Post-reperfusion Injury Research Articles

Letter by Greyson Regarding Article, “High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury”

To the Editor: Moens et al1 reported that high-dose folic acid (FA) prevents myocardial infarction after occlusion of the left anterior descending coronary artery and reperfusion in open-chest rats; more surprisingly, FA preserved contractile function in the ischemic territory during 30 minutes of ischemia that was otherwise severe enough to induce large infarcts in untreated control rats. The authors hypothesized, and an accompanying editorial discussed, the possibility that FA promotes increased ATP synthesis during ischemia, thereby preserving contractile function and preventing infarction.1,2 A search for previously unknown effects of FA on ATP synthesis is necessary if one accepts the conclusion that ischemic territory …

Acute Effects of “Delayed Postconditioning” With Periodic Acceleration After Asphyxia Induced Shock in Pigs

Asphyxia cardiac arrest and shock are models for whole body ischemia reperfusion injury. Periodic acceleration (pGz) achieved by moving the body on a platform is a novel method for inducing pulsatile vascular shear stress and endogenous production of endothelial nitric oxide, prostaglandin E2, tissue plasminogen activator, and adrenomedullin. The aforementioned are cardioprotective during and after ischemia reperfusion injury. We investigated whether pGz, applied 15 min after return of spontaneous circulation (ROSC) would serve as an effective "delayed" post conditioning tactic to lessen acute reperfusion injury markers in a pediatric swine model of asphyxia induced shock. Asphyxia shock was induced in 20 swine weight 3.9 +/- 0.6 kg. Fifteen minutes after ROSC, the animals were randomized to receive conventional mechanical ventilation (CMV, [Control]) or CMV with pGz. All animals had ROSC and no significant differences in blood gases or hemodynamics after ROSC. pGz treated had significantly less myocardial dysfunction post resuscitation, (i.e. better % ejection fraction (EF), % fractional shortening (FS), and wall motion score index) and lower biochemical indices of reperfusion injury (lower TNF-alpha, IL-6, and Troponin I, and myeloperoxidase activity). Delayed postconditioning with pGz ameliorates acute post resuscitation reperfusion injury and improves myocardial dysfunction after asphyxia-induced shock.

Emergency liver transplantation following severe liver trauma

Liver trauma is a major cause of mortality after major blunt and penetrating abdominal trauma. The need for life-saving emergency hepatectomy and liver transplantation is extremely rare. We report the management of 2 patients who required urgent liver transplantation for liver trauma. One patient developed hepatic failure following global ischemia after a gunshot injury. The second patient developed a severe postreperfusion injury following removal of a perihepatic pack after blunt abdominal trauma. We highlight the difficulties in the management of severe liver trauma with an emphasis on the clinical features, radiological investigations, and surgical treatment of these complex patients.

High dose folic acid pre-treatment blunts cardiac dysfunction during ischemia coupled to maintenance of high energy phosphates and reduces post-reperfusion injury

High dose folic acid pre-treatment blunts cardiac dysfunction during ischemia coupled to maintenance of high energy phosphates and reduces post-reperfusion injury

High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury

The B vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an antioxidant, and enhances nitric oxide synthase activity. Here, we tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury. Wistar rats were pretreated with either FA (10 mg/d) or placebo for 1 week and then underwent in vivo transient left coronary artery occlusion for 30 minutes with or without 90 minutes of reperfusion (total n=131; subgroups used for various analyses). FA (4.5x10(-6) mol/L i.c.) pretreatment and global ischemia/reperfusion (30 minutes/30 minutes) also were performed in vitro (n=28). After 30 minutes of ischemia, global function declined more in controls than in FA-pretreated rats (Delta dP/dtmax, -878+/-586 versus -1956+/-351 mm Hg/s placebo; P=0.03), and regional thickening was better preserved (37.3+/-5.3% versus 5.1+/-0.6% placebo; P=0.004). Anterior wall perfusion fell similarly (-78.4+/-9.3% versus -71.2+/-13.8% placebo at 30 minutes), yet myocardial high-energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA pretreatment (ATP: control, 2740+/-58 nmol/g; ischemia, 947+/-55 nmol/g; ischemia plus FA, 1332+/-101 nmol/g; P=0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA pretreatment but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124+/-280 cpm/mg FA versus 5898+/-474 cpm/mg placebo; P=0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8+/-1.2% versus 60.3+/-4.1% placebo area at risk; P<0.002) and less contraction band necrosis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg/d FA. FA pretreatment blunts myocardial dysfunction during ischemia and ameliorates postreperfusion injury. This is coupled to preservation of high-energy phosphates, reducing subsequent reactive oxygen species generation, eNOS-uncoupling, and postreperfusion cell death.

