Deleterious Effects Of Reperfusion Injury Research Articles

INCREASED PRODUCTION OF OXIDIZED PHOSPHOTIDYLCHOLINE MOLECULES IN PATIENTS PRESENTING WITH STEMI

BACKGROUND: Despite restoration of blood flow to myocardial cells after ischemia, a large percentage of myocardial cells die after reperfusion. Oxidized phophatidylcholines (OxPC) are a group of molecules that are generated during reperfusion that have been shown to mediate inflammation, platelet aggregation, thrombosis and cell death, however their presence and role in STEMI remains unclear. METHODS: Blood and coronary thrombectomy samples were collected from 13 subjects with STEMI and 4 subjects with non-obstructive CAD prior to, and at completion of angioplasty/angiography respectively. The complete oxidative lipidomic profile at the onset of STEMI and after reperfusion was compared to control prior to and after diagnostic angiography. The oxidative lipidomic profile of each was established and compared using high-performance electrospray mass spectrometry of plasma and coronary thrombectomy samples. RESULTS: Thirteen STEMI subjects age 57 8years and 4 patients age 56 8 years who presented for clinically indicated coronary angiography/angioplasty were enrolled in this study. Seventy-nine distinct OxPC molecules were identified in human plasma. During ischemia, 22 OxPC molecules were significantly different compared to control subjects and following reperfusion, 40 OxPC molecules were significantly different compared to control subjects. Fragmented OxPC molecules in the control vs ischemia population went from 3.8 vs 20.6ng/mg of protein, (p 1⁄4 0.07) and with reperfusion increased to 1.8 vs 34.7ng/mg of protein, (p1⁄40.01) and was 54.8ng/mg of protein in the coronary thrombus sample, increased compared to reperfusion (p1⁄40.3). The increase in fragmented OxPCs in plasma during reperfusion was due to a significant increase in carboxylic acid OxPCs and aldehyde OxPCs. In coronary thrombus, the increase in fragmented OxPCs was due to a significant increase in aldehyde OxPCs only. In all, fragmented OxPCs increased by 5 fold with onset of ischemia, 19 fold with reperfusion. While coronary thrombus had the highest concentration of fragmented OxPCs, it did not correlate with plasma samples indicating that thrombus and reperfusion samples were independent of one another. CONCLUSION: We have shown for the first time that OxPC molecules are present in human STEMI subjects during ischemia, reperfusion and coronary thrombus. Consistent with reperfusion injury, OxPC levels undergo marked increases with reperfusion. Coronary thrombus contains high levels of OxPCs due to coronary plaque disruption and is independent of reperfusion. In light of our findings, attenuation of the biologic effects of OxPCs may be a novel therapeutic approach to reduce the deleterious effects of reperfusion injury.

Effect of intravenous administration of antioxidants alone and in combination on myocardial reperfusion injury in an experimental pig model

Background: Several antioxidants have been found to have conflicting results in attenuating myocardial reperfusion injury. These studies were done primarily in experimental protocols that did not approximate clinical situations. Objective: The aim of this study was to test the efficacy of 3 different antioxidants (ascorbic acid [AA], desferrioxamine, and N-acetylcysteine [NAC]) administered IV alone and in combination in a closed-chest pig model. Methods: Farm-raised domestic male pigs (aged 3–5 months, weight of 30–35 kg) were assigned to 1 of 5 groups to receive treatment as follows: group A, AA 100 mg/kg; group B, desferrioxamine 60 mg/kg; group C, a loading dose of NAC 100 mg/kg for 20 minutes and a 20-mg/kg maintenance dose; group D, all 3 drugs in combination; and group E, normal saline (control group). The infusion of all drugs was started 15 minutes before and completed 5 minutes after reperfusion, except for the administration of NAC, which was terminated 60 minutes postreperfusion. Myocardial ischemia (45 minutes) and reperfusion (210 minutes) were achieved percutaneously by circumflex artery balloon occlusion. Ejection fraction, left ventricular end-diastolic pressure (LVEDP), flow in the infarcted artery, and all ventricular arrhythmias were recorded. Oxidative stress was estimated by serial measurements of thiobarbituric acid reactive substance (TBARS) concentration in coronary sinus blood. Infarct size was assessed as a percentage of the area at risk (I/R ratio) using the tetrazolium red staining method. Results: The 25 pigs were divided into 5 groups of 5 pigs each. No significant between-group differences were found in I/R ratio or in oxidative stress (as measured by TBARS concentration). Group C developed significantly more ventricular atrhythmias than the control group (80% vs 0%, P = 0.02). No other differences among groups were found. LVEDP was significantly elevated in all treatment groups (mean LVEDP difference [SD] for group A, 6.0 [1.6] mm Hg; group B, 17.6 [1.9] mm Hg; group C, 3.6 [1.7] mm Hg; group D, 6.8 [3.2] and group E, 5.4 [3.4] mm Hg). LVEDP elevation was found to be significantly higher in group B compared with all the other groups (all, P < 0.001). No significant between-group differences were found in the other parameters measured. Conclusion: In this experimental pig model, the antioxidants AA, desferrioxamine, and NAC administered alone or in combination did not reduce the deleterious effects of reperfusion injury and specifically the extent of myocardial necrosis.

