorded. The mean CBF, distal to the LAD occlusion site was measured at baseline and during reperfusion, with and without IABP counterpulsation. The IABP decreased SAP and aortic end-diastolic pressure in normal and reperfused myocardium, and maintained a peak aortic diastolic augmentation at the level of SAP. In normal myocardium, the IABP decreased mean CBF by 8.4+/-2.2% (p<0.001). At 2, 15, 30, 60, 90 and 120 min of reperfusion, the IABP increased mean CBF by 11.5+/-6.8%, 8.0+/-7.0%, 11.2+/-6.9%, 12.4+/-12.9%, 23.5+/-9.9% and 8.9+/-6.9%, of the corresponding value without the assistance of the IABP (all p<0.05). In the normal heart, IABP counterpulsation decreased CBF, probably because of a decrease in myocardial oxygen demand from a decreased afterload. During reperfusion the IABP increased CBF, suggesting that it might effectively mitigate the no-reflow phenomenon. Copyright 2008 Elsevier Ireland Ltd. All rights reserved.

Protection of ischaemic-reperfused rat heart by dimethylamiloride is associated with inhibition of mitochondrial permeability transition.

PubMed

Prendes, María G Marina; Torresín, Emilia; González, Marcela; Fernández, María A; Perazzo, Juan C; Savino, Enrique A; Varela, Alicia

2008-02-01

1. The aim of the present study was to assess whether protection afforded by the Na(+)/H(+) exchanger blocker dimethylamiloride (DMA) is associated with inhibition of mitochondrial permeability transition (MPT). The effects of DMA were compared with those of cyclosporine (Cs) A, an inhibitor of MPT. 2. Rat hearts were Langendorff perfused with Krebs'-bicarbonate medium containing 10 mmol/L glucose and were subjected to 25 min no-flow global ischaemia and 30 min reperfusion in the presence or absence of 10 micromol/L DMA or 0.2 micromol/L CsA. Cell viability was measured using tetrazolium stain. The MPT was determined by loading hearts with 2-deoxy-[(3)H]-glucose (2DG), which enters mitochondria only during MPT. Total heart 2DG content as an estimation of the extent of tissue damage was also measured. To assess whether DMA has any direct effect on glycolysis, a cell-free heart extract containing all the glycolytic enzymes was used. 3. Dimethylamiloride improved functional recovery (rate-pressure product) from 24 +/- 7 to 68 +/- 11% (P < 0.01) at reperfusion end, attenuated the increase in left ventricular end-diastolic pressure (from 29 +/- 7 to 6 +/- 3% 10 min after reperfusion onset; P < 0.01), improved cell viability (from 21.2 +/- 6.6 to 69.6 +/- 7.1% at reperfusion end; P < 0.05) and lessened lactate accumulation at the end of ischaemia (119 +/- 15 vs 163 +/- 14 micromol/g dry weight; P < 0.05). Dimethylamiloride limited MPT: 2DG mitochondrial entrapment, being 33.1 +/- 14.2 and 96.3 +/- 14.0 at reperfusion end in the treated and control hearts, respectively (P < 0.05), and concomitantly raised total 2DG content (51.3 +/- 4.4 vs 86.8 +/- 1.7 x 10(3) d.p.m./g wet weight in control and treated groups, respectively; P < 0.05). Cyclosporine A improved functional recovery and attenuated the amplitude of ventricular diastolic pressure in ischaemic-reperfused hearts. It also reduced mitochondrial entrapment (67.3 +/- 7.7%; P < 0.05 vs control) and increased total cell

Effect of picroside II on hind limb ischemia reperfusion injury in rats

PubMed Central

Kılıç, Yiğit; Özer, Abdullah; Tatar, Tolga; Zor, Mustafa Hakan; Kirişçi, Mehmet; Kartal, Hakan; Dursun, Ali Doğan; Billur, Deniz; Arslan, Mustafa; Küçük, Ayşegül

2017-01-01

Introduction Many structural and functional damages are observed in cells and tissues after reperfusion of previously viable ischemic tissues. Acute ischemia reperfusion (I/R) injury of lower extremities occurs especially when a temporary cross-clamp is applied to the abdominal aorta during aortic surgery. Research regarding the treatment of I/R injury has been increasing day-by-day. In this study, we aimed to investigate the effect of picroside II on skeletal muscle of rats experiencing simulated I/R. Materials and methods Twenty-four male Wistar albino rats weighing between 210 and 300 g were used in this study. Rats were randomly divided into 4 groups of 6 rats each (control, I/R, control + picroside II, and I/R + picroside II). The infrarenal section of the abdominal aorta was occluded with an atraumatic microvascular clamp in I/R group. The clamp was removed after 120 minutes and reperfusion was provided for a further 120 minutes. Picroside II (10 mg kg−1) was administered intraperitoneally to the animals in control + picroside II and I/R + picroside II groups. At the end of the study, skeletal muscle tissue was obtained for the determination of total oxidant status (TOS) and total antioxidant status (TAS) levels. Apoptosis was evaluated by TUNEL experiment. Results TOS levels were significantly higher in I/R group than that of control and I/R + picroside II groups (P=0.014, P=0.005, respectively). TAS levels were significantly higher in I/R group than that of control and I/R + picroside II groups (P=0.007 P=0.005, respectively). TUNEL assay revealed that picroside II reduced cell necrosis. Conclusion The results of this study demonstrated that picroside II plays a critical role to prevent I/R injury. Even though our results were found to be satisfactory, it should be encouraging to those who want to conduct future research on this topic. PMID:28721011

Cardioprotective effects of amlodipine on ischemia and reperfusion in two experimental models.

PubMed

Hoff, P T; Tamura, Y; Lucchesi, B R

1990-11-20

The cardioprotective effect of amlodipine, a long-acting dihydropyridine derivative, was studied in 2 experimental models of ischemia and reperfusion. Isolated and blood-perfused feline hearts were made globally ischemic for 60 minutes and then reperfused for 60 minutes. Alterations of left ventricular developed pressure and compliance were monitored in both amlodipine-treated hearts and saline-treated control animals. Changes in perfusion pressure indicated that amlodipine significantly reduced myocardial oxygen consumption and coronary vascular resistance. Furthermore, a progressive increase in resting left ventricular diastolic pressure indicated that amlodipine, administered before the onset of global ischemia, attenuated the development of ischemic contracture. Return of contractile function 60 minutes after reperfusion and maintenance of tissue concentrations of electrolytes were significantly better in the amlodipine-treated group than in the control animals. In intact canine hearts, regional myocardial ischemia was induced for 90 minutes, followed by 6 hours of reperfusion. Although the hemodynamic variables and the size of the region of risk did not differ significantly between treated animals and control animals, the infarct size was significantly smaller in the amlodipine-treated group than in the control animals, and a gradual reduction in coronary blood flow was observed in the control group that was prevented in the amlodipine group. A comparison of these findings with those observed with oxygen radical scavengers also is discussed. A detailed report of these studies was published in The American Journal of Cardiology (1989;64:101I-116I). This review is included here to maintain continuity of the symposium for the convenience of the reader.

PAH clearance after renal ischemia and reperfusion is a function of impaired expression of basolateral Oat1 and Oat3.

PubMed

Bischoff, Ariane; Bucher, Michael; Gekle, Michael; Sauvant, Christoph

2014-02-01

Determination of renal plasma flow (RPF) by para-aminohippurate (PAH) clearance leads to gross underestimation of this respective parameter due to impaired renal extraction of PAH after renal ischemia and reperfusion injury. However, no mechanistic explanation for this phenomenon is available. Based on our own previous studies we hypothesized that this may be due to impairment of expression of the basolateral rate limiting organic anion transporters Oat1 and Oat3. Thus, we investigated this phenomenon in a rat model of renal ischemia and reperfusion by determining PAH clearance, PAH extraction, PAH net secretion, and the expression of rOat1 and rOat3. PAH extraction was seriously impaired after ischemia and reperfusion which led to a threefold underestimation of RPF when PAH extraction ratio was not considered. PAH extraction directly correlated with the expression of basolateral Oat1 and Oat3. Tubular PAH secretion directly correlated with PAH extraction. Consequently, our data offer an explanation for impaired renal PAH extraction by reduced expression of the rate limiting basolateral organic anion transporters Oat1 and Oat3. Moreover, we show that determination of PAH net secretion is suitable to correct PAH clearance for impaired extraction after ischemia and reperfusion in order to get valid results for RPF.

Magnolol attenuates the lung injury in hypertonic saline treatment from mesenteric ischemia reperfusion through diminishing iNOS.

PubMed

Shih, Hsin-Chin; Huang, Mu-Shun; Lee, Chen-Hsen

2012-06-15

Hypertonic saline (HTS) administration can decrease the inflammation following ischemia reperfusion. Magnolol is a potent antioxidant. The present study investigated whether combined treatment of magnolol and HTS could provide further protection in mesenteric ischemia reperfusion injury. Male C3H/HeOuJ mice were randomly segregated into the following groups: sham-operated (sham), vehicle treatment and mesenteric ischemia reperfusion (MSIR) (vehicle-treated), magnolol treatment and MSIR (magnolol-treated), HTS treatment and MSIR (HTS-treated), as well as co-administration of magnolol plus HTS and MSIR (combined-treated). In MSIR, mice were subjected to mesenteric ischemia for 60 min followed by reperfusion for 30 min. Lung injury was evaluated by lung edema (water ratio) and myeloperoxide (MPO) activity; RNA expression of inducible nitric oxide synthetase (iNOS), TNF-α, and IL-6 were assayed by real time RT-PCR. The formation of peroxynitrite in plasma was assayed by the peroxynitrite-dependent oxidation of dihydrorhodamine 123 (DHR 123) to rhodamine. Compared with those in the sham-treated group, lung edema and MPO activity, expressions of iNOS, TNF-α and IL-6, and plasma peroxynitrite were significantly increased in the vehicle-treated group. Significant attenuations of these parameters were found in the magnolol-treated or HTS-treated animals. Combined treatment of magnolol and HTS further suppressed the lung edema, iNOS, and TNF-α expressions, and plasma peroxynitrite, compared with the results of a single treatment of magnolol or HTS. Compared with single-agent use, co-administration of magnolol and HTS further decreases iNOS expression and plasma peroxynitrite as well as the degree of lung injury from MISR. These results may provide another treatment measure for post-injury immunomodulation. Copyright © 2012 Elsevier Inc. All rights reserved.

Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury

PubMed Central

Castro, Angela M.; Lupu, Traian S.; Weinheimer, Carla; Smith, Craig; Kovacs, Attila

2016-01-01

Fibroblast growth factor (FGF) signaling is cardioprotective in various models of myocardial infarction. FGF receptors (FGFRs) are expressed in multiple cell types in the adult heart, but the cell type-specific FGFR signaling that mediates different cardioprotective endpoints is not known. To determine the requirement for FGFR signaling in endothelium in cardiac ischemia-reperfusion injury, we conditionally inactivated the Fgfr1 and Fgfr2 genes in endothelial cells with Tie2-Cre (Tie2-Cre, Fgfr1f/f, Fgfr2f/f DCKO mice). Tie2-Cre, Fgfr1f/f, Fgfr2f/f DCKO mice had normal baseline cardiac morphometry, function, and vessel density. When subjected to closed-chest, regional cardiac ischemia-reperfusion injury, Tie2-Cre, Fgfr1f/f, Fgfr2f/f DCKO mice showed a significantly increased hypokinetic area at 7 days, but not 1 day, after reperfusion. Tie2-Cre, Fgfr1f/f, Fgfr2f/f DCKO mice also showed significantly worsened cardiac function compared with controls at 7 days but not 1 day after reperfusion. Pathophysiological analysis showed significantly decreased vessel density, increased endothelial cell apoptosis, and worsened tissue hypoxia in the peri-infarct area at 7 days following reperfusion. Notably, Tie2-Cre, Fgfr1f/f, Fgfr2f/f DCKO mice showed no impairment in the cardiac hypertrophic response. These data demonstrate an essential role for FGFR1 and FGFR2 in endothelial cells for cardiac functional recovery and vascular remodeling following in vivo cardiac ischemia-reperfusion injury, without affecting the cardiac hypertrophic response. This study suggests the potential for therapeutic benefit from activation of endothelial FGFR pathways following ischemic injury to the heart. PMID:26747503

Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury.

PubMed

House, Stacey L; Castro, Angela M; Lupu, Traian S; Weinheimer, Carla; Smith, Craig; Kovacs, Attila; Ornitz, David M

2016-03-01

Fibroblast growth factor (FGF) signaling is cardioprotective in various models of myocardial infarction. FGF receptors (FGFRs) are expressed in multiple cell types in the adult heart, but the cell type-specific FGFR signaling that mediates different cardioprotective endpoints is not known. To determine the requirement for FGFR signaling in endothelium in cardiac ischemia-reperfusion injury, we conditionally inactivated the Fgfr1 and Fgfr2 genes in endothelial cells with Tie2-Cre (Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice). Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice had normal baseline cardiac morphometry, function, and vessel density. When subjected to closed-chest, regional cardiac ischemia-reperfusion injury, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed a significantly increased hypokinetic area at 7 days, but not 1 day, after reperfusion. Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice also showed significantly worsened cardiac function compared with controls at 7 days but not 1 day after reperfusion. Pathophysiological analysis showed significantly decreased vessel density, increased endothelial cell apoptosis, and worsened tissue hypoxia in the peri-infarct area at 7 days following reperfusion. Notably, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed no impairment in the cardiac hypertrophic response. These data demonstrate an essential role for FGFR1 and FGFR2 in endothelial cells for cardiac functional recovery and vascular remodeling following in vivo cardiac ischemia-reperfusion injury, without affecting the cardiac hypertrophic response. This study suggests the potential for therapeutic benefit from activation of endothelial FGFR pathways following ischemic injury to the heart. Copyright © 2016 the American Physiological Society.

[Ischemic postconditioning attenuates ischemia/reperfusion injury in isolated hypertrophied rat heart].

PubMed

Peng, Long-yun; Ma, Hong; He, Jian-gui; Gao, Xiu-ren; Zhang, Yan; He, Xiao-hong; Zhai, Yuan-sheng; Zhang, Xue-jiao

2006-08-01

To explore the effects of ischemic postconditioning on ischemia/reperfusion injury in isolated hypertrophied rat heart and investigate the signal transduction pathway changes induced by ischemia postconditioning. Cardiac hypertrophy was induced in rats by abdominal aortic banding, and isolated hypertrophied rat heart ischemia/reperfusion model was made by Langendorff technique to evaluate the effects of ischemia postconditioning on left ventricular systole pressure, coronary artery flow, creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) release, myocardial infarction size, and the level of myocardial phospho-protein kinase B/Akt (Ser473), phospho-glycogen synthase kinase-3beta (Ser9). Following groups were studied (n = 12 each group): IR, 30 min ischemia (I)/60 min Reperfusion (R); Post: 30 min ischemia, 6 circles of 10 s I/10 s R followed by 60 min R; Post Wort: 30 min ischemia, 6 circles of 10 s I/10 s R, wortmannin (10(-7) mol/L) followed by 60 min R; Wort: 30 min ischemia, wortmannin (10(-7) mol/L) followed by 60 min R. Left ventricular systolic pressure and coronary artery flow were significantly increased, myocardial infarction size and the release of CPK, LDH significantly reduced in Post group compared to that in IR group. Phospho-protein kinase B/Akt (Ser473) and phospho-glycogen synthase kinase-3beta (Ser9) levels were also significantly higher in Post group than that in IR group. Phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin prevented the increase of phospho-protein kinase B/Akt (Ser473) and phospho-glycogen synthase kinase-3beta (Ser9) induced by ischemic postconditioning, but only partly abolished the cardioprotection of ischemic postconditioning. Ischemic postconditioning attenuates ischemia/reperfusion injury in isolated hypertrophied rat heart. The cardioprotective effects of ischemic postconditioning were partly mediated through PI3K/Akt/GSK-3beta signaling pathway.

Vitamin C prophylaxis promotes oxidative lipid damage during surgical ischemia-reperfusion.