Temporal Thresholds for Infarction and Hypothermic Protection in Long-Evans Rats

Some previous studies in Long-Evans rats noted larger infarcts after transient middle cerebral artery (MCA) occlusions than after permanent occlusions, interpreted to demonstrate "reperfusion injury." Recent experiments failed to reproduce this phenomenon, prompting an investigation of the sources of variability in this animal model. Male Long-Evans rats were subjected to surgical occlusion of the right MCA and ipsilateral common carotid artery. Variables tested included duration of occlusion and halothane anesthesia exposure and targeting of proximal or distal MCA occlusion sites. The temporal window for hypothermic protection was also investigated. MCA occlusions at the level of the rhinal fissure produced graded increases in infarct volume with ischemia duration, and lesion size did not differ between 3-hour and permanent occlusions independent of anesthesia duration. Occlusions at a more distal site produced infarcts of comparable size after transient 3-hour occlusions and after permanent occlusions accompanied by prolonged anesthesia, but significantly smaller infarcts were seen when permanent occlusions were followed by rapid anesthesia termination. Hypothermia conferred protection only when initiated before reperfusion after transient proximal occlusions. These results indicate that previously described "reperfusion injury" after transient MCA occlusions conversely reflects unexpected injury reduction when rats with permanent occlusions experience early anesthesia termination. More rapid blood pressure recovery under such conditions permits improved collateral perfusion. The absence of a detectable postischemic window for hypothermic protection further argues against a significant component of delayed postreperfusion injury in this model.

Post-resuscitation reperfusion injury: Comparison of periodic Gz acceleration versus Thumper CPR

The effects of whole body, periodic acceleration (pGz) on cardiopulmonary resuscitation outcome, organ blood flow and tissue inflammatory injury were examined in an experimental pig model, and compared with Thumper (TH)-CPR. VF was induced in 16 pigs, and remained untreated for 3 min, followed by either pGz-CPR or TH-CPR for 15 min. Defibrillation attempts were made at 18 min of VF. Six of eight animals had ROSC in both groups. Post-arrest myocardial dysfunction was present in both groups and progressed over hours. pGz-CPR animals had less wall motion abnormality and higher left ventricular ejection fraction than TH-CPR. The post-resuscitation haemodynamic variables returned to baseline after 3h of ROSC in pGz-CPR group, and remained low in TH-CPR group. The brain blood flow during CPR was similar between TH-CPR and pGz-CPR, 17% and 20% of pre-fibrillation values, respectively. The cardiac blood flow during CPR was significantly lower in pGz-CPR than TH-CPR (TH: 10.2% and pGz: 1.9% of pre-fibrillation value), as well as in other organs. The brain and heart blood flow was significantly higher than pre-fibrillation values after 30 min of ROSC in both groups. The pGz group had significantly higher blood flow in brain, heart and kidney than TH-CPR after 30 min of ROSC. Blood flow in all organs decreased below pre-fibrillation values at 2h of ROSC. Tissue inflammatory injury progressed over hours in the post-resuscitation phase. pGz-CPR group had significantly lower myeloperoxidase (MPO) activity and plasma creatine phosphokinase (CPK) and cardiac troponin I, TNF-alpha, and IL-6 than TH-CPR. Results from the present study demonstrate again that pGz-CPR is an effective method of cardiopulmonary resuscitation, with less post-reperfusion injury compared to TH-CPR.

INHIBITON OF NF-&amp;kappa;B ACTIVATION DURING ISCHEMIA REDUCES HEPATIC ISCHEMIA/REPERFUSION INJURY IN RATS

The aim of this study was to determine whether nuclear factor-kappaB (NF-kappaB) inhibitors are efficient against hepatic ischemia/reperfusion (I/R) injury. We previously demonstrated that xanthine oxidase-derived reactive oxygen species activate NF-kappaB during ischemia. However, the role of NF-kappaB activation during ischemia in post-reperfusion injury remains unclear. Therefore, while we examined the effects of NF-kappaB inhibitors, sulfasalazine and pyrrolidinedithiocarbamate on hepatic I/R injury using a rat lobar hepatic I/R model, we estimated the relationship between NF-kappaB activation during ischemia and following hepatic damage caused by reperfusion. The portal vein and the hepatic artery were clamped for 1 hr followed by reperfusion for up to 24 hr. NF-kappaB activation was determined by Western blot analysis. NF-kappaB activation was observed in the ischemic lobe of the liver, and the activation was prevented by pre-administration with NF-kappaB inhibitors. Although the serum ALT level, hepatic MPO activity and BSP clearance, as an index of hepatic injury, were increased after reperfusion, the increase was attenuated by pre-administration with NF-kappaB inhibitors. These findings suggest that NF-kappaB activation during ischemia is relevant to hepatic I/R injury. Moreover, we first showed that pre-administration with NF-kappaB inhibitors is effective against hepatic I/R injury.