Effects of Tempol, a Membrane-Permeable Radical Scavenger, on Local and Remote Organ Injuries Caused by Intestinal Ischemia/Reperfusion in Rats

Tempol is a stable piperidine nitroxide of low molecular weight that permeates biological membranes and scavenges superoxide anions in vitro. In a variety of animal models, deleterious effects of reperfusion injury on both local and remote organs have been demonstrated. In this study, we aimed to investigate the effects of a membrane-permeable radical scavenger, Tempol, on local and remote organ injuries caused by intestinal ischemia/reperfusion (I/R) in rats. Male Wistar-albino rats were randomized into three groups: (I) Sham-operated control group, laparotomy without I/R injury (n = 12); (II) Intestinal I/R group, 60 min of ischemia by superior mesenteric artery occlusion followed by 2-h of reperfusion (n = 12); and (III) I/R + Tempol-treated group, identical to I/R group except for Tempol administration, 30 mg/kg bolus injection 5 min before reperfusion, followed by an infusion of 30 mg/kg/h intravenously (n = 12). Histopathologically, intestinal mucosal lesions were assessed by Chiu's classification, and pulmonary parenchymal damage was appraised by pulmonary neutrophil infiltration and acute lung injury scaling. Biochemically, myeloperoxidase activity, malondialdehyde, glutathione, and nitrite/nitrate (NO(x)) levels were determined in both intestinal mucosa and lung parenchyma. Evans blue dye concentration and organ wet/dry weight ratios were used as a marker of organ edema. Animal survival was observed up to 1 week. Intestinal mucosal lesions and pulmonary parenchymal damage were significantly attenuated with Tempol treatment, histopathologically (P < 0.05). Tempol administration significantly reduced myeloperoxidase activity and malondialdehyde levels, and also significantly increased glutathione and NO(x) levels of both intestinal and lung tissues, biochemically (P < 0.05). Evans blue dye extravasation and wet/dry weight ratios of organs were significantly reduced with Tempol injection (P < 0.05). The survival rates of rats in Tempol-treated group were significantly higher than that of I/R-treated group (P < 0.05). The present study suggests that Tempol administration significantly reduces both local and remote organ injuries caused by intestinal I/R before and throughout the reperfusion period. Further clinical studies are needed to clarify whether Tempol may be a useful therapeutic agent to use in particular operations where the reperfusion injury occurs.

Cardiopulmonary bypass, controlled reperfusion and C-1 esterase inhibitor prevent reperfusion injury in clinical lung transplantation

Postoperative graft failure remains the major risk factor for early mortality after lung transplantation. To reduce potential deleterious effects of reperfusion injury, cardiopulmonary bypass was routinely used allowing for controlled allograft reperfusion by pulmonary artery (PA) venting. In addition, C-1 esterase inhibitor (C1-INH) was given. Allograft function and recipient survival in bilateral sequential lung transplantation were assessed.

Prevention of deleterious effects of reperfusion injury using one-week high-dose allopurinol.

Allopurinol has been widely used to reduce the severity of the reperfusion injury. However, conflicting data have been reported regarding the dosage, the duration of the timing, and the administrative regimen of the drug. The aim of this study was, therefore, to evaluate the effects of short versus long periods of allopurinol pretreatment on the anastomotic healing of intestines, directly after being subjected to ischemia-reperfusion (IR) stress. Furthermore, the effects of an allopurinol pretreatment on the survival rate following IR stress, was also assessed. One hundred thirty-seven male Wistar rats with a median weight of 235 (range, 180-275) g used in the study. In group I (control group, N = 20) superior mesenteric artery (SMA) and collateral vessels were isolated but not occluded. In group II, the profound IR group (PIR, N = 42), the SMA was occluded immediately distal to the aorta with collateral interruption using an atraumatic arterial clip for 30 min. In group III [two days of allopurinol (ALL) pretreatment group, 2ALL, N = 38], allopurinol (100 mg/kg body wt) was given intraperitoneally on a daily basis for two days prior to the experiment. In group IV (seven days of allopurinol pretreatment group, 7ALL, N = 37), the same pretreatment and the allopurinol schedule was performed for seven days before surgery. All animals underwent 3 cm of ileal resection and primary anastomosis, 10 cm proximal to ileocecal valve. Within each group, animals were anesthetized either on the third or seventh postoperative days. Abdominal wound healing, intraabdominal adhesions, anastomotic complications, anastomotic bursting pressure measurements, and bursting site were recorded as were the histopathologic evaluation. No rats in group I, 20 rats in group II, 18 rats in group III, and 7 rats in group IV died (P = 0.0003). Anastomotic dehiscence was found in one of 20 group I, in 11 of 22 in group II, in 9 of 20 in group III, and in 3 of 30 in group IV (P = 0.0003). On the third and seventh days, the median bursting pressures of the anastomosis were determined: 42 and 235 mm Hg in group I, 17 and 105 mm in Hg in group II, 22 and 183 mm Hg in group III, and 36 and 214 mm Hg in group IV (P < 0.0001). The burst occurred at the anastomoses in all animals tested on the third postoperative day, one in group I, six in group II, four in group III and one in group IV on the seventh postoperative day (P < 0.01). All deleterious effects of reperfusion injury on intestinal anastomosis healing, including survival rates and the histopathological parameters, were significantly prevented by seven days, but not two days, of high-dose allopurinol pretreatment.