PubMed

Bailey, Damian M; Raman, Sudarsanam; McEneny, Jane; Young, Ian S; Parham, Kelly L; Hullin, David A; Davies, Bruce; McKeeman, Gareth; McCord, Joe M; Lewis, Michael H

2006-02-15

Reactive oxygen species (ROS) have been implicated in the cellular membrane damage and postoperative morbidity associated with obligatory ischemia-reperfusion (I-R) during vascular surgery. Thus, a clinical study was undertaken to evaluate the effects of ascorbate prophylaxis on ROS exchange kinetics in 22 patients scheduled for elective abdominal aortic aneurysm (AAA) or infra-inguinal bypass (IIB) repair. Patients were assigned double-blind to receive intravenous sodium ascorbate (2 g vitamin C, n=10) or placebo (0.9% saline, n=12) administered 2 h prior to surgery. Blood samples were obtained from the arterial and venous circulation proximal to the respective sites of surgical repair (local) and from an antecubital vein (peripheral) during cross-clamping (ischemia) and within 60 s of clamp release (reperfusion). Ascorbate supplementation increased the venoarterial concentration difference (v-adiff) of lipid hydroperoxides (LH), interleukin (IL)-6 and vascular endothelial growth factor (VEGF) protein during ischemia. This increased the peripheral concentration of LH, total creatine phosphokinase (CPK), and VEGF protein during reperfusion (P<0.05 vs placebo). Electron paramagnetic resonance (EPR) spectroscopy confirmed that free iron was available for oxidative catalysis in the local ischemic venous blood of supplemented patients. An increased concentration of the ascorbate radical (A.-) and alpha-phenyl-tert-butylnitrone (PBN) adducts assigned as lipid-derived alkoxyl (LO.) and alkyl (LC.) species were also detected in the peripheral blood of supplemented patients during reperfusion (P<0.05 vs ischemia). In conclusion, these findings suggest that ascorbate prophylaxis may have promoted iron-induced oxidative lipid damage via a Fenton-type reaction initiated during the ischemic phase of surgery. The subsequent release of LH into the systemic circulation may have catalyzed formation of second-generation radicals implicated in the regulation of vascular permeability

DNA damage response in renal ischemia-reperfusion and ATP-depletion injury of renal tubular cells.

PubMed

Ma, Zhengwei; Wei, Qingqing; Dong, Guie; Huo, Yuqing; Dong, Zheng

2014-07-01

Renal ischemia-reperfusion leads to acute kidney injury (AKI) that is characterized pathologically by tubular damage and cell death, followed by tubular repair, atrophy and interstitial fibrosis. Recent work suggested the possible presence of DNA damage response (DDR) in AKI. However, the evidence is sketchy and the role and regulation of DDR in ischemic AKI remain elusive. In this study, we demonstrated the induction of phosphorylation of ATM, H2AX, Chk2 and p53 during renal ischemia-reperfusion in mice, suggesting DDR in kidney tissues. DDR was also induced in vitro during the recovery or "reperfusion" of renal proximal tubular cells (RPTCs) after ATP depletion. DDR in RPTCs was abrogated by supplying glucose to maintain ATP via glycolysis, indicating that the DDR depends on ATP depletion. The DDR was also suppressed by the general caspase inhibitor z-VAD and the overexpression of Bcl-2, supporting a role of apoptosis-associated DNA damage in the DDR. N-acetylcysteine (NAC), an antioxidant, suppressed the phosphorylation of ATM and p53 and, to a less extent, Chk2, but NAC increased the phosphorylation and nuclear foci formation of H2AX. Interestingly, NAC increased apoptosis, which may account for the observed H2AX activation. Ku55933, an ATM inhibitor, blocked ATM phosphorylation and ameliorated the phosphorylation of Chk2 and p53, but it increased H2AX phosphorylation and nuclear foci formation. Ku55933 also increased apoptosis in RPTCs following ATP depletion. The results suggest that DDR occurs during renal ischemia-reperfusion in vivo and ATP-depletion injury in vitro. The DDR is partially induced by apoptosis and oxidative stress-related DNA damage. ATM, as a sensor in the DDR, may play a cytoprotective role against tubular cell injury and death. Copyright © 2014 Elsevier B.V. All rights reserved.

5'- Adenosine monophosphate induced hypothermia reduces early stage myocardial ischemia/reperfusion injury in a mouse model.

PubMed

Tao, Zhenyin; Zhao, Zhaoyang; Lee, Cheng Chi

2011-08-15

Early intervention using hypothermia treatment has been shown to reduce early inflammation, apoptosis and infarct size in animal models of cardiac ischemia/reperfusion. We have shown that 5'-adenosine monophosphate (5'-AMP) can induce a reversible deep hypothermia in mammals. We hypothesize that 5'-AMP-induced hypothermia (AIH) may reduce ischemic/reperfusion damage following myocardial infarct. C57BL/6J male mice were subjected to myocardial ischemia by ligating the left anterior descending coronary artery (LAD) followed by reperfusion. Compared to euthermic controls, mice given AIH treatment exhibited significant inhibition of neutrophil infiltration and a reduction in matrix metallopeptidase 9 (MMP-9) expressions in the infarcted myocardium. A decrease in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive nuclei in the left ventricle myocardium were also observed. The overall infarct size of the heart was significantly smaller in AIH treated mice. Myocardial ischemia in mice given 5'-AMP without hypothermia had similar ischemia/reperfusion injuries as the euthermic control. Thus, the AIH cardio-protective effects were primarily hypothermia based.

[Antiarrhythmic and cardioprotective effect of stimulation of delta1-opiate receptors in myocardial ischemia and reperfusion].

PubMed

Lasukova, T V; Krylatov, A V; Maslov, L N; Lishmanov, Iu B; Gross, G J; Podoksenov, Iu K; Podoksenov, A Iu

2004-01-01

Pretreatment with intravenous peptide delta1-opioid receptor (OR) agonist DPDPE (0.5 mg/kg) decreases the incidence of occlusion (10 min) and reperfusion (10 min) arrhythmias in rats. The agonist of delta2-OR DSLET has no effect on arrhythmias in coronary artery occlusion and reperfusion. Pretreatment with selective delta-antagonists ICI 174,864 (2.5 mg/kg) eliminates an antiarrhythmic effect of DPDPE. The addition of DPDPE to the perfusion solution in a final concentration of 0.1 mg/l and/or 0.5 mg/l fifteen min before ischemia also decreases the incidence of reperfusion arrhythmias in a concentration-dependent manner. The addition of DPDPE to the perfusion solution in a final concentration of 0.1 mg/l decreases creatine kinase levels in the coronary sinus effluent. However, DPDPE has no cardioprotective effect in a concentration of 0.5 mg/l or after intravenous administration. It is suggested that antiarrhythmic and cardioprotective effects of DPDPE during reperfusion may be due to stimulation of cardiac delta1-receptors.

Immersing lungs in hydrogen-rich saline attenuates lung ischaemia-reperfusion injury.

PubMed

Takahashi, Mamoru; Chen-Yoshikawa, Toyofumi F; Saito, Masao; Tanaka, Satona; Miyamoto, Ei; Ohata, Keiji; Kondo, Takeshi; Motoyama, Hideki; Hijiya, Kyoko; Aoyama, Akihiro; Date, Hiroshi

2017-03-01

Anti-oxidant effects of hydrogen have been reported in studies examining ischaemia-reperfusion injury (IRI). In this study, we evaluated the therapeutic efficacy of immersing lungs in hydrogen-rich saline on lung IRI. Lewis rats were divided into three groups: (i) sham, (ii) normal saline and (iii) hydrogen-rich saline. In the first experiment, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline for 1 h. Then, we measured the hydrogen concentration in the left lung using a sensor gas chromatograph ( N = 3 per group). In the second experiment, lung IRI was induced by occlusion of the left pulmonary hilum for 1 h, followed by reperfusion for 3 h. During the ischaemic period, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline. After reperfusion, we assessed lung function, histological changes and cytokine production ( N = 5-7 per group). Immersing lungs in hydrogen-rich saline resulted in an elevated hydrogen concentration in the lung (6.9 ± 2.9 μmol/1 g lung). After IRI, pulmonary function (pulmonary compliance and oxygenation levels) was significantly higher in the hydrogen-rich saline group than in the normal saline group ( P  < 0.05). Similarly, pro-inflammatory cytokine levels (interleukin-1β and interleukin-6) in the left lung were significantly lower in the hydrogen-rich saline group than in the normal saline group ( P  < 0.05). Immersing lungs in hydrogen-rich saline delivered hydrogen into the lung and consequently attenuated lung IRI. Hydrogen-rich solution appears to be a promising approach to managing lung IRI. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Low-energy shock wave preconditioning reduces renal ischemic reperfusion injury caused by renal artery occlusion.

PubMed

Xue, Yuquan; Xu, Zhibin; Chen, Haiwen; Gan, Weimin; Chong, Tie

2017-07-01

To evaluate whether low energy shock wave preconditioning could reduce renal ischemic reperfusion injury caused by renal artery occlusion. The right kidneys of 64 male Sprague Dawley rats were removed to establish an isolated kidney model. The rats were then divided into four treatment groups: Group 1 was the sham treatment group; Group 2, received only low-energy (12 kv, 1 Hz, 200 times) shock wave preconditioning; Group 3 received the same low-energy shock wave preconditioning as Group 2, and then the left renal artery was occluded for 45 minutes; and Group 4 had the left renal artery occluded for 45 minutes. At 24 hours and one-week time points after reperfusion, serum inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), creatinine (Cr), and cystatin C (Cys C) levels were measured, malondialdehyde (MDA) in kidney tissue was detected, and changes in nephric morphology were evaluated by light and electron microscopy. Twenty-four hours after reperfusion, serum iNOS, NGAL, Cr, Cys C, and MDA levels in Group 3 were significantly lower than those in Group 4; light and electron microscopy showed that the renal tissue injury in Group 3 was significantly lighter than that in Group 4. One week after reperfusion, serum NGAL, KIM-1, and Cys C levels in Group 3 were significantly lower than those in Group 4. Low-energy shock wave preconditioning can reduce renal ischemic reperfusion injury caused by renal artery occlusion in an isolated kidney rat model.

Therapeutic time window and underlying therapeutic mechanism of breviscapine injection against cerebral ischemia/reperfusion injury in rats.

PubMed

Guo, Chao; Zhu, Yanrong; Weng, Yan; Wang, Shiquan; Guan, Yue; Wei, Guo; Yin, Ying; Xi, Miaomaio; Wen, Aidong

2014-01-01

Breviscapine injection is a Chinese herbal medicine standardized product extracted from Erigeron breviscapus (Vant.) Hand.-Mazz. It has been widely used for treating cardiovascular and cerebrovascular diseases. However, the therapeutic time window and the action mechanism of breviscapine are still unclear. The present study was designed to investigate the therapeutic time window and underlying therapeutic mechanism of breviscapine injection against cerebral ischemic/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 2h followed by 24h of reperfusion. Experiment part 1 was used to investigate the therapeutic time window of breviscapine. Rats were injected intravenously with 50mg/kg breviscapine at different time-points of reperfusion. After 24h of reperfusion, neurologic score, infarct volume, brain water content and serum level of neuron specific enolase (NSE) were measured in a masked fashion. Part 2 was used to explore the therapeutic mechanism of breviscapine. 4-Hydroxy-2-nonenal (4-HNE), 8-hydroxyl-2'- deoxyguanosine (8-OHdG) and the antioxidant capacity of ischemia cortex were measured by ELISA and ferric-reducing antioxidant power (FRAP) assay, respectively. Immunofluorescence and western blot analysis were used to analyze the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Part 1: breviscapine injection significantly ameliorated neurologic deficit, reduced infarct volume and water content, and suppressed the levels of NSE in a time-dependent manner. Part 2: breviscapine inhibited the increased levels of 4-HNE and 8-OHdG, and enhanced the antioxidant capacity of cortex tissue. Moreover, breviscapine obviously raised the expression of Nrf2 and HO-1 proteins after 24h of reperfusion. The therapeutic time window of breviscapine injection for cerebral ischemia/reperfusion injury seemed to be within 5h after reperfusion. By up-regulating the expression of Nrf2/HO-1 pathway

Effects of various timings and concentrations of inhaled nitric oxide in lung ischemia-reperfusion. The Paris-Sud University Lung Transplantation Group.

PubMed

Murakami, S; Bacha, E A; Mazmanian, G M; Détruit, H; Chapelier, A; Dartevelle, P; Hervé, P

1997-08-01

Experimental studies reveal that inhaled nitric oxide (NO) can prevent, worsen, or have no effect on lung injury in the setting of ischemia-reperfusion (I-R). We tested the hypothesis that these disparate effects could be related to differences in the timing of administration and/or concentration of inhaled NO during I-R. Isolated rat lungs were subjected to 1-h periods of ischemia followed by 1-h periods of blood reperfusion. We investigated the effects of NO (30 ppm) given during ischemia, NO (30 or 80 ppm) begun immediately at reperfusion, or NO (30 ppm) given 15 min after the beginning of reperfusion, on total pulmonary vascular resistance (PVR), the coefficient of filtration (Kfc), the lung wet/dry weight ratio (W/D) of lung tissue, and lung myeloperoxidase activity (MPO). A control group did not receive NO. NO given during ischemia had no effect on Kfc or MPO, but decreased PVR. NO (30 ppm) during reperfusion (early or delayed) decreased PVR, W/D, Kfc and MPO. NO at 80 ppm decreased PVR and MPO but not W/D or Kfc. In conclusion, NO at 30 ppm, given immediately or in a delayed fashion during reperfusion, attenuates I-R-induced lung injury. NO at 30 ppm given during ischemia or at 80 ppm during reperfusion is not protective.

Do Facilitated Online Dual Credit Classes Result in Deep Learning?

ERIC Educational Resources Information Center

Stark Education Partnership, 2015

2015-01-01

This study, with funding from the Jennings Foundation, sought to answer the following broad research question: Do facilitated online dual credit courses result in deep learning? The answer to this question is key to addressing barriers many students face in bridging from high school to college. This report includes a descriptive case study that…

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury.

PubMed

Godar, Rebecca J; Ma, Xiucui; Liu, Haiyan; Murphy, John T; Weinheimer, Carla J; Kovacs, Attila; Crosby, Seth D; Saftig, Paul; Diwan, Abhinav

2015-01-01

Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from in-vivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEB-mediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fasting-induced autophagy in myocardial ischemia-reperfusion injury.

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

PubMed Central

Godar, Rebecca J; Ma, Xiucui; Liu, Haiyan; Murphy, John T; Weinheimer, Carla J; Kovacs, Attila; Crosby, Seth D; Saftig, Paul; Diwan, Abhinav

2015-01-01

Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from in-vivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEB-mediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fasting-induced autophagy in myocardial ischemia-reperfusion injury. PMID:26103523

[Effect of hydrogen-rich saline on cardiomyocyte autophagy during myocardial ischemia-reperfusion in aged rats].

PubMed

Pan, Zhenhua; Zhao, Yue; Yu, Hongying; Liu, Dayi; Xu, Hua

2015-07-07

To investigate the effects of hydrogen-rich saline on cardiomyocyte autophagy during myocardial ischemia-reperfusion in aged rats. One hundred and fifty healthy male Sprague Dawley rats, 18 months old, weighing 400-540 g were selected. The rats were then randomly divided into 5 groups (n = 30): Normal control group (group I); Sham operation group (group II); Myocardial ischemia-reperfusion group (group III); Hydrogen-rich saline group (group IV); Normal saline group (group V). No any processing in group I. In group II, the anterior descending branch was only exposed but not ligated. Myocardial I/R was induced by occlusion of anterior descending branch of left coronary artery for 30 min followed by 12 h and 24 h of reperfusion with Bimbaum. Hydrogen-rich saline 1 ml/100 g were injected intraperitoneally 5 min before reperfusion in group IV. Normal saline 1 ml/100 g were injected intraperitoneally 5 min before reperfusion in group V. The rats were sacrificed at 12 h and 24 h of reperfusion and hearts were removed. The pathological changes of myocardial tissue were detected by HE staining. The rate of cardiomyocyte autophagy were detected by the MDC fluorescent dye and flow cytometry instrument. The expression of AMPK, mTOR, Beclin1, LC3 in myocardial tissue was investigated by Western blot. Compared with groups I and II, the rate of cardiomyocyte autophagy, the expression of AMPK, mTOR, Beclin1, LC3 in myocardial tissue were significantly increased at 12 h, 24 h in groups III, IV and V (F = 23.45, 26.65, 25.58; F = 23.16, 25.15, 27.85; F = 21.04, 24.83, 27.43; F = 22.15, 25.79, 29.05; F = 22.58, 27.25, 28.46), P < 0.05. Compared with group III and V, the rate of cardiomyocyte autophagy, the expression of AMPK, mTOR, Beclin1, LC3 were significantly decreased at 12 h, 24 h in group IV (F = 21.29, 24.71; F = 22.37, 25.84; F = 20.48, 22.38; F = 21.76, 28.43; F = 22.54, 27.21), P < 0.05. Hydrogen-rich saline can attenuate myocardial reperfusion injury through inhibiting

Mechanisms of nephroprotective effect of mitochondria-targeted antioxidants under rhabdomyolysis and ischemia/reperfusion.

