Mitigation Of Ischemia-reperfusion Injury Research Articles

Nanotechnology-based Strategies for Molecular Imaging, Diagnosis, and Therapy of Organ Transplantation.

Organ transplantation is the preferred paradigm for patients with end-stage organ failures. Despite unprecedented successes, complications such as immune rejection, ischemia-reperfusion injury, and graft dysfunction remain significant barriers to long-term recipient survival after transplantation. Conventional immunosuppressive drugs have limited efficacy because of significant drug toxicities, high systemic immune burden, and emergence of transplant infectious disease, leading to poor quality of life for patients. Nanoparticle-based drug delivery has emerged as a promising medical technology and offers several advantages by enhancing the delivery of drug payloads to their target sites, reducing systemic toxicity, and facilitating patient compliance over free drug administration. In addition, nanotechnology-based imaging approaches provide exciting diagnostic methods for monitoring molecular and cellular changes in transplanted organs, visualizing immune responses, and assessing the severity of rejection. These noninvasive technologies are expected to help enhance the posttransplantation patient survival through real time and early diagnosis of disease progression. Here, we present a comprehensive review of nanotechnology-assisted strategies in various aspects of organ transplantation, including organ protection before transplantation, mitigation of ischemia-reperfusion injury, counteraction of immune rejection, early detection of organ dysfunction posttransplantation, and molecular imaging and diagnosis of immune rejection.

Discussion to: Mitsugumin 53 mitigation of ischemia-reperfusion injury in a mouse model

Discussion to: Mitsugumin 53 mitigation of ischemia-reperfusion injury in a mouse model

Role of curcumin in ischemia and reperfusion injury.

Ischemia-reperfusion injury (IRI) is an inevitable pathological process after organic transplantations. Although traditional treatments restore the blood supply of ischemic organs, the damage caused by IRI is always ignored. Therefore, the ideal and effective therapeutic strategy to mitigate IRI is warrented. Curcumin is a type of polyphenols, processing such properties as anti-oxidative stress, anti-inflammation and anti-apoptosis. However, although many researches have been confirmed that curcumin can exert great effects on the mitigation of IRI, there are still some controversies about its underlying mechanisms among these researches. Thus, this review is to summarize the protective role of curcumin against IRI as well as the controversies of current researches, so as to clarify its underlying mechanisms clearly and provide clinicians a novel idea of the therapy for IRI.

Differential Effects of Reperfusion on Cardiac Mitochondrial Subpopulations in a Preclinical Porcine Model of Acute Myocardial Infarction.

Acute myocardial infarction (AMI) leads to localized cardiac ischemia and can be fatal if untreated. Despite being treatable, the threat of ischemia-reperfusion (IR) injury remains high. Mitochondria are central to both propagation and mitigation of IR injury, and cardiac mitochondria are categorized into two major subtypes—subsarcolemmal and interfibrillar mitochondria (SSM and IFM, respectively). We hypothesized that, in our pre-clinical porcine model of AMI, SSM and IFM are differentially affected by reperfusion. AMI was induced in female pigs by balloon occlusion of the left anterior descending artery for 45 min, followed by 4 h of reperfusion. At the end of reperfusion, animals were euthanized. Cardiac SSM and IFM from the affected ischemic area and a nearby non-ischemic area were isolated to compare mitochondrial function using substrates targeting mitochondrial electron transport chain complexes I and II. Despite detecting overall significant differences in mitochondrial function including yield, mitochondrial S3 and S4 respirations, and calcium retention, consistent individual functional differences in the two mitochondrial subpopulations were not observed, both between the two mitochondrial subtypes, as well as between the ischemic and non-ischemic tissue. Nonetheless, this study describes the mitochondrial subtype response within the initial few hours of reperfusion in a clinically relevant model of AMI, which provides valuable information needed to develop novel mitochondrially targeted therapies for AMI.

Protective Effect of Antiapoptosis Potency of Prolonged Preservation by Desiccation Using High-Pressure Carbon Monoxide on Isolated Rabbit Hearts