Intracoronary e-/l-selectin blockade reduces neutrophil infiltration in heart transplantation

Background This study examined the effect of local intracoronary delivery of a unique monoclonal antibody (mAb) to both E- and L-selectin (EL-246) on neutrophil infiltration after global ischemia during cardiac transplantation. Methods In 12 ovine heart transplants, allograft coronary arteries were locally perfused with EL-246 (n = 6), or isotype-matched control antibodies (n = 2) or saline (n = 4). At 24 hours posttransplant, myocardium was analyzed for neutrophil infiltration and myocardial water content. Results The mean number of intramyocardial neutrophils per area (PMN/hpf) was greatly reduced in the allografts perfused with EL-246 (3.45 ± 0.4 PMN/hpf), compared with an average 6.5 ± 0.97 PMN/hpf in control hearts ( p = 0.004). Peripheral leukocyte counts were unaffected; myocardial water content was not significantly reduced. Conclusions Local perfusion of cardiac allografts with blocking antibody EL-246 before reperfusion significantly reduced the neutrophilic infiltration that occurs early after transplantation. Prohibiting neutrophil–endothelial adhesion and transmigration may be useful in decreasing neutrophil-dependent post-reperfusion injury in transplantation and routine cardiac surgery.

The contribution of Na +/H + exchange to postreperfusion injury and recovery of transplanted kidney

Acute kidney injury soon after reperfusion seems to anticipate short- and long-term graft prognosis. Sodium-hydrogen exchanger (NHE) is involved in several steps of kidney graft function recovery, such as the restoration of intracellular pH, acute postreperfusion inflammation, and tubular epithelium repair and proliferation. We studied 20 first kidney transplantations by measuring the erythrocyte NHE of both recipient and donor as well as recipient serum and urine indices of renal structural and functional integrity every day since grafting. Heightened exchange activity in the donor-recipient couple resulted, which was associated to a prompt graft recovery together with a short stay for the donor in the intensive care unit, brief cold ischemia time, and a nonatherogenic lipoprotein profile for the recipient. Additional positive prognostic indices were time-zero diuresis and urinary excretion rates of N-acetyl-beta-D-glucosaminidase (NAG) and albumin. Over the one-year follow-up period, a long post-transplantation hospital stay was associated with a significantly increased risk of rejection, and the urinary alanine-aminopeptide (AAP) excretion rate was confirmed as a useful criterion for evaluating the clinical course of kidney graft.

Monocytes-macrophages and cytokines/chemokines in fine-needle aspiration biopsy cultures: enhanced interleukin-1 receptor antagonist synthesis in rejection-free kidney transplant patients.

Monocytes-macrophages are found within kidney allografts during the first days after surgery, where they perform "housekeeping" tasks, participate in postreperfusion injury, and act as antigen-presenting cells, as well as become involved in the effector phase of acute rejection. They also seem to play a prominent role in chronic rejection. We quantified their presence in fine-needle aspiration biopsies and studied the growth factors that, we hypothesized, would mark the different implications of the presence of monocytes-macrophages. Fine-needle aspiration biopsies were obtained from 56 adult renal transplants and analyzed for CD14+ using the alkaline phosphatase-anti-alkaline phosphatase procedure. Thirty-three patients were studied on the production of interleukin (IL)-1 receptor antagonist (IL-1ra), IL-6, IL-8, macrophage colony-stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1alpha by aspiration biopsies cultures using enzyme-linked immunosorbent assay techniques. CD14+ cells were present at significantly higher numbers in steroid-resistant acute rejections but also during the first days after surgery, especially if acute tubular necrosis was present. We found a significantly higher production of IL-1ra by rejection-free patients compared with acutely rejecting patients, and this difference was already established on day 7 after surgery (10+/-10.5 days before rejection). Monocytes-macrophages are present at higher numbers in aspiration biopsies of kidney transplant patients suffering either acute tubular necrosis or steroid-resistant rejections, but they are present during the first days after transplant in stable patients, too. The production of IL-1ra is significantly up-regulated in stable patients, which suggests that monocytes-macrophages may constitute an early key factor in the down-regulation of the anti-allograft immune response.