PubMed

Plotnikov, E Y; Chupyrkina, A A; Jankauskas, S S; Pevzner, I B; Silachev, D N; Skulachev, V P; Zorov, D B

2011-01-01

Oxidative stress-related renal pathologies apparently include rhabdomyolysis and ischemia/reperfusion phenomenon. These two pathologies were chosen for study in order to develop a proper strategy for protection of the kidney. Mitochondria were found to be a key player in these pathologies, being both the source and the target for excessive production of reactive oxygen species (ROS). A mitochondria-targeted compound which is a conjugate of a positively charged rhodamine molecule with plastoquinone (SkQR1) was found to rescue the kidney from the deleterious effect of both pathologies. Intraperitoneal injection of SkQR1 before the onset of pathology not only normalized the level of ROS and lipid peroxidized products in kidney mitochondria but also decreased the level of cytochrome c in the blood, restored normal renal excretory function and significantly lowered mortality among animals having a single kidney exposed to ischemia/reperfusion. The SkQR1-derivative missing plastoquinone (C12R1) possessed some, although limited nephroprotective properties and enhanced animal survival after ischemia/reperfusion. SkQR1 was found to induce some elements of nephroprotective pathways providing ischemic tolerance such as an increase in erythropoietin levels and phosphorylation of glycogen synthase kinase 3β in the kidney. SkQR1 also normalized renal erythropoietin level lowered after kidney ischemia/reperfusion and injection of a well-known nephrotoxic agent gentamicin. Copyright © 2010 Elsevier B.V. All rights reserved.

Expression and significance of angiostatin, vascular endothelial growth factor and matrix metalloproteinase-9 in brain tissue of diabetic rats with ischemia reperfusion.

PubMed

Liang, Yu-Zhi; Zeng, Zhi-Lei; Hua, Lin-Lin; Li, Jin-Feng; Wang, Yun-Liang; Bi, Xi-Zhuang

2016-06-01

To discuss the expression and significance of angiostatin, vascular endothelial growth factor and matrix metalloproteinase-9 in the brain tissue of diabetic rats with ischemia reperfusion. A total of 60 male Wistar rats were randomly divided into the normal group, sham group, diabetic cerebral infarction group and single cerebral infarction group according to the random number table, with 15 rats in each group. The high sucrose diet and intraperitoneal injection of streptozotocin were performed for the modeling of diabetic rats, while the thread-occlusion method was employed to build the model of cerebral ischemia reperfusion. The immunohistochemical staining was performed to detect the expression of angiostatin, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in the brain tissue. The expression of angiostatin after the reperfusion in the brain tissue of rats in the single cerebral infarction group and diabetic cerebral infarction group was increased 6 h after the reperfusion, reached to the peak on 1 d and then decreased gradually. The expression of angiostatin in the diabetic cerebral infarction group 6 h, 1 d, 3 d and 7 d after the reperfusion was significantly higher than that in the single cerebral infarction group (P < 0.05). VEGF began to be increased 1 h after the reperfusion in the single cerebral infarction group and diabetic cerebral infarction group, reached to the peak at 6 h and then decreased gradually. The expression of VEGF in the diabetic cerebral infarction group at each time point after the reperfusion was significantly lower than that in the single cerebral infarction group (P < 0.05). MMP-9 began to be increased 1 h after the reperfusion in the single cerebral infarction group and diabetic cerebral infarction group, reached to the peak on 1 d and then decreased gradually. The expression of MMP-9 in the diabetic cerebral infarction group at each time point after the reperfusion was significantly

The effects of Y-27632 on pial microvessels during global brain ischemia and reperfusion in rabbits.

PubMed

Shintani, Noriyuki; Ishiyama, Tadahiko; Kotoda, Masakazu; Asano, Nobumasa; Sessler, Daniel I; Matsukawa, Takashi

2017-03-07

Global brain ischemia-reperfusion during propofol anesthesia provokes persistent cerebral pial constriction. Constriction is likely mediated by Rho-kinase. Cerebral vasoconstriction possibly exacerbates ischemic brain injury. Because Y-27632 is a potent Rho-kinase inhibitor, it should be necessary to evaluate its effects on cerebral pial vessels during ischemia-reperfusion period. We therefore tested the hypotheses that Y-27632 dilates cerebral pial arterioles after the ischemia-reperfusion injury, and evaluated the time-course of cerebral pial arteriolar status after the ischemia-reperfusion. Japanese white rabbits were anesthetized with propofol, and a closed cranial window inserted over the left hemisphere. Global brain ischemia was produced by clamping the brachiocephalic, left common carotid, and left subclavian arteries for 15 min. Rabbits were assigned to cranial window perfusion with: (1) artificial cerebrospinal fluid (Control group, n = 7); (2) topical infusion of Y-27632 10 -6 mol · L -1 for 30 min before the initiation of global brain ischemia (Pre group, n = 7); (3) topical infusion of Y-27632 10 -6 mol · L -1 starting 30 min before ischemia and continuing throughout the study period (Continuous group, n = 7); and, (4) topical infusion of Y-27632 10 -6 mol · L -1 starting 10 min after the ischemia and continuing until the end of the study (Post group, n = 7). Cerebral pial arterial and venule diameters were recorded 30 min before ischemia, just before arterial clamping, 10 min after clamping, and 5, 10, 20, 40, 60, 80, 100, and 120 min after unclamping. Mean arterial blood pressure and blood glucose concentration increased significantly after global brain ischemia except in the Continuous group. In the Pre and Continuous groups, topical application of Y-27632 produced dilation of large (mean 18-19%) and small (mean; 25-29%) pial arteries, without apparent effect on venules. Compared with the Control and Pre groups

Osthole ameliorates renal ischemia-reperfusion injury by inhibiting inflammatory response.

PubMed

Zheng, Yi; Lu, Min; Ma, Lulin; Zhang, Shudong; Qiu, Min; Ma, Xin

2013-01-01

Renal ischemia-reperfusion (I/R) injury is a primary cause of acute renal failure that results in high mortality. This study aimed to investigate the effect of osthole, a natural coumarin derivative, on renal I/R injury in a rat model. Rats were randomly allocated to the sham operation + vehicle, I/R + vehicle, and I/R + osthole groups. Renal I/R injury was induced by clamping the left renal artery for 45 min followed by 12 h of reperfusion and a contralateral nephrectomy. Osthole (40 mg/kg) was intraperitoneally injected 30 min before inducing I/R. Renal function and histological damage were determined subsequently. Myeloperoxidase activity, monocyte/macrophage infiltration, as well as tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys were also assessed. Osthole treatment significantly ameliorated I/R-induced renal functional and morphological injuries. Moreover, osthole treatment attenuated myeloperoxidase activity, monocyte/macrophage infiltration, and tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys. Osthole treatment ameliorates renal I/R injury by inhibiting inflammatory responses in kidneys. Thus, osthole may represent a novel practical strategy to prevent renal I/R injury. Copyright © 2013 S. Karger AG, Basel.

Erythropoietin and sildenafil protect against ischemia/reperfusion injury following testicular torsion in adult rats.

PubMed

Kostakis, Ioannis D; Zavras, Nick; Damaskos, Christos; Sakellariou, Stratigoula; Korkolopoulou, Penelope; Misiakos, Evangelos P; Tsaparas, Petros; Vaos, George; Karatzas, Theodoros

2017-06-01

Testicular torsion/detorsion causes severe tissue damage due to ischemia/reperfusion injury. The present study investigated the protective effect of erythropoietin and sildenafil against ischemia/reperfusion injury following unilateral testicular torsion/detorsion in adult rats. A total of 28 adult male rats were included, and were divided into the following groups: Group A (n=5), sham operated; groups B (n=5), C (n=5), D (n=5) and E (n=8), undergoing right testis torsion and detorsion after 90 min. Group B received no drug treatment. Rats in the groups C and D received low-dose (1,000 IU/kg) or high-dose (3,000 IU/kg) erythropoietin, while those in group E received sildenafil (0.7 mg/kg), through intraperitoneal injection after 60 min of torsion. The right testis was extracted 24 h after detorsion, and the tissue was subjected to histopathological examination and immunohistochemical assessment of cleaved caspase-3 expression. Histological alterations and the quality of spermatogenesis were scored according to the Cosentino and the Johnsen scoring systems, respectively. The results demonstrated normal testicular architecture in group A, while the other groups showed ischemic cellular damages, with the worst scores observed in group B. Groups D and E presented better scores compared with group C. Regarding the quality of spermatogenesis, the best scores were observed in group A, and the worst in group B. Groups C, D and E presented similar results, which were improved in comparison to group B, however, not compared to group A. Furthermore, cleaved caspase-3 levels were lower in groups A, D and E, with equal results observed. Group C had higher levels of cleaved caspase-3 compared with these groups, but lower than group B, which presented the highest cleaved caspase-3 levels. In conclusion, erythropoietin and sildenafil protect testis from ischemia/reperfusion injury by decreasing cellular damage and attenuating apoptosis.

Erythropoietin and sildenafil protect against ischemia/reperfusion injury following testicular torsion in adult rats

PubMed Central

Kostakis, Ioannis D.; Zavras, Nick; Damaskos, Christos; Sakellariou, Stratigoula; Korkolopoulou, Penelope; Misiakos, Evangelos P.; Tsaparas, Petros; Vaos, George; Karatzas, Theodoros

2017-01-01

Testicular torsion/detorsion causes severe tissue damage due to ischemia/reperfusion injury. The present study investigated the protective effect of erythropoietin and sildenafil against ischemia/reperfusion injury following unilateral testicular torsion/detorsion in adult rats. A total of 28 adult male rats were included, and were divided into the following groups: Group A (n=5), sham operated; groups B (n=5), C (n=5), D (n=5) and E (n=8), undergoing right testis torsion and detorsion after 90 min. Group B received no drug treatment. Rats in the groups C and D received low-dose (1,000 IU/kg) or high-dose (3,000 IU/kg) erythropoietin, while those in group E received sildenafil (0.7 mg/kg), through intraperitoneal injection after 60 min of torsion. The right testis was extracted 24 h after detorsion, and the tissue was subjected to histopathological examination and immunohistochemical assessment of cleaved caspase-3 expression. Histological alterations and the quality of spermatogenesis were scored according to the Cosentino and the Johnsen scoring systems, respectively. The results demonstrated normal testicular architecture in group A, while the other groups showed ischemic cellular damages, with the worst scores observed in group B. Groups D and E presented better scores compared with group C. Regarding the quality of spermatogenesis, the best scores were observed in group A, and the worst in group B. Groups C, D and E presented similar results, which were improved in comparison to group B, however, not compared to group A. Furthermore, cleaved caspase-3 levels were lower in groups A, D and E, with equal results observed. Group C had higher levels of cleaved caspase-3 compared with these groups, but lower than group B, which presented the highest cleaved caspase-3 levels. In conclusion, erythropoietin and sildenafil protect testis from ischemia/reperfusion injury by decreasing cellular damage and attenuating apoptosis. PMID:28587411

(-)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury.

PubMed

Chang, Cheng-Fu; Lai, Jing-Huei; Wu, John Chung-Che; Greig, Nigel H; Becker, Robert E; Luo, Yu; Chen, Yen-Hua; Kang, Shuo-Jhen; Chiang, Yung-Hsiao; Chen, Kai-Yun

2017-12-15

Stroke commonly leads to adult disability and death worldwide. Its major symptoms are spastic hemiplegia and discordant motion, consequent to neuronal cell death induced by brain vessel occlusion. Acetylcholinesterase (AChE) is upregulated and allied with inflammation and apoptosis after stroke. Recent studies suggest that AChE inhibition ameliorates ischemia-reperfusion injury and has neuroprotective properties. (-)-Phenserine, a reversible AChE inhibitor, has a broad range of actions independent of its AChE properties, including neuroprotective ones. However, its protective effects and detailed mechanism of action in the rat middle cerebral artery occlusion model (MCAO) remain to be elucidated. This study investigated the therapeutic effects of (-)-phenserine for stroke in the rat focal cerebral ischemia model and oxygen-glucose deprivation/reperfusion (OGD/RP) damage model in SH-SY5Y neuronal cultures. (-)-Phenserine mitigated OGD/PR-induced SH-SY5Y cell death, providing an inverted U-shaped dose-response relationship between concentration and survival. In MCAO challenged rats, (-)-phenserine reduced infarction volume, cell death and improved body asymmetry, a behavioral measure of stoke impact. In both cellular and animal studies, (-)-phenserine elevated brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) levels, and decreased activated-caspase 3, amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP) expression, potentially mediated through the ERK-1/2 signaling pathway. These actions mitigated neuronal apoptosis in the stroke penumbra, and decreased matrix metallopeptidase-9 (MMP-9) expression. In synopsis, (-)-phenserine significantly reduced neuronal damage induced by ischemia/reperfusion injury in a rat model of MCAO and cellular model of OGD/RP, demonstrating that its anti-apoptotic/neuroprotective/neurotrophic cholinergic and non-cholinergic properties warrant further evaluation in conditions of brain injury

Protective effect of dexpanthenol on ischemia-reperfusion-induced renal injury in rats.

PubMed

Altintas, Ramazan; Parlakpinar, Hakan; Beytur, Ali; Vardi, Nigar; Polat, Alaadin; Sagir, Mustafa; Odabas, Gul Pelin

2012-01-01

This experimental study was designed to investigate protective and therapeutic effects of Dexpanthenol (Dxp), an alcoholic analogue of pantothenic acid, on kidney damage induced by ischemia-reperfusion (I/R) in rats. Forty rats were randomly divided into a control group and 4 I/R groups (1 h ischemia followed by 23 h reperfusion). Three I/R groups were treated by Dxp (500 mg/kg, i.p.) at 3 different time points (before ischemia, during ischemia and late reperfusion). The histopathological findings including apoptotic changes, and also tissue malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), blood urea nitrogen (BUN), serum creatinine (Cr) and albumin (Alb) levels were determined. Kidney tissue MDA levels were found to be significantly higher in the I/R group, whereas the values of GPX were lower when compared to the control group. The levels of SOD and CAT did not reach to statistical meaning level in I/R group. Dxp given during ischemia reduced the elevated MDA levels to the nearly control levels and this ameliorating effect was found as parallel to the result of GPX. Serum levels of BUN and Cr were significantly higher in I/R group. Dxp given during ischemia significantly reduced the elevated BUN and Cr levels when compared to I/R group. Renal I/R injury also induced extensive tubular necrosis, glomerular damage and apoptosis in the histological evaluation. Dxp ameliorated these histological damages in different amounts in all treatment groups. In this study the protective effects of Dxp against renal I/R injury has been evaluated for the first time. Copyright © 2012 S. Karger AG, Basel.

Radix Ilicis Pubescentis total flavonoids combined with mobilization of bone marrow stem cells to protect against cerebral ischemia/reperfusion injury

PubMed Central

Miao, Ming-san; Guo, Lin; Li, Rui-qi; Ma, Xiao

2016-01-01

Previous studies have shown that Radix Ilicis Pubescentis total flavonoids have a neuroprotective effect, but it remains unclear whether Radix Ilicis Pubescentis total flavonoids have a synergistic effect with the recombinant human granulocyte colony stimulating factor-mobilized bone marrow stem cell transplantation on cerebral ischemia/reperfusion injury. Rat ischemia models were administered 0.3, 0.15 and 0.075 g/kg Radix Ilicis Pubescentis total flavonoids from 3 days before modeling to 2 days after injury. Results showed that Radix Ilicis Pubescentis total flavonoids could reduce pathological injury in rats with cerebral ischemia/reperfusion injury. The number of Nissl bodies increased, Bax protein expression decreased, Bcl-2 protein expression increased and the number of CD34-positive cells increased. Therefore, Radix Ilicis Pubescentis total flavonoids can improve the bone marrow stem cell mobilization effect, enhance the anti-apoptotic ability of nerve cells, and have a neuroprotective effect on cerebral ischemia/reperfusion injury in rats. PMID:27073381

Poloxamer-188 reduces muscular edema after tourniquet-induced ischemia-reperfusion injury in rats.