Heart transplantation has been widely accepted as a therapy for end-stage heart failure. Mitigation of ischemia-reperfusion injury by inhibiting the apoptotic process plays an important role in organ transplantation. Desiccation using high-pressure carbon monoxide (CO) is a new method of preserving donor hearts; however, its mechanism of antiapoptosis remains unclear. This study was intended to elucidate the efficacy and mechanism of preservation by desiccation for 18 hours using high-pressure CO on myocardial apoptosis. Rabbit heterotopic abdominal cardiac transplantation models were established. New Zealand rabbits were divided randomly into 3 groups: naive group (n = 16), HTK group (n = 16), and desiccation using high-pressure CO group (n = 16). The donor hearts of the naive group were transplanted immediately after being extracted. In the HTK group, the donor hearts were extracted and steeped in 4°C HTK cardioplegic solution for 18 hours and then transplanted; in the desiccation using high-pressure CO group, the donor hearts were extracted and exposed to a gas mixture (Po2 = 3200 hPa, Pco = 800 hPa) in the chamber before being preserved in a refrigerator at 4°C for 18 hours and then transplanted. Apoptotic cardiomyocytes were detected using TUNEL technique and histopathology was performed by hematoxylin-eosin staining. The expression of the ratio of Bcl-2/Bax and caspase-3 proteins was detected using the Western blot method. These findings suggest that compared with traditional HTK preservation, preservation by desiccation using high-pressure CO could alleviate rabbits' myocardial histopathology and apoptosis induced by ischemia-reperfusion injury through adjusting the ratio of Bcl-2/Bax protein expression, thus resulting in the reduction of expression of caspase-3.

Role of PI3K/Akt/GSK-3β signaling pathway in mitigation of ischemia-reperfusion injury by diazoxide postconditioning in isolated rat hearts

Objective To evaluate the role of phosphoinositide 3 kinase/protein kinase B/glycogen synthase kinase 3β (PI3K/Akt/GSK-3β) signaling pathway in mitigation of ischemia-reperfusion (I/R) injury by diazoxide postconditioning in isolated rat hearts.Methods Pathogen-free Sprague-Dawley rats were used in the study.Thirty hearts were excised and passively perfused in a Langendorff apparatus with oxygenated K-H solution at 37 ℃.The hearts were randomly divided into 5 groups (n =6 each) using a random number table:control group (group C),I/R group,diazoxide postconditioning group (group DZ),PI3K inhibitor LY294002 group (group LY),and diazoxide postconditioning + LY294002 group (group DZ + LY).In group C,the hearts were continuously perfused with K-H solution for 70 min.In group I/R,the hearts were perfused with cardioplegic solution 4 ℃ ST-Thomas 10 ml/kg,the perfusion pump was then stopped to induce global ischemia,and 40 min later the hearts were perfused with K-H solution for 30 min.In DZ group,5 min of retrograde perfusion with diazoxide 50μmol/L was performed through the aorta starting from the onset of reperfusion.In LY group,5 min of retrograde perfusion with LY294002 15 μnol/L was performed through the aorta starting from the onset of reperfusion.In LY + DZ group,5 min of retrograde perfusion with LY294002 15 μmol/L was performed through the aorta starting from the onset of reperfusion,followed by 5 min of retrograde perfusion with diazoxide 50 μmol/L.At 20 min of stabilization (T1) and 30 min of reperfusion (T2),heart rate (HR),coronary flow (CF),left ventricular developed pressure (LVDP),left ventricular developed pressure (LVEDP) and ± dp/dtmax were measured.The expression of total Akt (t-Akt) and total GSK-3β (t-GSK-3β) and phosphorylation of Akt and GSK-3β in myocardial tissues were determined by Western blot.Results Compared with C group,HR,LVDP and ± dp/dtmax were significantly decreased,and LVEDP was increased at T2 in the other four groups,CF was decreased in I/R,LY and DZ + LY groups,and the phosphorylation of Akt and GSK-3β in myocardial tissues was increased in DZ group.Compared with I/R group,HR,CF,LVDP and ± dp/dtmax were significantly increased,and LVEDP was decreased at T2,and the phosphorylation of Akt and GSK-3β in myocardial tissues was increased in DZ group,and no significant changes were found in the phosphorylation of Akt and GSK-3 β in LY and DZ + LY groups.Compared with DZ group,HR,CF,LVDP and ± dp/dtmax were significantly decreased,LVEDP was increased,and the phosphorylation of Akt and GSK-3β in myocardial tissues was decreased in LY and DZ + LY groups.Conclusion PI3K/Akt/GSK-3β signaling pathway is involved in the mechanism by which diazoxide postconditioning mitigates I/R injury in isolated rat hearts. Key words: Diazoxide ; Myocardial reperfusion injury ; 1-Phosphatidylinositol 3-kinase; Protein-serine-threonine kinases; Glycogen synthase kinase 3

Hydrogen sulfide: improved hemodynamics and mitigation of ischemia-reperfusion injury in a large animal model (54.8)