PubMed

Walters, Thomas J; Mase, Vincent J; Roe, Janet L; Dubick, Michael A; Christy, Robert J

2011-05-01

Skeletal muscle injury can result in significant edema, which can in turn lead to the development of acute extremity compartment syndrome (CS). Poloxamer-188 (P-188), a multiblock copolymer surfactant, has been shown to decrease edema by sealing damaged membranes in a number of tissues after a variety of injury modalities. The objective is to determine whether the administration of P-188 significantly reduces skeletal muscle edema associated with ischemia/reperfusion injury (I-R). Male Sprague-Dawley rats underwent 180 minutes of tourniquet-induced ischemia. Five minutes before tourniquet release, rats received either a bolus of (1) P-188 (150 mg/kg; P-188 group) or (2) vehicle (Vehicle group) via a jugular catheter (n=10 per group). After 240 minutes reperfusion, both groups received a second bolus of either P-188 (P-188) or vehicle (Vehicle) via a tail vein catheter. Sixteen hours later, rats were killed; muscle weights were determined, infarct size (2,3,5-triphenyltetrazolium chloride method), and blinded histologic analysis (hematoxylin and eosin) were performed on the gastrocnemius and tibialis anterior muscles, as well as indices of antioxidant status. P-188 resulted in significantly less edema (wet weight) and reduced an index of lipid peroxidation compared with Vehicle (p<0.05). Wet:dry weight ratios were less in the P-188 group (indicating less edema). Muscle viability as indicated by 2,3,5-triphenyltetrazolium chloride staining or routine histology did not reveal statistically significant differences between groups. P-188 significantly reduced ischemia-reperfusion-related muscle edema and lipid peroxidation but did not impact muscle viability. Excess edema can lead to acute extremity CS, which is associated with significant morbidity and mortality. P-188 may provide a potential adjunctive treatment for the reduction of CS.

The Effect of Pentoxifylline on bcl-2 Gene Expression Changes in Hippocampus after Ischemia-Reperfusion in Wistar Rats by a Quatitative RT-PCR Method

PubMed Central

Sari, Soyar; Hashemi, Mehrdad; Mahdian, Reza; Parivar, Kazem; Rezayat, Mehdi

2013-01-01

Ischemia-reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. Ischemia-reperfusion brain injury initiates an inflammatory response involving the expression of adhesion molecules and cytokines. Twenty–four male Wistar rats (250-300 g body wt) were used in this study. The animals were divided into four groups of 6 rats each: I: Control group that was subjected to ischemia-reperfusion, II: Ischemia-reperfusion group that was subjected to all surgical procedures, III: Drug group that received pentoxifylline (200, 400 and 600 mg/kg) 60 min before and after ischemia and IV: Vehicle group that received saline. Seventy two h after ischemia-reperfusion, the hippocampus was taken for studying the changes in bcl-2 gene expression. We used quantitative real-time PCR for the detection of bcl-2 gene expression in ischemia and drug groups and then compared them to normal samples. The results showed the gene dosage ratio of 0.66 and 1.5 for ischemia group and the drug groups, respectively. The results also showed the bcl-2 gene expression declined in ischemia group as compared to the drug group. Furthermore, we observed a significant difference in the bcl-2 gene expression between ischemia and drug groups. These findings are consistent with anti-apoptotic properties of bcl-2 gene. Furthermore this method provides a powerful tool for the investigators to study brain ischemia and respond to the treatment drugs with anti-apoptotic agents. PMID:24250655

Adverse remodeling of the electrophysiological response to ischemia-reperfusion in human heart failure is associated with remodeling of metabolic gene expression.

PubMed

Ng, Fu Siong; Holzem, Katherine M; Koppel, Aaron C; Janks, Deborah; Gordon, Fabiana; Wit, Andrew L; Peters, Nicholas S; Efimov, Igor R

2014-10-01

Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia-reperfusion although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute ischemia-reperfusion in heart failure and its potential causes, including the remodeling of metabolic gene expression. We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to ischemia-reperfusion, with greater action potential duration shortening (P<0.001 at 8-minute ischemia; P=0.001 at 12-minute ischemia) and greater conduction slowing during ischemia, delayed recovery of electric excitability after reperfusion (F, 4.8±1.8 versus D, 1.0±0 minutes; P<0.05), and incomplete restoration of action potential duration and conduction velocity early after reperfusion. Expression of 46 metabolic genes was probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%. We demonstrate, for the first time in human hearts, that the electrophysiological response to ischemia-reperfusion in heart failure is accelerated during ischemia with slower recovery after reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes. © 2014 American Heart Association, Inc.

TRIIODOTHYRONINE INCREASES MYOCARDIAL FUNCTION AND PYRUVATE ENTRY INTO THE CITRIC ACID CYCLE AFTER REPERFUSION IN A MODEL OF INFANT CARDIOPULMONARY BYPASS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olson, Aaron; Bouchard, Bertrand; Ning, Xue-Han

We utilized a translational model of infant CPB to test the hypothesis that T3 modulates pyruvate entry into the citric acid cycle (CAC) thereby providing the energy support for improved cardiac function after ischemia-reperfusion. Methods and Results: Neonatal piglets received intracoronary [2-13Carbon(13C)]-pyruvate for 40 minutes (8 mM) during control aerobic conditions (Cont) or immediately after reperfusion (IR) from global hypothermic ischemia. A third group (IR-Tr) received T3 (1.2 ug/kg) during reperfusion. We assessed absolute CAC intermediate levels (aCAC) and flux parameters into the CAC through oxidative pyruvate decarboxylation (PDC ) and anaplerotic carboxylation (PC; ) using 13C-labeled pyruvate and isotopomermore » analysis by gas and liquid chromatography-mass spectrometry and 13C NMR. Neither IR nor IR-Tr modified aCAC. However, compared to IR, T3 (group IR-Tr) increased cardiac power and oxygen consumption after CPB while elevating both PDC and PC (~ four-fold). T3 inhibited IR induced reductions in CAC intermediate molar percent enrichment (MPE) and oxaloacetate(citrate)/malate MPE ratio; an index of aspartate entry into the CAC. Conclusions: T3 markedly enhances PC and PDC thereby providing substrate for elevated cardiac function and work after reperfusion. The increases in pyruvate flux occur with preservation of the CAC intermediate pool. Additionally, T3 inhibition of reductions in CAC intermediate MPEs indicates that T3 reduces the reliance on amino acids (AA) for anaplerosis after reperfusion. Thus, AA should be more available for other functions such as protein synthesis.« less

The Study of Pentoxifylline Drug Effects on Renal Apoptosis and BCL-2 Gene Expression Changes Following Ischemic Reperfusion Injury in Rat

PubMed Central

Hashemi, Mehrdad

2014-01-01

Ischemia Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. In this study, the effect of pentoxyfylline on BCL-2 gene expression changes and cell injury in kidney of rat following Ischemia Reperfusion were evaluated. In this experimental study, 20 male wistar rats with average weight of 250-300 g were selected and then were accidently divided them on two tenth group of control and treatment groups. In the control group, celiotomy was performed by ventral midline incision. The left kidney was isolated, and then both the renal artery and vein were obstructed. After 60 minutes of warm ischemia, vessel obstruction resolved and the right kidney was removed. 72 hours after reperfusion, tissue samples were taken from left kidney for Tunel assay. We used quantitative real time PCR for detection of BCL-2 gene expression in treated groups and then compared them to control samples. In the treatment group, the cell death changes, showed lower level than the control group. The results also showed the BCL-2 gene expression was declined in ischemia group as campared to PNT drug group. The pentoxyfylline might have a role in control of apoptosis result from Ischemia- reperfusion and quantitative real-time PCR can be used as a direct method for detection BCL-2 gene expression in tested samples and normal samples. PMID:24734070

Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model

PubMed Central

2010-01-01

Background Polymorphonuclear neutrophils, stimulated by the activated complement factor C5a, have been implicated in cardiac ischemia/reperfusion injury. ADC-1004 is a competitive C5a receptor antagonist that has been shown to inhibit complement related neutrophil activation. ADC-1004 shields the neutrophils from C5a activation before they enter the reperfused area, which could be a mechanistic advantage compared to previous C5a directed reperfusion therapies. We investigated if treatment with ADC-1004, according to a clinically applicable protocol, would reduce infarct size and microvascular obstruction in a large animal myocardial infarct model. Methods In anesthetized pigs (42-53 kg), a percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 minutes, followed by 4 hours of reperfusion. Twenty minutes after balloon inflation the pigs were randomized to an intravenous bolus administration of ADC-1004 (175 mg, n = 8) or saline (9 mg/ml, n = 8). Area at risk (AAR) was evaluated by ex vivo SPECT. Infarct size and microvascular obstruction were evaluated by ex vivo MRI. The observers were blinded to the treatment at randomization and analysis. Results ADC-1004 treatment reduced infarct size by 21% (ADC-1004: 58.3 ± 3.4 vs control: 74.1 ± 2.9%AAR, p = 0.007). Microvascular obstruction was similar between the groups (ADC-1004: 2.2 ± 1.2 vs control: 5.3 ± 2.5%AAR, p = 0.23). The mean plasma concentration of ADC-1004 was 83 ± 8 nM at sacrifice. There were no significant differences between the groups with respect to heart rate, mean arterial pressure, cardiac output and blood-gas data. Conclusions ADC-1004 treatment reduces myocardial ischemia-reperfusion injury and represents a novel treatment strategy of myocardial infarct with potential clinical applicability. PMID:20875134

A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury.

PubMed

Bopassa, Jean Chrisostome; Eghbali, Mansoureh; Toro, Ligia; Stefani, Enrico

2010-01-01

Several studies have recently demonstrated that G protein-coupled receptor 30 (GPER) can directly bind to estrogen and mediate its action. We investigated the role and the mechanism of estrogen-induced cardioprotection after ischemia-reperfusion using a specific GPER agonist G1. Isolated hearts from male mice were perfused using Langendorff technique with oxygenated (95% O(2) and 5% CO(2)) Krebs Henseleit buffer (control), with G1 (1 microM), and G1 (1 microM) together with extracellular signal-regulated kinase (Erk) inhibitor PD-98059 (5 microM). After 20 min of perfusion, hearts were subjected to 20 min global normothermic (37 degrees C) ischemia followed by 40 min reperfusion. Cardiac function was measured, and myocardial necrosis was evaluated by triphenyltetrazolium chloride staining at the end of the reperfusion. Mitochondria were isolated after 10 min of reperfusion to assess the Ca(2+) load required to induce mitochondria permeability transition pore (mPTP) opening. G1-treated hearts developed better functional recovery with higher rate pressure product (RPP, 6140 +/- 264 vs. 2,640 +/- 334 beats mmHg(-1) min(-1), P < 0.05). The infarct size decreased significantly in G1-treated hearts (21 +/- 2 vs. 46 +/- 3%, P < 0.001), and the Ca(2+) load required to induce mPTP opening increased (2.4 +/- 0.06 vs. 1.6 +/- 0.11 microM/mg mitochondrial protein, P < 0.05) compared with the controls. The protective effect of G1 was abolished in the presence of PD-98059 [RPP: 4,120 +/- 46 beats mmHg(-1) min(-1), infarct size: 53 +/- 2%, and Ca(2+) retention capacity: 1.4 +/- 0.11 microM/mg mitochondrial protein (P < 0.05)]. These results suggest that GPER activation provides a cardioprotective effect after ischemia-reperfusion by inhibiting the mPTP opening, and this effect is mediated by the Erk pathway.

Acute rosiglitazone treatment is cardioprotective against ischemia-reperfusion injury by modulating AMPK, Akt, and JNK signaling in nondiabetic mice.

PubMed

Morrison, Alex; Yan, Xiaoyan; Tong, Chao; Li, Ji

2011-09-01

Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-γ agonist, has been demonstrated to possess cardioprotective properties during ischemia-reperfusion. However, this notion remains controversial as recent evidence has suggested an increased risk in cardiac events associated with long-term use of RGZ in patients with type 2 diabetes. In this study, we tested the hypothesis that acute RGZ treatment is beneficial during I/R by modulating cardioprotective signaling pathways in a nondiabetic mouse model. RGZ (1 μg/g) was injected intravenously via the tail vein 5 min before reperfusion. Myocardial infarction was significantly reduced in mice treated with RGZ compared with vehicle controls (8.7% ± 1.1% vs. 20.2% ± 2.5%, P < 0.05). Moreover, isolated hearts were subjected to 20 min of global, no-flow ischemia in an ex vivo heart perfusion system. Postischemic recovery was significantly improved with RGZ treatment administered at the onset of reperfusion compared with vehicle (P < 0.001). Immunoblot analysis data revealed that the levels of both phospho-AMP-activated protein kinase (Thr(172)) and phospho-Akt (Ser(473)) were significantly upregulated when RGZ was administered 5 min before reperfusion compared with vehicle. On the other hand, inflammatory signaling [phospho-JNK (Thr(183)/Tyr(185))] was significantly downregulated as a result of RGZ treatment compared with vehicle (P < 0.05). Intriguingly, pretreatment with the selective PPAR-γ inhibitor GW-9662 (1 μg/g iv) 10 min before reperfusion significantly attenuated these beneficial effects of RGZ on the ischemic heart. Taken together, acute treatment with RGZ can reduce ischemic injury in a nondiabetic mouse heart via modulation of AMP-activated protein kinase, Akt, and JNK signaling pathways, which is dependent on PPAR-γ activation.

Kcne2 deletion attenuates acute post-ischaemia/reperfusion myocardial infarction

PubMed Central

Hu, Zhaoyang; Crump, Shawn M.; Zhang, Ping; Abbott, Geoffrey W.

2016-01-01

Aims Most cardiac arrhythmia-associated genes encode ion channel subunits and regulatory proteins that are also expressed outside the heart, suggesting that diseases linked to their disruption may be multifactorial. KCNE2 is a ubiquitously expressed potassium channel β subunit associated with cardiac arrhythmia, atherosclerosis, and myocardial infarction (MI) in human populations. Here, we tested the hypothesis that Kcne2 disruption in mice would influence the acute outcome of experimentally induced MI. Methods and results One-year-old male Kcne2+/+ and Kcne2−/− mice were subjected to cardiac ischaemia/reperfusion injury (IRI) by left anterior descending coronary artery ligation. After reperfusion (3 h), infarct size and markers of tissue damage were quantified. Unexpectedly, post-reperfusion, Kcne2−/− mice exhibited 40% lower infarct size, decreased myocardial apoptosis and damage, and more than two-fold lower serum levels of damage markers, lactate dehydrogenase and creatine kinase, than Kcne2+/+ mice. Kcne2 deletion, despite increasing normalized heart weight and prolonging baseline QTc by 70%, helped preserve post-infarct cardiac function (quantified by a Millar catheter), with parameters including left ventricular maximum pressure, max dP/dt (P < 0.01), contractility index, and pressure/time index (P < 0.05) all greater in Kcne2−/− compared with Kcne2+/+ mice. Western blotting indicated two-fold-increased glycogen synthase kinase 3β (GSK-3β) phosphorylation (inactivation) before and after IRI (P < 0.05) in Kcne2−/− mice compared with Kcne2+/+ mice. GSK-3β inhibition by SB216763 mimicked in Kcne2+/+ mice the cardioprotective effects of Kcne2 deletion, but did not further enhance them in Kcne2−/− mice, suggesting that GSK-3β inactivation was a primary cardioprotective mechanism arising from Kcne2 deletion. Conclusions Kcne2 deletion preconditions the heart, attenuating the acute tissue damage caused by an imposed IRI. The findings

L-Arginine Modulates Intestinal Inflammation in Rats Submitted to Mesenteric Ischemia-Reperfusion Injury.

PubMed

Taha, M O; de Oliveira, J V; Dias Borges, M; de Lucca Melo, F; Gualtieri, F G; E Silva Aidar, A L; Pacheco, R L; de Melo Alexandre E Silva, T; Klajner, R K; Iuamoto, L R; Munhoz Torres, L; Morais Mendes de Paula, B J; de Campos, K; Oliveira-Junior, I S; Fagundes, D J

2016-03-01

The goal of this study was to investigate whether exogenous offer of L-arginine (LARG) modulates the gene expression of intestinal dysfunction caused by ischemia and reperfusion. Eighteen Wistar-EPM1 male rats (250-300 g) were anesthetized and subjected to laparotomy. The superior mesenteric vessels were exposed, and the rats were randomized into 3 groups (n = 6): the control group (CG), with no superior mesenteric artery interruption; the ischemia/reperfusion group (IRG), with 60 minutes of ischemia and 120 minutes of reperfusion and saline injections; and the L-arginine group (IRG + LARG), with L-arginine injected in the femoral vein 5 minutes before ischemia, 5 minutes after reperfusion, and after 55 minutes of reperfusion. The total RNA was extracted and purified from samples of the small intestine. The concentration of each total RNA sample was determined by using spectrophotometry. The first-strand complementary DNA (cDNA) was synthesized in equal amounts of cDNA and the Master Mix SYBR Green qPCR Mastermix (SABiosciences, a Qiagen Company, Frederick, Md). Amounts of cDNA and Master Mix SYBR Green qPCR Mastermix were distributed to each well of the polymerase chain reaction microarray plate containing the predispensed gene-specific primer sets for Bax and Bcl2. Each sample was evaluated in triplicate, and the Student t test was applied to validate the homogeneity of each gene expression reaction (P < .05). The gene expression of Bax in IRG (+1.48) was significantly higher than in IRG-LARG (+9.69); the expression of Bcl2L1 in IRG (+1.01) was significantly higher than IRG-LARG (+22.89). The apoptotic cell pathway of 2 protagonists showed that LARG improves the gene expression of anti-apoptotic Bcl2l1 (Bcl2-like 1) more than the pro-apoptotic Bax (Bcl2-associated X protein). Copyright © 2016. Published by Elsevier Inc.

The protective effect of baicalin against renal ischemia-reperfusion injury through inhibition of inflammation and apoptosis

PubMed Central

2014-01-01

Background Renal ischemia-reperfusion injury (IRI) increases the rates of acute kidney failure, delayed graft function, and early mortality after kidney transplantation. The pathophysiology involved includes oxidative stress, mitochondrial dysfunction, and immune-mediated injury. The anti-oxidation, anti-apoptosis, and anti-inflammation properties of baicalin, a flavonoid glycoside isolated from Scutellaria baicalensis, have been verified. This study therefore assessed the effects of baicalin against renal IRI in rats. Methods Baicalin was intraperitoneally injected 30 min before renal ischemia. Serum and kidneys were harvested 24 h after reperfusion. Renal function and histological changes were assessed. Markers of oxidative stress, the Toll-like receptor (TLR)2 and TLR4 signaling pathway, mitochondrial stress, and cell apoptosis were also evaluated. Results Baicalin treatment decreased oxidative stress and histological injury, and improved kidney function, as well as inhibiting proinflammatory responses and tubular apoptosis. Baicalin pretreatment also reduced the expression of TLR2, TLR4, MyD88, p-NF-κB, and p-IκB proteins, as well as decreasing caspase-3 activity and increasing the Bcl-2/Bax ratio. Conclusions Baicalin may attenuate renal ischemia-reperfusion injury by inhibiting proinflammatory responses and mitochondria-mediated apoptosis. These effects are associated with the TLR2/4 signaling pathway and mitochondrial stress. PMID:24417870

The effects of propofol on hippocampal caspase-3 and Bcl-2 expression following forebrain ischemia-reperfusion in rats.

PubMed

Li, Jun; Han, Baoqing; Ma, Xuesong; Qi, Sihua

2010-10-14

Transient cerebral ischemia may result in neuronal apoptosis. During this process, several apoptosis-regulatory genes are induced in apoptotic cells. Among these genes, cysteinyl aspartate-specific protease-3 (caspase-3) and B-cell leukemia-2 (Bcl-2) are the most effective apoptotic regulators because they play a decisive role in the occurrence of apoptosis. Research has shown that propofol, which is an intravenous anesthetic agent, exhibits neuroprotective effects against cerebral ischemia-reperfusion injury, although the neuroprotective mechanism is still unclear. In this study, we examined the effects of propofol in rats after forebrain ischemia-reperfusion. We assessed the expression of hippocampal caspase-3, which acts as an apoptotic activator, and Bcl-2, which acts as an apoptotic suppressor. Forebrain ischemia was induced in hypotensive rats by clamping the bilateral common carotid arteries for 10 min. Propofol was administered via a lateral cerebral ventricle injection using a microsyringe after the induction of ischemia. Neuronal damage was determined by histological examination of brain sections at the level of the dorsal hippocampus. Caspase-3 and Bcl-2 expression in the hippocampus were detected using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. We also used an immunohistochemical method after ischemia-reperfusion. In the hippocampus, caspase-3 and Bcl-2 mRNA were dramatically increased at 24h after forebrain ischemia. Following 6-24h of reperfusion, forebrain ischemia for 10 min induced a gradual increase in the expression of caspase-3 and Bcl-2 protein in the rat hippocampus, which peaked at 24h. In the propofol (1.0mg/kg) intervention group, the hippocampal expression of caspase-3 mRNA decreased significantly in rats 24h after ischemia; Bcl-2 mRNA was increased at the same time point. During the 24-h reperfusion period and after treatment with propofol, the level of caspase-3 protein expression

Cellular mechanisms against ischemia reperfusion injury induced by the use of anesthetic pharmacological agents.

PubMed

Álvarez, P; Tapia, L; Mardones, L A; Pedemonte, J C; Farías, J G; Castillo, R L

2014-07-25

Ischemia-reperfusion (IR) cycle in the myocardium is associated with activation of an injurious cascade, thus leading to new myocardial challenges, which account for up to 50% of infarct size. Some evidence implicates reactive oxygen species (ROS) as a probable cause of myocardial injury in prooxidant clinical settings. Damage occurs during both ischemia and post-ischemic reperfusion in animal and human models. The mechanisms that contribute to this damage include the increase in cellular calcium (Ca(2+)) concentration and induction of ROS sources during reperfusion. Pharmacological preconditioning, which includes pharmacological strategies that counteract the ROS burst and Ca(2+) overload followed to IR cycle in the myocardium, could be effective in limiting injury. Currently widespread evidence supports the use of anesthetics agents as an important cardioprotective strategy that act at various levels such as metabotropic receptors, ion channels or mitochondrial level. Their administration before a prolonged ischemic episode is known as anesthetic preconditioning, whereas when given at the very onset of reperfusion, is termed anesthetic postconditioning. Both types of anesthetic conditioning reduce, albeit not to the same degree, the extent of myocardial injury. This review focuses on cellular and pathophysiological concepts on the myocardial damage induced by IR and how anesthetic pharmacological agents commonly used could attenuate the functional and structural effects induced by oxidative stress in cardiac tissue. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury

PubMed Central

Masuzawa, Akihiro; Black, Kendra M.; Pacak, Christina A.; Ericsson, Maria; Barnett, Reanne J.; Drumm, Ciara; Seth, Pankaj; Bloch, Donald B.; Levitsky, Sidney; Cowan, Douglas B.

2013-01-01

Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 ± 1.7 × 106/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased (P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI-mitochondria (7.9 ± 2.9%) compared with RI-vehicle (34.2 ± 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2–8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high-energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury. PMID:23355340

Endothelin-a receptor antagonist treatment improves the periosteal microcirculation after hindlimb ischemia and reperfusion in the rat.

PubMed

Wolfárd, Antal; Császár, József; Gera, László; Petri, András; Simonka, János Aurél; Balogh, Adáa; Boros, Mihály

2002-12-01

To examine the microcirculatory changes in the rat tibial periosteum after hindlimb ischemia and reperfusion and to evaluate the effects of endothelin-A (ET-A) receptor antagonist therapy in this condition. The healing and functioning of vascularized bone autografts depend mainly on the patency of the microcirculation, and the activation of ET-A receptors may be an important component of the tissue response that occurs during ischemia-reoxygenation injuries. Wistar rats were subjected to 1 hour of hindlimb ischemia and 3 hours of reperfusion. The periosteal microcirculation was visualized by intravital fluorescence microscopy. The leukocyte rolling and adherence in the postcapillary venules and the functional capillary density of the periosteum were determined. Two separate groups were treated with the selective ET-A receptor antagonist BQ 610 or the novel ET-A receptor antagonist ETR-p1/fl peptide at the onset of reperfusion. Reperfusion was accompanied by a significant decrease in functional capillary density and by an increase in the primary and secondary leukocyte-endothelial cell interactions. ET-A receptor inhibition reduced the leukocyte rolling and firm adherence and attenuated the decrease in functional capillary density in both treated groups. ET-1 plays a major role in microvascular dysfunction in the periosteum during reperfusion. The ET-1-ET-A receptor system might be an important target for tissue salvage therapy in transplantation surgery.

Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers

PubMed Central

van Rijn, Rianne; van Leeuwen, Otto B.; Matton, Alix P. M.; Burlage, Laura C.; Wiersema‐Buist, Janneke; van den Heuvel, Marius C.; de Kleine, Ruben H. J.; de Boer, Marieke T.; Gouw, Annette S. H.

2018-01-01

Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia/reperfusion injury (IRI). This study aimed to determine whether DHOPE reduces IRI of the bile ducts in donation after circulatory death (DCD) liver transplantation. In a recently performed phase 1 trial, 10 DCD livers were preserved with DHOPE after static cold storage (SCS; http://www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semiquantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as controls. Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, the degree of stroma necrosis (P = 0.002) and injury of the deep peribiliary glands (PBG; P = 0.02) increased after reperfusion compared with baseline. In contrast, in DHOPE‐preserved livers, the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep PBG (P = 0.04) after reperfusion in the DHOPE group compared with controls. In conclusion, this study suggests that DHOPE reduces IRI of bile ducts after DCD liver transplantation. Liver Transplantation 24 655–664 2018 AASLD. PMID:29369470

Protective effect of L-arginine against necrosis and apoptosis induced by experimental ischemic and reperfusion in rat liver.

PubMed

Chattopadhyay, Pronobesh; Shukla, Gunjan; Wahi, Arun Kumar

2009-01-01

To study the effect of L-arginine on apoptosis and necrosis induced by 1-h ischemia followed by 3-h reperfusion. Adult Wistar rats underwent 60 min of partial liver ischemia followed by 3-h reperfusion. Eighteen Wistar rats were divided into sham-operated control group (I) (n = 6), ischemia and reperfusion (I/R) group (0.9 % saline (5 mL/kg, orally) for 7 days) (II) (n = 6), and L-arginine-treated group (10 mg/kg body weight daily orally for 7 days before inducing ischemia-reperfusion maneuver) (III) (n = 6). Apoptotic and necrotic hepatocytes, nitric oxide levels in hepatocytes, Bcl-2 mRNA, and Bcl-2 protein were measured. Liver injury was assessed by plasma alanine transaminases (ALT), aspartate transaminases (AST), liver histopathology, and electron microscopy. An ischemic and reperfusion hepatocellular injury occurred as was indicated by increased serum ALT, AST, histopathology, and electron microscopy. Apoptosis and necrosis associated marker gene Bcl-2 mRNA and protein expression were decreased in I/R group. Pretreatment with L-arginine significantly decreased serum ALT and AST level and apoptotic and necrotic cells after 1 h ischemia followed by 3 h of reperfusion. Nitric oxide production in hepatocytes was increased twofold by L-arginine treatment when compared with I/R group. Histopathology and transmission electron microscopy (TEM) studies showed markedly diminished hepatocellular injury in L-arginine-pretreated rats during the hepatic I/R. Thus, it may be concluded that L-arginine afforded significant protection from necrosis and apoptosis in I/R injury by upregulated Bcl-2 gene and nitric oxide production.

SOD1 aggregation in astrocytes following ischemia/reperfusion injury: a role of NO-mediated S-nitrosylation of protein disulfide isomerase (PDI).

PubMed

Chen, Xueping; Guan, Teng; Li, Chen; Shang, Huifang; Cui, Liying; Li, Xin-Min; Kong, Jiming

2012-10-12

Ubiquitinated-protein aggregates are implicated in cerebral ischemia/reperfusion injury. The very presence of these ubiquitinated-protein aggregates is abnormal and seems to be disease-related. However, it is not clear what leads to aggregate formation and whether the aggregations represent a reaction to aggregate-mediated neurodegeneration. To study the nitrosative stress-induced protein aggregation in cerebral ischemia/reperfusion injury, we used primary astrocyte cultures as a cell model, and systematically examined their iNOS expression and consequent NO generation following oxygen glucose deprivation and reperfusion. The expression of protein disulfide isomerase (PDI) and copper-zinc superoxide dismutase (SOD1) were also examined, and the biochemical interaction between PDI and SOD1 was determined by immunoprecipitation. In addition, the levels of S-nitrosylated PDI in cultured astrocytes after oxygen glucose deprivation and reperfusion treatment were measured using the biotin-switch assay. The formation of ubiquitinated-protein aggregates was detected by immunoblot and immunofluorescence staining. Our data showed that the up-regulation of iNOS expression after oxygen glucose deprivation and reperfusion treatment led to excessive NO generation. Up-regulation of PDI and SOD1 was also identified in cultured astrocytes following oxygen glucose deprivation and reperfusion, and these two proteins were found to bind to each other. Furthermore, the increased nitrosative stress due to ischemia/reperfusion injury was highly associated with NO-induced S-nitrosylation of PDI, and this S-nitrosylation of PDI was correlated with the formation of ubiquitinated-protein aggregates; the levels of S-nitrosylated PDI increased in parallel with the formation of aggregates. When NO generation was pharmacologically inhibited by iNOS specific inhibitor 1400W, S-nitrosylation of PDI was significantly blocked. In addition, the formation of ubiquitinated-protein aggregates in cultured

Vascular calcification abrogates the nicorandil mediated cardio-protection in ischemia reperfusion injury of rat heart.

PubMed

Ravindran, Sriram; Murali, Jeyashri; Amirthalingam, Sunil Kumar; Gopalakrishnan, Senthilkumar; Kurian, Gino A

2017-02-01

The present study was aimed to determine the efficacy of nicorandil in treating cardiac reperfusion injury with an underlying co-morbidity of vascular calcification (VC). Adenine diet was used to induce VC in Wistar rat and the heart was isolated to induce global ischemia reperfusion (IR) by Langendorff method, with and without the nicorandil (7.5mg/kg) pre-treatment and compared with those fed on normal diet. The adenine-treated rats displayed abnormal ECG changes and altered mitochondrial integrity compared to a normal rat heart. These hearts, when subjected to IR increased the infarct size, cardiac injury (measured by lactate dehydrogenase and creatine kinase activity in the coronary perfusate) and significantly altered the hemodynamics compared to the normal perfused heart. Nicorandil pretreatment in rat fed on normal diet enhanced the hemodynamics significantly (P<0.05) along with a substantial reduction in the mitochondrial dysfunction (measured by high ADP to oxygen consumption ratio, respiratory control ratio, enzyme activities and less swelling behavior) when subjected to IR. However, this cardio-protective effect of nicorandil was absent in rat heart with underlying calcification. Our results suggest that, the protective effect of nicorandil, a known mitochondrial ATP linked K + channel opener, against myocardial reperfusion injury was confined to normal rat heart. Copyright © 2017 Elsevier Inc. All rights reserved.

Microparticles Mediate Hepatic Ischemia-Reperfusion Injury and Are the Targets of Diannexin (ASP8597)

PubMed Central

Wong, Heng Jian; Croft, Kevin; Mori, Trevor; Farrell, Geoffrey C.