Abstract Hemorrhagic shock can lead to ischemia-reperfusion (IR) injury followed by multi-organ failure and death. We tested intravenous Hydrogen sulfide (H2S) in a porcine hemorrhagic shock-resuscitation model evaluating IR injury. Experimental design: Sham (n=3); H2S untreated group (n=5); and H2S treated group (n=14). Animals were splenectomized, induced 35% hemorrhage and ischemia by cross-clamping the supraceliac aorta for 50 minutes. Intravenous fluid and H2S were administered at cross-clamp. Serial hemodynamic measurements and blood plasma analysis were followed for 6 h post-cross clamp release. The mean lactate levels (a measure of injury) were markedly lower in H2S group (7.0±1.6 mmol/L) compared to untreated group (9.3±1.2 mmol/L). Epinephrine requirement was significantly (P<0.05) lower in H2S group (727±645 µg) compared to untreated group (3052±1700 µg). Cardiac output was significantly (P<0.05) lower in H2S treated pigs. The intravenous fluid, hematocrit, and body temperature did not differ significantly (P<0.05). Blood plasma pro-inflammatory cytokines (IL1-β, IL-6, IFN-γ, TNF-α) at 6 h post-cross clamp release were significantly lower (P<0.05) compared to baseline in both H2S treated (n=4) and untreated groups (n=3). Organ (liver, kidney, heart, lung, small bowel, aorta) histopathology and gene expression (iNOS, eNOS, HO-1, HIF-1α, TNFα, IL-6, IFN-γ, IL1-β, etc.,) analyses are in progress. H2S improved hemodynamics and appears to be protective against IR injury.

A Novel Murine Island Skin Flap for Ischemic Preconditioning

Ischemia reperfusion injury is a well-known phenomenon affecting skin flap viability. One method to improve flap viability is ischemic preconditioning. Previous murine flap models used random flaps. We developed a single pedicle island skin flap which allows us to create true ischemia by clamping the single pedicle. Our first aim was to describe a novel murine skin flap model with a definable, reproducible injury. Our second aim was to test the usefulness of this model by demonstrating mitigation of injury via ischemic preconditioning. Dorsal lateral thoracic artery pedicle island skin flaps (3.5 x 1.5 cm) were elevated in 39 male C57/BL6 mice: a Control group (n = 7), 10 h of ischemia (n = 21), and Preconditioning (2 cycles of 20 min ischemia: 20 minutes reperfusion) + 10-h ischemia (n = 11). After flap elevation, a silicon sheet barrier was placed. The axial pedicles were occluded, and the flaps were inset with 6-0 prolene. In all mice, ischemia was followed by 1 wk of reperfusion. At 1 wk, percent necrosis was measured and an analysis of variance was performed. The percent of flap necrosis was 1.1% +/- 1.11% in controls. Animals that were subjected to 10 h of ischemia developed 33.14% +/- 7.23% necrosis. Preconditioned animals that underwent 10 h of ischemia demonstrated a 43% reduction in necrosis (18.82% +/- 5.68%). There was a statistically significant difference among all groups (P < or = 0.001). Rat models have been the standard for skin flap experiments. We have developed a novel murine single pedicle island skin flap model with reproducible injury. This model has numerous advantages, including ease of handling, low cost, appropriateness for biomedical studies, and the availability of genetically altered animals. We also confirmed this model's usefulness in a study of mitigation of ischemia reperfusion injury through ischemic preconditioning.

Cardioprotection by Sulfaphenazole, a Cytochrome P450 Inhibitor: Mitigation of Ischemia-Reperfusion Injury by Scavenging of Reactive Oxygen Species

Cytochrome P450 (P450) enzymes play a significant role in promoting myocardial ischemia-reperfusion (I/R) injury. CYP2C9, an isoform of P450, is known to generate superoxide radicals in the reperfused heart. Sulfaphenazole (SPZ), a CYP2C9 inhibitor, has been shown to decrease I/R injury; however, the mechanism of cardioprotection by SPZ is not well elucidated. The objective of this study was to test whether SPZ mitigates myocardial I/R injury by scavenging reactive oxygen species (ROS). Isolated rat hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Hearts were perfused with SPZ and/or N(omega)-nitro-L-arginine methylester (L-NAME). Coronary flow (CF), left-ventricular developed pressure (LVDP), and rate-pressure product (RPP) were monitored. Superoxide and nitric oxide (NO) generation in the reperfused tissue was determined using fluorescence methods. Myocardial infarct size was measured using triphenyltetrazolium chloride staining. The SPZ-treated group showed a significant recovery of cardiac function compared with the untreated I/R group (CF, 53 versus 45%; LVDP, 48 versus 22%; RPP, 51 versus 20%). The infarct size was significantly reduced in the SPZ-treated group (15%) compared with the I/R control (42%). Coadministration of L-NAME with SPZ significantly attenuated the beneficial effects of SPZ. In addition, SPZ treatment showed significantly decreased superoxide levels and enhanced NO bioavailability in the reperfused heart. In conclusion, the protective effect of SPZ against I/R-mediated myocardial damage appears to be due to a reduction in the superoxide level caused by its inhibition of CYP2C9, as well as scavenging of oxygen free radicals generated in the reperfused heart.