2014-01-01

Background & Aims Ischemia–reperfusion injury (IRI) can cause hepatic failure after liver surgery or transplantation. IRI causes oxidative stress, which injures sinusoidal endothelial cells (SECs), leading to recruitment and activation of Kupffer cells, platelets and microcirculatory impairment. We investigated whether injured SECs and other cell types release microparticles during post-ischemic reperfusion, and whether such microparticles have pro-inflammatory, platelet-activating and pro-injurious effects that could contribute to IRI pathogenesis. Methods C57BL6 mice underwent 60 min of partial hepatic ischemia followed by 15 min–24 hrs of reperfusion. We collected blood and liver samples, isolated circulating microparticles, and determined protein and lipid content. To establish mechanism for microparticle production, we subjected murine primary hepatocytes to hypoxia-reoxygenation. Because microparticles express everted phosphatidylserine residues that are the target of annexin V, we analyzed the effects of an annexin V-homodimer (Diannexin or ASP8597) on post-ischemia microparticle production and function. Results Microparticles were detected in the circulation 15–30 min after post-ischemic reperfusion, and contained markers of SECs, platelets, natural killer T cells, and CD8+ cells; 4 hrs later, they contained markers of macrophages. Microparticles contained F2-isoprostanes, indicating oxidative damage to membrane lipids. Injection of mice with TNF-α increased microparticle formation, whereas Diannexin substantially reduced microparticle release and prevented IRI. Hypoxia-re-oxygenation generated microparticles from primary hepatocytes by processes that involved oxidative stress. Exposing cultured hepatocytes to preparations of microparticles isolated from the circulation during IRI caused injury involving mitochondrial membrane permeability transition. Microparticles also activated platelets and induced neutrophil migration in vitro. The inflammatory

Liver grafts from selected older donors do not have significantly more ischaemia reperfusion injury

PubMed Central

Martins, Paulo N; Chang, Sue; Mahadevapa, Basant; Martins, Ann-Britt; Sheiner, Patricia

2011-01-01

Background There is a general concern that aged organs are more susceptible to ischaemia. In the light of recent proposals to change the liver allocation system by expanding regional sharing, it is feared that increased cold ischaemia time of grafts from older donors may reduce graft survival. The aim of this study was to correlate donor age and the patterns of ischaemia reperfusion injury and synthetic function early after liver transplantation. Methods We performed a retrospective study of first transplants using a single-centre electronic database. Patterns of liver injury (based on transaminases and post-reperfusion biopsy), synthetic function (international normalized ratio [INR]), and graft and patient survival in recipients receiving liver grafts from donors aged ≥65 years (group 1, n= 50) were compared with equivalent patterns in a matched cohort of recipients transplanted with grafts from donors aged <65 years (group 2, n= 50). Results There was no significant difference in transaminase levels from day 0 to day 6 after transplantation. When groups 1 and 2 were subdivided into two subgroups based on the duration of graft cold ischaemia time (<8 h and ≥8 h), there was no statistical difference in transaminase levels during the first 7 days. There were two cases (4%) of primary non-function in group 1 and one (2%) in group 2. Initial poor function did not differ significantly between the groups (26% vs. 24%; P= 0.81). In addition, there was no difference in histological changes in post-reperfusion biopsies (21% vs. 34%; P= 0.078) and rate of acute rejection episodes in the first year (30% vs. 32%; P= 0.99). There was no significant difference between groups 1 and 2 in 1-year patient and graft survivals (78% vs. 90% [P= 0.17]; 88% vs. 94% [P= 0.48], respectively). Conclusions Judiciously selected livers from aged donors are not associated with major increased susceptibility to ischaemia reperfusion injury. PMID:21309940

Oxidized phosphatidylcholines are produced in renal ischemia reperfusion injury

PubMed Central

Solati, Zahra; Edel, Andrea L.; Shang, Yue; O, Karmin

2018-01-01

Background The aim of this study was to determine the individual oxidized phosphatidylcholine (OxPC) molecules generated during renal ischemia/ reperfusion (I/R) injury. Methods Kidney ischemia was induced in male Sprague–Dawley rats by clamping the left renal pedicle for 45 min followed by reperfusion for either 6h or 24h. Kidney tissue was subjected to lipid extraction. Phospholipids and OxPC species were identified and quantitated using liquid chromatography coupled to electrospray ionization tandem mass spectrometry using internal standards. Result We identified fifty-five distinct OxPC in rat kidney following I/R injury. These included a variety of fragmented (aldehyde and carboxylic acid containing species) and non-fragmented products. 1-stearoyl-2-linoleoyl-phosphatidylcholine (SLPC-OH), which is a non-fragmented OxPC and 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PAzPC), which is a fragmented OxPC, were the most abundant OxPC species after 6h and 24 h I/R respectively. Total fragmented aldehyde OxPC were significantly higher in 6h and 24h I/R groups compared to sham operated groups (P = 0.03, 0.001 respectively). Moreover, levels of aldehyde OxPC at 24h I/R were significantly greater than those in 6h I/R (P = 0.007). Fragmented carboxylic acid increased significantly in 24h I/R group compared with sham and 6h I/R groups (P = 0.001, 0.001). Moreover, levels of fragmented OxPC were significantly correlated with creatinine levels (r = 0.885, P = 0.001). Among non-fragmented OxPC, only isoprostanes were elevated significantly in 6h I/R group compared with sham group but not in 24h I/R group (P = 0.01). No significant changes were observed in other non-fragmented OxPC including long chain products and terminal furans. Conclusion We have shown for the first time that bioactive OxPC species are produced in renal I/R and their levels increase with increasing time of reperfusion in a kidney model of I/R and correlate with severity of I/R injury. Given the

Multiphoton microscopy can visualize zonal damage and decreased cellular metabolic activity in hepatic ischemia-reperfusion injury in rats

NASA Astrophysics Data System (ADS)

Thorling, Camilla A.; Liu, Xin; Burczynski, Frank J.; Fletcher, Linda M.; Gobe, Glenda C.; Roberts, Michael S.

2011-11-01

Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery. In orthotopic transplantation, the donor liver is exposed to periods of ischemia and when oxygenated blood is reintroduced to the liver, oxidative stress may develop and lead to graft failure. The aim of this project was to investigate whether noninvasive multiphoton and fluorescence lifetime imaging microscopy, without external markers, were useful in detecting early liver damage caused by I/R injury. Localized hepatic ischemia was induced in rats for 1 h followed by 4 h reperfusion. Multiphoton and fluorescence lifetime imaging microscopy was conducted prior to ischemia and up to 4 h of reperfusion and compared to morphological and biochemical assessment of liver damage. Liver function was significantly impaired at 2 and 4 h of reperfusion. Multiphoton microscopy detected liver damage at 1 h of reperfusion, manifested by vacuolated cells and heterogeneous spread of damage over the liver. The damage was mainly localized in the midzonal region of the liver acinus. In addition, fluorescence lifetime imaging showed a decrease in cellular metabolic activity. Multiphoton and fluorescence lifetime imaging microscopy detected evidence of early I/R injury both structurally and functionally. This provides a simple noninvasive technique useful for following progressive liver injury without external markers.

Hydroxyl radicals' production and ECG parameters during ischemia and reperfusion in rat, guinea pig and rabbit isolated heart.

PubMed

Paulova, Hana; Stracina, Tibor; Jarkovsky, Jiri; Novakova, Marie; Taborska, Eva

2013-06-01

Ischemic and reperfusion injury is a serious condition related to numerous biochemical and electrical abnormalities of the myocardium. It has been repeatedly studied in various animal models. In this study, the production of hydroxyl radicals and electrophysiological parameters were compared in three species. Rat, guinea pig and rabbit isolated hearts were perfused according to Langendorff under strictly identical conditions. The heart rate and arrhythmia were monitored during ischemia and reperfusion periods at defined time intervals; the production of hydroxyl radical was determined by HPLC as 2.5-dihydroxybenzoic acid (2.5-DHBA) formed by salicylic acid hydroxylation. Relationship between arrhythmias and production of 2.5-DHBA was studied. The inter-species differences were observed in timing of arrhythmias onset and their severity, and in the production of 2.5-DHBA in both ischemia and reperfusion. The most considerable changes were observed in rats, where arrhythmias appeared early and with highest severity during ischemia on one side and the regular rhythm was restored early and completely during reperfusion. The corresponding changes in the production of 2.5-DHBA were observed. It can be concluded that rat isolated heart is the most suitable model for evaluation of ischemia/reperfusion injury under given experimental conditions.

Repetitive postprandial hyperglycemia increases cardiac ischemia/reperfusion injury: prevention by the alpha-glucosidase inhibitor acarbose.

PubMed

Frantz, Stefan; Calvillo, Laura; Tillmanns, Jochen; Elbing, Inka; Dienesch, Charlotte; Bischoff, Hilmar; Ertl, Georg; Bauersachs, Johann

2005-04-01

Protective effects of the alpha-glucosidase inhibitor acarbose have been reported for various diabetic complications. In the STOP-NIDDM study, even patients without overt diabetes, but with impaired glucose tolerance, had a reduction in cardiovascular events when treated with acarbose. Therefore, we investigated the effect of repetitive postprandial hyperglycemia on the cardiac ischemia/reperfusion injury in vivo. Mice were treated daily by single applications of placebo, sucrose (4 g/kg body weight), or sucrose + acarbose (10 mg/kg body weight) by gavage for 7 days. Acarbose treatment significantly reduced the sucrose-induced increase in plasma glucose concentration. Subsequently, animals underwent 30 min of ischemia by coronary artery ligation and 24 h of reperfusion in vivo. In the sucrose group, ischemia/reperfusion damage was significantly increased (infarct/area at risk, placebo vs. sucrose, 38.8+/-7.5% vs. 62.2+/-4.8%, P<0.05). This was prevented by acarbose treatment (infarct/area at risk 30.7+/-7.2%). While myocardial inflammation was similar in all groups, oxidative stress as indicated by a significant increase in lipid peroxides was enhanced in the sucrose, but not in the sucrose + acarbose group. In summary, repetitive postprandial hyperglycemia increases ischemia/reperfusion damage. This effect can be prevented by treatment with the alpha-glucosidase inhibitor acarbose.

Beneficial effects of enteral nutrition containing with hydrolyzed whey peptide on warm ischemia/reperfusion injury in the rat liver.

PubMed

Hanaoka, Jun; Shimada, Mitsuo; Utsunomiya, Toru; Morine, Yuji; Imura, Satoru; Ikemoto, Tetsuya; Mori, Hiroki; Sugimoto, Koji; Saito, Yu; Yamada, Shinichiro; Asanoma, Michihito

2014-01-01

This study examined the efficacy of enteral nutrition containing hydrolyzed whey peptide (HWP) on warm ischemia/reperfusion (I/R) injury in the rat liver. Male Wistar rats were subjected to 30 min of warm hepatic ischemia followed by immediate p.o. intake of enteral nutrition with WHP (HWP group) or 20% glucose solution (control group) (0.025 mL/g). The animals were killed at 6 or 12 h after reperfusion. The serum aspartate aminotransferase (AST) and alanine aminotransferase alt (ALT) levels were measured. The necrotic areas were assessed histologically. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activation were assessed to evaluate apoptosis. The expressions of hepatic tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nuclear factor (NF)-κB in the liver tissue were assessed by real time reverse transcription polymerase chain reaction. Significant reductions in the serum AST and ALT levels were seen in the HWP group compared with the control group at both 6 and 12 h after reperfusion. The necrotic areas and numbers of TUNEL positive cells were significantly decreased in the HWP group at 6 and 12 h after reperfusion. The caspase-3/7 activities were significantly decreased in HWP group at 6 and 12 h after reperfusion. The mRNA expressions of TNF-α and IL-6 were significantly reduced in the HWP group at 12 h after reperfusion. NF-κB mRNA expression was significantly increased in the HWP group at 6 and 12 h after reperfusion. Enteral nutrition containing HWP ameliorated the hepatic warm I/R injury possibly through the suppression of pro-inflammatory cytokine expressions and the induction of NF-κB in the rat liver. © 2013 The Japan Society of Hepatology.

Does lung ischemia and reperfusion have an impact on coronary flow? A quantitative coronary blood-flow analysis with inflammatory cytokine profile†

PubMed Central

Karapanos, Nikolaos Tsirikos; Wettstein, Peter J.; Li, Zhuo; Huebner, Marianne; Park, Soon J.; Deschamps, Claude; Cassivi, Stephen D.

2012-01-01

OBJECTIVE Ischemia-reperfusion (IR) injury remains a major cause of early morbidity and mortality after lung transplantation with poorly documented extrapulmonary repercussions. To determine the hemodynamic effect due to lung IR injury, we performed a quantitative coronary blood-flow analysis in a swine model of in situ lung ischemia and reperfusion. METHODS In 14 healthy pigs, blood flow was measured in the ascending aorta, left anterior descending (LAD), circumflex (Cx), right coronary artery (RCA), right common carotid artery (RCCA), and left internal mammary artery (LIMA), along with left-and right-ventricular pressures (LVP and RVP), aortic pressure (AoP), and pulmonary artery pressure (PAP). Cardiac Troponin (cTn), interleukin 6 and 10 (IL-6 and IL-10), and tumor necrosis factor A (TNF-A) were measured in coronary sinus blood samples. The experimental (IR) group (n = 10) underwent 60 min of lung ischemia followed by 60 min of reperfusion by clamping and releasing the left pulmonary hilum. Simultaneous measurements of all parameters were made at baseline and during IR. The control group (n = 4) had similar measurements without lung IR. RESULTS In the IR group, total coronary flow (TCF = LAD + Cx + RCA blood-flow) decreased precipitously and significantly from baseline (113 ± 41 ml min”1) during IR (p < 0.05), with the lowest value observed at 60 min of reperfusion (-37.1%, p < 0.003). Baseline cTn (0.08 ± 0.02 ng ml−1) increased during IR and peaked at 45 min of reperfusion (+138%, p < 0.001). Baseline IL-6 (9.2 ± 2.17 pg ml−1) increased during IR and peaked at 60 min of reperfusion (+228%, p < 0.0001). Significant LVP drop at 5 min of ischemia ( p < 0.05) was followed by a slow return to baseline at 45 min of ischemia. A second LVP drop occurred at reperfusion ( p < 0.05) and persisted. Conversely, RVP increased throughout ischemia (p < 0.05) and returned toward baseline during reperfusion. Coronary blood flow and hemodynamic

Protective effect of remote ischemic per-conditioning in the ischemia and reperfusion-induce renal injury in rats.

PubMed

Yamaki, Vitor Nagai; Gonçalves, Thiago Barbosa; Coelho, João Vitor Baia; Pontes, Ruy Victor Simões; Costa, Felipe Lobato da Silva; Brito, Marcus Vinicius Henriques

2012-12-01

To evaluate the protective effect of remote ischemic per-conditioning in ischemia and reperfusion-induced renal injury. Fifteen rats (Rattus norvegicus) were randomized into three groups (n = 5): Group Normality (GN), Control Ischemia and Reperfusion (GIR) and Group remote ischemic per-conditioning (GPER). With the exception of the GN group, all others underwent renal ischemia for 30 minutes. In group GPER we performed the ischemic remote per-conditioning, consisting of three cycles of ischemia and reperfusion applied every five minutes during the ischemic period, to the left hindlimb of the rats by means of a tourniquet. To quantify the lesions we measured serum levels of creatinine and urea, as well as analyzed renal histopathology. The GPER group presented with better levels of urea (83.74 ± 14.58%) and creatinine (0.72 ± 26.14%) when compared to GIR group, approaching the GN group. Histopathologically, the lower levels of medullary congestion and hydropic degeneration were found in group GPER. The remote ischemic per-conditioning had a significant protective effect on renal ischemia and reperfusion.

Ameliorating effects of dexpanthenol in cerebral ischaemia reperfusion induced injury in rat brain.

PubMed

Zakaria, Mohammad Mehdi Hosseinian; Hajipour, Babak; Khodadadi, Ali; Afshari, Fatemeh

2011-09-01

To study the attenuating effect of Dexpanthenol (Dxp) provitamin B5 on neuronal damage after cerebral ischaemia/reperfusion. This was a randomized, controlled experimental study conducted at the Islamic Azad University, Tabriz, Iran, from April to September 2008. Male wistar rats were divided into 4 groups randomly (n=13): 1- sham group, Group 2 :two hours occlusion of middle cerebral artery (MCA) and 24 hours reperfusion. Group 3: two hours occlusion of MCA and 24 hours reperfusion + Dxp (250mg/kg) since 3 days before ischaemia. Group 4: two hours occlusion of MCA and 24 hours reperfusion which had received Dxp (500mg/kg) since 3 days before ischaemia. Glutathione (GSH) and malondialdehyde (MDA) levels were studied in brain tissue and numbers of cornu ammonis (CA1 and CA3) pyramidal neurons were studied with light microscopy. The GSH levels were significantly higher in groups 3 and 4 as compared with group 2. In group 3 and group 4 animals, the MDA levels were significantly lower than in group 2 (P < 0.05). Numbers of CA1 and CA3 neurons were completely normal in appearance in the group 1. The surviving neurons in the CA1 and CA3 subfield were markedly decreased in number, in group 2 (P < 0.05). Our pathologic and biochemical study has proven positive effect of Dxp on protection of cerebral tissue after I/R. The present findings correlate with previous studies on the protective effects of Dxp against cell and tissue injury by I/R.

Interleukin 1 alpha-induced expression of manganous superoxide dismutase reduces myocardial reperfusion injury in the rat.

PubMed

Nogae, C; Makino, N; Hata, T; Nogae, I; Takahashi, S; Suzuki, K; Taniguchi, N; Yanaga, T

1995-10-01

We investigated the effects of pretreatment with interleukin (IL)-1 alpha on the expression of manganous (Mn) superoxide dismutase (SOD) mRNA and reperfusion-induced arrhythmias and the size of myocardial infarct in rats. Male Wistar rats received 10 mg intraperitoneal injections of human recombinant IL-1 alpha. Their hearts were thereafter isolated at 6, 12, 24, 36 h. A Northern analysis showed that Mn-SOD mRNA was mainly expressed in the heart and slightly in kidney, but not in any other organs. The expression of Mn-SOD mRNA peaked at 6 h after the injection of IL-1 alpha. The Mn-SOD protein content was most increased 12 h after injection. In the isolated heart model, the rats were pretreated with IL-1 alpha 24 h earlier and their hearts were perfused by the Langendorff method. After 20 min of ischemia which was induced by a ligation of a coronary artery, reperfusion-induced arrhythmias were observed. There were no significant differences in the incidence of ventricular arrhythmias between the IL-1 alpha pretreated and the untreated hearts. IL-1 alpha pretreatment significantly reduced the mean duration of the ventricular arrhythmias and also delayed the onset of arrhythmias. The effect of IL-1 alpha pretreatment was also investigated in a 30-min model of ischemia followed by a 3-min reperfusion in anesthetized rats. The infarct size expressed as a percentage of the area at risk was significantly reduced in the IL-1 alpha pretreated hearts compared with the untreated hearts. The left ventricular systolic pressure increased significantly in rat hearts pretreated with IL-1 alpha. Our results therefore showed that the pretreatment with IL-1 alpha induced the overexpression of Mn-SOD mRNA in the rat hearts and also suggested that pretreatment with IL-1 alpha 24 h before ischemia reduced the risk of ischemia-reperfusion injury.

Agmatine attenuates intestinal ischemia and reperfusion injury by reducing oxidative stress and inflammatory reaction in rats.

PubMed

Turan, Inci; Ozacmak, Hale Sayan; Ozacmak, V Haktan; Barut, Figen; Araslı, Mehmet

2017-11-15

Oxidative stress and inflammatory response are major factors causing several tissue injuries in intestinal ischemia and reperfusion (I/R). Agmatine has been reported to attenuate I/R injury of various organs. The present study aims to analyze the possible protective effects of agmatine on intestinal I/R injury in rats. Four groups were designed: sham control, agmatine-treated control, I/R control, and agmatine-treated I/R groups. IR injury of small intestine was induced by the occlusion of the superior mesenteric artery for half an hour to be followed by a 3-hour-long reperfusion. Agmatine (10mg/kg) was administered intraperitoneally before reperfusion period. After 180min of reperfusion period, the contractile responses to both carbachol and potassium chloride (KCl) were subsequently examined in an isolated-organ bath. Malondialdehyde (MDA), reduced glutathione (GSH), and the activity of myeloperoxidase (MPO) were measured in intestinal tissue. Plasma cytokine levels were determined. The expression of the intestinal inducible nitric oxide synthase (iNOS) was also assessed by immunohistochemistry. The treatment with agmatine appeared to be significantly effective in reducing the MDA content and MPO activity besides restoring the content of GSH. The treatment also attenuated the histological injury. The increases in the I/R induced expressions of iNOS, IFN-γ, and IL-1α were brought back to the sham control levels by the treatment as well. Our findings indicate that the agmatine pretreatment may ameliorate reperfusion induced injury in small intestine mainly due to reducing inflammatory response and oxidative stress. Copyright © 2017 Elsevier Inc. All rights reserved.

Plasma exosomes protect the myocardium from ischemia-reperfusion injury.

PubMed

Vicencio, Jose M; Yellon, Derek M; Sivaraman, Vivek; Das, Debashish; Boi-Doku, Claire; Arjun, Sapna; Zheng, Ying; Riquelme, Jaime A; Kearney, Jessica; Sharma, Vikram; Multhoff, Gabriele; Hall, Andrew R; Davidson, Sean M

2015-04-21

Exosomes are nanometer-sized vesicles released from cells into the blood, where they can transmit signals throughout the body. Shown to act on the heart, exosomes' composition and the signaling pathways they activate have not been explored. We hypothesized that endogenous plasma exosomes can communicate signals to the heart and provide protection against ischemia and reperfusion injury. This study sought to isolate and characterize exosomes from rats and healthy volunteers, evaluate their cardioprotective actions, and identify the molecular mechanisms involved. The exosome-rich fraction was isolated from the blood of adult rats and human volunteers and was analyzed by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. This was then used in ex vivo, in vivo, and in vitro settings of ischemia-reperfusion, with the protective signaling pathways activated on cardiomyocytes identified using Western blot analyses and chemical inhibitors. Exosomes exhibited the expected size and expressed marker proteins CD63, CD81, and heat shock protein (HSP) 70. The exosome-rich fraction was powerfully cardioprotective in all tested models of cardiac ischemia-reperfusion injury. We identified a pro-survival signaling pathway activated in cardiomyocytes involving toll-like receptor (TLR) 4 and various kinases, leading to activation of the cardioprotective HSP27. Cardioprotection was prevented by a neutralizing antibody against a conserved HSP70 epitope expressed on the exosome surface and by blocking TLR4 in cardiomyocytes, identifying the HSP70/TLR4 communication axis as a critical component in exosome-mediated cardioprotection. Exosomes deliver endogenous protective signals to the myocardium by a pathway involving TLR4 and classic cardioprotective HSPs. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Blockade of Central Angiotensin II AT1 Receptor Protects the Brain from Ischemia/Reperfusion Injury in Normotensive Rats

PubMed Central

Panahpour, Hamdolah; Nekooeian, Ali Akbar; Dehghani, Gholam Abbas

2014-01-01

Background: Stroke is the third leading cause of invalidism and death in industrialized countries. There are conflicting reports about the effects of Angiotensin II on ischemia-reperfusion brain injuries and most data have come from chronic hypertensive rats. In this study, hypotensive and non-hypotensive doses of candesartan were used to investigate the effects of angiotensin II AT1 receptor blockade by transient focal cerebral ischemia in normotensive rats. Methods: In this experimental study, 48 male Sprague-Dawley rats were randomly divided into four groups (n=12). Sham group, the control ischemic group, and two ischemic groups received candesartan at doses of 0.1 or 0.5 mg/kg at one hour before ischemia. Transient focal cerebral ischemia was induced by 60 minutes occlusion of the middle cerebral artery, followed by 24 h reperfusion. The neurological deficit score was evaluated at the end of the reperfusion period. The total cortical and striatal infarct volumes were determined using triphenyltetrazolium chloride staining technique. Tissue swelling was calculated for the investigation of ischemic brain edema formation. Results: In comparison with the control ischemic group, AT1 receptor blockade with both doses of candesartan (0.1 or 0.5 mg/kg) significantly improved neurological deficit and lowered cortical and striatal infarct sizes. In addition, pretreatment with candesartan significantly reduced ischemia induced tissue swelling. Conclusion: Angiotensin II by stimulating AT1 receptors, participates in ischemia-reperfusion injuries and edema formation. AT1 receptor blockade with candesartan decreased ischemic brain injury and edema and improved neurological outcome. PMID:25429176

[Effect of curcumine on the nuclear pathway of JNK during hippocampal ischemia/reperfusion injury in SHR].

PubMed

Ye, Ke-Ping; Chen, Chun-Ru; Zheng, Jin-Wei; Cao, Hong; Ji, Bin; Zhou, Rui; Meng, Zhi-Yan; Li, Jun; Lian, Qing-Quan

2010-11-01

To investigate the diversify of the nuclear pathway of c-Jun NH2-terminal kinases (JNK) during transient brain ischemia/reperfusion injury in hippocampal neuron apoptosis in spontaneously hypertensive rats (SHR) and to test whether the neuroprotection of curcumine on transient brain ischemia/reperfusion injury in SHR is related to the nuclear pathway of JNK. Male Wistar-Kyoto (WKY) rats and SHR were randomly divided into five groups (n = 6): WKY sham group (W-Sham), WKY ischemia/reperfusion group (W-I/ R), SHR sham group (S-Sham), SHR ischemia/reperfusion group (S-I/R) and SHR curcumine (a chinese traditional medicine)100 mg/kg treatment group (S-Cur), which were sacrificed at 2 h, 6 h, 24 h, 3 d and 7 d after reperfusion. Global brain ischemic model was established by 4-VO method. The TdT-mediated dUTP nick end labeling (TUNEL) method was used to detect the neuron apoptosis in hippocampal CA1 region. The immunohistochemical method was applied to investigate the expressions of c-jun and c-fos in hippocampal CA1 region. The expressions of apoptosis and c-jun and c-fos in CA1 region in S-Sham group, W-I/R group and S-I/R group were more than those in W-Sham group (P < 0.05), were significantly increased in S-I/R group than those in W-I/R group (P < 0.05), and were significantly decreased in S-Cur group than those in S-I/R group (P < 0.05). Neuronal apoptosis and the expressions of c-jun and c-fos are more in SHR hippocampal. Global brain ischemia/reperfusion injury induces more expressions of apoptosis in hippocampal neuron in SHR, and the more expressions of c-jun and c-fos may participate in that process. The neuroprotection of curcumine in SHR is related to c-jun and c-fos.

Protectant activity of defibrotide in cardioplegia followed by ischemia/reperfusion injury in the isolated rat heart.

PubMed

Rossoni, G; Pompilio, G; Biglioli, P; Alamanni, F; Tartara, P; Rona, P; Porqueddu, M; Berti, F

1999-01-01

Previous studies have shown that defibrotide, a polydeoxyribonucleotide obtained by depolymerization of DNA from porcine tissues, has important protective effects on myocardial ischemia, which may be associated with a prostacyclin-related mechanism. The purpose of this study was to investigate the direct effects of defibrotide (given in cardioplegia or after ischemia) on a model of rat heart recovery after cardioplegia followed by ischemia/reperfusion injury. Isolated rat hearts, undergoing 5 minutes of warm cardioplegic arrest followed by 20 minutes of global ischemia and 30 minutes of reperfusion, were studied using the modified Langendorff model. The cardioplegia consisted of St. Thomas' Hospital solution augmented with defibrotide (50, 100, and 200 microg/mL) or without defibrotide (controls). Left ventricular mechanical function and the levels of creatine kinase, lactate dehydrogenase, and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha; the stable metabolite of prostacyclin) were measured during preischemic and reperfusion periods. After global ischemia, hearts receiving defibrotide in the cardioplegic solution (n = 8) manifested in a concentration-dependent fashion lower left ventricular end-diastolic pressure (p < 0.001), higher left ventricular developed pressure (p < 0.01), and lower coronary perfusion pressure (p < 0.001) compared to the control group. After reperfusion, hearts receiving defibrotide in the cardioplegic solution also had, in a dose-dependent way, lower levels of creatine-kinase (p < 0.01), lactate dehydrogenase (p < 0.001), and higher levels of 6-keto-PGF1alpha (p < 0.001) compared to the control group. Furthermore, when defibrotide was given alone to the hearts at the beginning of reperfusion (n = 7), the recovery of postischemic left ventricular function was inferior (p < 0.05) to that obtained when defibrotide was given in cardioplegia. Defibrotide confers to conventional crystalloid cardioplegia a potent concentration

Mechanical assistance by intra-aortic balloon pump counterpulsation during reperfusion increases coronary blood flow and mitigates the no-reflow phenomenon: an experimental study.

PubMed

Pierrakos, Charalampos N; Bonios, Michael J; Drakos, Stavros G; Charitos, Efstratios I; Tsolakis, Elias J; Ntalianis, Argirios; Nanas, Serafim N; Charitos, Christos E; Nanas, John N; Terrovitis, John V

2011-09-01

The effects of the intra-aortic balloon pump (IABP) counterpulsation on the extent of myocardial infarction (MI), the no-reflow phenomenon (NRP), and coronary blood flow (CBF) during reperfusion in an ischemia-reperfusion experimental model have not been clarified. Eleven pigs underwent occlusion of the mid left anterior descending coronary artery for 1 h, followed by reperfusion for 2 h. CBF, distal to the occlusion site, was measured. In six experiments, IABP support began 10 min before, and continued throughout reperfusion (IABP Group). Five pigs without IABP support served as controls. At the end of each experiment, the myocardial area at risk (MAR) of infarction and the extent of MI and NRP were measured. Hemodynamic measurements at baseline and during coronary occlusion were similar in both groups. During reperfusion, systolic aortic blood pressure was significantly lower in the IABP Group than in controls. In the IABP Group, CBF reached a peak at 5 min of reperfusion, gradually decreased, but remained higher than at baseline, and significantly higher than in controls throughout the 2 h of reperfusion. In controls, CBF increased significantly above baseline immediately after the onset of reperfusion, then returned to baseline within 90 min. The extent of NRP (37 ± 25% vs. 68 ± 17%, P = 0.047) and MI (39 ± 23% vs. 67 ± 13%, P = 0.036), both expressed as percentage of MAR, was significantly less in the IABP group than in controls. After prolonged myocardial ischemia, IABP assistance started just 10 min before and throughout reperfusion increased CBF and limited infarct size and extent of NRP. © 2011, Copyright the Authors. Artificial Organs © 2011, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Expression of HSP 70 and its mRNAS during ischemia-reperfusion in the rat bladder.

PubMed

Saito, Motoaki; Tominaga, Lika; Nanba, Eiji; Kinoshita, Yukako; Housi, Daisuke; Miyagawa, Ikuo; Satoh, Keisuke

2004-08-27

HSP 70 is an important protein that repairs damaged tissue after injury. In the present study, we investigated the expression of HSP 70 and its mRNAs during ischemia-reperfusion in the rat bladder. Rat abdominal aorta was clamped with a small clip to induce ischemia-reperfusion injury in the bladder dome. Male Wistar rats, 8 weeks old, were divided into six groups: controls, 30-min ischemia, 30-min ischemia and 30-, 60-minute, 1- and 7-day reperfusion, groups A, B, C, D, E, and F, respectively. In functional studies, contractile responses to carbachol were measured in these groups. The expression of HSP 70-1/2 mRNAs was quantified using a real-time PCR method, and that of HSP 70 proteins was measured using ELISA in the bladders. In the functional study, Emax values of carbachol to bladders in the A, B, C, D, E and F groups were 9.3 +/- 1.3, 7.9 +/- 1.7, 4.3 +/- 0.8, 4.2 +/- 0.7, 4.5 +/- 0.6, and 8.1 +/- 1.2 g/mm2, respectively. In the control group, the expression of HSP 70-1/2 mRNA was detected, and the expression of HSP 70-1 mRNAs was significantly higher than that of HSP 70-2 mRNAs in each group. The expression of HSP 70-1 mRNA increased in groups B and C, but decreased in groups D, E, and F. The expression of HSP 70-2 mRNA in group C was significantly higher than that of groups A, D, E, and F. The expression of HSP 70-1/2 mRNAs after 1 day or 1 week of reperfusion was similar to control levels. The expression of HSP 70 proteins was increased shortly after the expression of their mRNAs. The expression of HSP 70 after 1 day or 1 week of reperfusion was almost identical to control levels. Our data indicate that contractile responses of the bladder were decreased by ischemia reperfusion, and that expression of HSP 70 and its mRNAs appeared to increase after a short period of the insult.

Concomitant Phosphodiesterase 5 Inhibition Enhances Myocardial Protection by Inhaled Nitric Oxide in Ischemia-Reperfusion Injury.

PubMed

Lux, Arpad; Pokreisz, Peter; Swinnen, Melissa; Caluwe, Ellen; Gillijns, Hilde; Szelid, Zsolt; Merkely, Bela; Janssens, Stefan P

2016-02-01

Enhanced cyclic guanosine monophosphate (cGMP) signaling may attenuate myocardial ischemia-reperfusion injury (I/R) and improve left ventricular (LV) functional recovery after myocardial infarction (MI). We investigated the cardioprotection afforded by inhaled NO (iNO), the phosphodiesterase 5 (PDE5)-specific inhibitor tadalafil (TAD), or their combination (iNO+TAD) in C57Bl6J mice subjected to 6-minute left anterior descending artery ligation followed by reperfusion. We measured plasma and cardiac concentrations of cGMP during early reperfusion, quantified myocardial necrosis and inflammation by serial troponin-I (TnI) and myeloperoxidase-positive cell infiltration at day 3, and evaluated LV function and remodeling after 4 weeks using echocardiography and pressure-conductance catheterization. Administration of iNO, TAD, or both during I/R was safe and hemodynamically well tolerated. Compared with untreated mice (CON), only iNO+TAD increased plasma and cardiac-cGMP levels during early reperfusion (80 ± 12 versus 36 ± 6 pmol/ml and 0.15 ± 0.02 versus 0.05 ± 0.01 pmol/mg protein, P < 0.05 for both). Moreover, iNO+TAD reduced TnI at 4 hours to a greater extent (P < 0.001 versus CON) than either alone (P < 0.05 versus CON) and was associated with significantly less myocardial inflammatory cell infiltration at day 3. After 4 weeks and compared with CON, iNO+TAD was associated with increased fractional shortening (43 ± 1 versus 33 ± 2%, P < 0.01), larger stroke volumes (14.9 ± 1.2 versus 10.2 ± 0.9 μl, P < 0.05), enhanced septal and posterior wall thickening (P < 0.05 and P < 0.001, respectively), and attenuated LV dilatation (P < 0.001), whereas iNO or TAD alone conferred less benefit. Thus, iNO+TAD has superior efficacy to limit early reperfusion injury and attenuate adverse LV remodeling. Combination of inhaled NO with a long-acting PDE5 inhibitor may represent a promising strategy to reduce ischemic damage following reperfusion and better preserve LV

Selenium effect on ischemia-reperfusion injury of gastrocnemius muscle in adult rats.

PubMed

Gholami, Mohammadreza; Zendedel, Abolfazl; Khanipour khayat, Zahra; Ghanad, Kourosh; Nazari, Afshin; Pirhadi, Atieh

2015-04-01

Selenium is a trace element that has antioxidant and neuroprotective effects. The aim of this study is to investigate the effects of selenium in reducing ischemia-reperfusion injury of the gastrocnemius muscle. In this experimental study, 80 adult male Wistar rats weighing 250-300 g were divided into ten groups (N = 8 per group). Group 1 is control group (without ischemia-reperfusion). Group 2 received 0.2 mg/kg selenium. Group 3 received ischemia + 3 d reperfusion + 0.2 mg/kg selenium, group 4 received ischemia + 3 d reperfusion + 0.2 mg/kg placebo, group 5 received ischemia + 7 d reperfusion + 0.2 mg/kg selenium, group 6 received ischemia + 7 d reperfusion + 0.2 mg/kg placebo, group 7 received ischemia + 14 d reperfusion + 0.2 mg/kg selenium, group 8 received ischemia + 14 d reperfusion + 0.2 mg/kg placebo, group 9 received ischemia + 28 d reperfusion + 0.2 mg/kg selenium and group 10 received ischemia + 3 d reperfusion + 0.2 mg/kg placebo. External iliac artery blocked for 3 h. After reperfusion, rats killed and gastrocnemius muscle removed, fixed, and tissue processing performed. Samples stained with hematoxylin-eosin for edema evaluation, toluidine blue for mast cell infiltration evaluation and immunohistochemistry for detection TNF-alpha and NF-kappa B proteins. Comparison of mast cell infiltration, edema of the interstitial fluid on the tissue, expression of TNF-alpha protein, and expression of NF-kappa B protein in the groups that received selenium with corresponding placebo group showed that selenium can reduce edema, mast cell infiltration, and TNF-alpha expression and inactivated NF-kappa B. The use of selenium simultaneously with creating ischemia can reduce ischemia-reperfusion injury of the gastrocnemius muscle.

High-molecular-weight polyethylene glycol inhibits myocardial ischemia-reperfusion injury in vivo.

PubMed

Xu, Xianyao; Philip, Jennifer L; Razzaque, Md Abdur; Lloyd, James W; Muller, Charlie M; Akhter, Shahab A

2015-02-01

Cardiac ischemia-reperfusion (I-R) injury remains a significant problem as there are no therapies available to minimize the cell death that can lead to impaired function and heart failure. We have shown that high-molecular-weight polyethylene glycol (PEG) (15-20 kD) can protect cardiac myocytes in vitro from hypoxia-reoxygenation injury. In this study, we investigated the potential protective effects of PEG in vivo. Adult rats underwent left anterior descending artery occlusion for 60 minutes followed by 48 hours or 4 weeks of reperfusion. One milliliter of 10% PEG solution or phosphate-buffered saline (PBS) control (n = 10 per group) was administered intravenously (IV) immediately before reperfusion. Fluorescein-labeled PEG was robustly visualized in the myocardium 1 hour after IV delivery. The PEG group had significant recovery of left ventricular ejection fraction at 4 weeks versus a 25% decline in the PBS group (P < .01). There was 50% less LV fibrosis in the PEG group versus PBS with smaller peri-infarct and remote territory fibrosis (P < .01). Cell survival signaling was upregulated in the PEG group with increased Akt (3-fold, P < .01) and ERK (4-fold, P < .05) phosphorylation compared to PBS controls at 48 hours. PEG also inhibited apoptosis as measured by TUNEL-positive nuclei (56% decrease, P < .02) and caspase 3 activity (55% decrease, P < .05). High-molecular-weight PEG appears to have a significant protective effect from I-R injury in the heart when administered IV immediately before reperfusion. This may have important clinical translation in the setting of acute coronary revascularization and myocardial protection in cardiac surgery. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers.

PubMed

Wiggers, Jimme K; van Golen, Rowan F; Verheij, Joanne; Dekker, Annemiek M; van Gulik, Thomas M; Heger, Michal

2017-04-11

Extrahepatic cholestasis sensitizes the liver to ischemia/reperfusion (I/R) injury during surgery for perihilar cholangiocarcinoma. It is associated with pre-existent sterile inflammation, microvascular perfusion defects, and impaired energy status. Statins have been shown to protect against I/R injury in normal and steatotic mouse livers. Therefore, the hepatoprotective properties of atorvastatin were evaluated in a rat model of cholestatic I/R injury. Male Wistar rats were subjected to 70% hepatic ischemia (during 30 min) at 7 days after bile duct ligation. Rats were randomized to atorvastatin treatment or vehicle-control in three test arms: (1) oral treatment with 5 mg/kg during 7 days after bile duct ligation; (2) intravenous treatment with 2.5, 5, or 7.5 mg/kg at 24 h before ischemia; and (3) intravenous treatment with 5 mg/kg at 30 min before ischemia. Hepatocellular damage was assessed by plasma alanine aminotransferase (ALT) and histological necrosis. I/R induced severe hepatocellular injury in the cholestatic rat livers (~10-fold increase in ALT at 6 h after I/R and ~30% necrotic areas at 24 h after I/R). Both oral and intravenous atorvastatin treatment decreased ALT levels before ischemia. Intravenous atorvastatin treatment at 5 mg/kg at 24 h before ischemia was the only regimen that reduced ALT levels at 6 h after reperfusion, but not at 24 h after reperfusion. None of the tested regimens were able to reduce histological necrosis at 24 h after reperfusion. Pre-treatment with atorvastatin did not protect cholestatic livers from hepatocellular damage after I/R. Clinical studies investigating the role of statins in the protection against hepatic I/R injury should not include cholestatic patients with perihilar cholangiocarcinoma. These patients require (pharmacological) interventions that specifically target the cholestasis-associated hepatopathology.

Ultraearly assessed reperfusion status after middle cerebral artery recanalization predicting clinical outcome.

PubMed

Gölitz, P; Muehlen, I; Gerner, S T; Knossalla, F; Doerfler, A

2018-06-01

Mechanical thrombectomy has high evidence in stroke therapy; however, successful recanalization guarantees not a favorable clinical outcome. We aimed to quantitatively assess the reperfusion status ultraearly after successful middle cerebral artery (MCA) recanalization to identify flow parameters that potentially allow predicting clinical outcome. Sixty-seven stroke patients with acute MCA occlusion, undergoing recanalization, were enrolled. Using parametric color coding, a post-processing algorithm, pre-, and post-interventional digital subtraction angiography series were evaluated concerning the following parameters: pre- and post-procedural cortical relative time to peak (rTTP) of MCA territory, reperfusion time, and index. Functional long-term outcome was assessed by the 90-day modified Rankin Scale score (mRS; favorable: 0-2). Cortical rTTP was significantly shorter before (3.33 ± 1.36 seconds; P = .03) and after intervention (2.05 ± 0.70 seconds; P = .003) in patients with favorable clinical outcome. Additionally, age (P = .005) and initial National Institutes of Health Stroke Scale score (P = .02) were significantly different between the patients, whereas reperfusion index and time as well as initially estimated infarct size were not. In multivariate analysis, only post-procedural rTTP (P = .005) was independently associated with favorable clinical outcome. 2.29 seconds for post-procedural rTTP might be a threshold to predict favorable clinical outcome. Ultraearly quantitative assessment of reperfusion status after successful MCA recanalization reveals post-procedural cortical rTTP as possible independent prognostic value in predicting favorable clinical outcome, even determining a threshold value might be possible. In consequence, focusing stroke therapy on microcirculatory patency could be valuable to improve outcome. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Single-Center Experience Using the 3MAX Reperfusion Catheter for the Treatment of Acute Ischemic Stroke with Distal Arterial Occlusions.

PubMed

Premat, Kévin; Bartolini, Bruno; Baronnet-Chauvet, Flore; Shotar, Eimad; Degos, Vincent; Muresan, Paul; Di Maria, Federico; Gabrieli, Joseph; Rosso, Charlotte; Pistocchi, Silvia; Chiras, Jacques; Sourour, Nader; Alamowitch, Sonia; Samson, Yves; Clarençon, Frédéric

2017-05-15

Most recent guidelines recommend the use of stent retriever devices in endovascular treatment of acute ischemic stroke with large vessel occlusion (LVO). Recently published data reported convincing results with thromboaspiration devices such as the Penumbra System (Penumbra, Alameda, CA, USA) combined with supple reperfusion catheters by using the ADAPT (A Direct Aspiration First-Pass Thrombectomy) technique. The aim of this study was to report our initial experience with the 3MAX (3.8 F) reperfusion catheter for the recanalization of distal intracranial arteries. From August 2015 to December 2016, 32 consecutive patients (16 females, 50%; mean age = 67.4 ± 18.7 years, range: 22-91) for 38 distal occlusions underwent mechanical thrombectomy (MT) by thromboaspiration using the 3MAX. Median NIHSS score at admission was 14 (IQR: 9-19). Distal occlusions were distributed as follows: M2 (n: 23), M3 (n: 6), P1 (n: 3), P2 (n: 2), P3 (n: 2), A3 segment (n: 1) and superior cerebellar artery (n: 1). In 1/38 (2.6%) target artery, the 3MAX could not be navigated. Of the 37 (59.5%) remaining arteries, 22 were successfully reperfused (TICI 2b/3) after ADAPT with the 3MAX alone. Additional stent retriever thrombectomy allowed a 76.3% final reperfusion rate. Good functional outcome (mRS ≤2) was obtained in 45.5% of patients at 3 months. Three (9.4%) 3MAX-related complications occurred: 2 emboli to new territory (ENT) and one vascular perforation. The 3MAX is well-navigable in distal arteries making it useful as a frontline technique. However, the reperfusion rate with the 3MAX catheter alone seems lower than the ones reported with stent retrievers for such distal occlusions.

Protective effects of Tribulus terrestris L extract against acute kidney injury induced by reperfusion injury in rats.

PubMed

Najafi, Houshang; Firouzifar, Mohammad Reza; Shafaat, Omid; Changizi Ashtiyani, Saeed; Hosseini, Nasser

2014-07-01

This study aimed to investigate the protective effect of aerial parts of the Tribulus terrestris L extract on acute kidney injury (AKI) induced by ischemia for 30 minutes and reperfusion for 24 hours in rats. Ten male Sprague-Dawley rats in the AKI and 10 in the Tribulus terrestris groups received the extract solvent and extract of the plant (11 mg/kg), respectively, for 13 days (oral administration). On day 14, ischemia for 30 minutes and reperfusion for 24 hours were induced on the rats. In the last 6 hours of the reperfusion period (24 hours), urine samples were collected in metabolic cages. At the end of this period, blood samples were also taken to determine plasma urea nitrogen, creatinine, and electrolyte concentrations. The kidney tissues were collected for measuring the level of oxidative stress and histological studies. They were compared with the sham operation group and a control group with normal diet and no operation. In the Tribulus terrestris group, the increase in plasma creatinine and urea nitrogen concentrations was significantly less following reperfusion, and their values reached the same level as that in the sham group. Creatinine clearance and urine osmolarity in the Tribulus terrestris group was higher in comparison with the AKI group, whereas sodium absolute excretion, fractional excretion of potassium, oxidative stress, and cellular damages were less. Oral administration of Tribulus terrestris extract for 2 weeks can decrease kidney functional disturbance, oxidative stress, and cellular damages following reperfusion injury in rats.

Delivery of Hydrogen Sulfide by Ultrasound Targeted Microbubble Destruction Attenuates Myocardial Ischemia-reperfusion Injury

PubMed Central

Chen, Gangbin; Yang, Li; Zhong, Lintao; Kutty, Shelby; Wang, Yuegang; Cui, Kai; Xiu, Jiancheng; Cao, Shiping; Huang, Qiaobing; Liao, Wangjun; Liao, Yulin; Wu, Juefei; Zhang, Wenzhu; Bin, Jianping

2016-01-01

Hydrogen sulfide (H2S) is an attractive agent for myocardial ischemia-reperfusion injury, however, systemic delivery of H2S may cause unwanted side effects. Ultrasound targeted microbubble destruction has become a promising tool for organ specific delivery of bioactive substance. We hypothesized that delivery of H2S by ultrasound targeted microbubble destruction attenuates myocardial ischemia-reperfusion injury and could avoid unwanted side effects. We prepared microbubbles carrying hydrogen sulfide (hs-MB) with different H2S/C3F8 ratios (4/0, 3/1, 2/2, 1/3, 0/4) and determined the optimal ratio. Release of H2S triggered by ultrasound was investigated. The cardioprotective effect of ultrasound targeted hs-MB destruction was investigated in a rodent model of myocardial ischemia-reperfusion injury. The H2S/C3F8 ratio of 2/2 was found to be an optimal ratio to prepare stable hs-MB with higher H2S loading capability. Ultrasound targeted hs-MB destruction triggered H2S release and increased the concentration of H2S in the myocardium and lung. Ultrasound targeted hs-MB destruction limited myocardial infarct size, preserved left ventricular function and had no influence on haemodynamics and respiratory. This cardioprotective effect was associated with alleviation of apoptosis and oxidative stress. Delivery of H2S to the myocardium by ultrasound targeted hs-MB destruction attenuates myocardial ischemia-reperfusion injury and may avoid unwanted side effects. PMID:27469291

Oxidative stress gene expression profile in inbred mouse after ischemia/reperfusion small bowel injury.

PubMed

Bertoletto, Paulo Roberto; Ikejiri, Adauto Tsutomu; Somaio Neto, Frederico; Chaves, José Carlos; Teruya, Roberto; Bertoletto, Eduardo Rodrigues; Taha, Murched Omar; Fagundes, Djalma José

2012-11-01

To determine the profile of gene expressions associated with oxidative stress and thereby contribute to establish parameters about the role of enzyme clusters related to the ischemia/reperfusion intestinal injury. Twelve male inbred mice (C57BL/6) were randomly assigned: Control Group (CG) submitted to anesthesia, laparotomy and observed by 120 min; Ischemia/reperfusion Group (IRG) submitted to anesthesia, laparotomy, 60 min of small bowel ischemia and 60 min of reperfusion. A pool of six samples was submitted to the qPCR-RT protocol (six clusters) for mouse oxidative stress and antioxidant defense pathways. On the 84 genes investigated, 64 (76.2%) had statistic significant expression and 20 (23.8%) showed no statistical difference to the control group. From these 64 significantly expressed genes, 60 (93.7%) were up-regulated and 04 (6.3%) were down-regulated. From the group with no statistical significantly expression, 12 genes were up-regulated and 8 genes were down-regulated. Surprisingly, 37 (44.04%) showed a higher than threefold up-regulation and then arbitrarily the values was considered as a very significant. Thus, 37 genes (44.04%) were expressed very significantly up-regulated. The remained 47 (55.9%) genes were up-regulated less than three folds (35 genes - 41.6%) or down-regulated less than three folds (12 genes - 14.3%). The intestinal ischemia and reperfusion promote a global hyper-expression profile of six different clusters genes related to antioxidant defense and oxidative stress.