Anita Patt

Xanthine oxidase-derived hydrogen peroxide contributes to ischemia reperfusion-induced edema in gerbil brains.

The contribution of toxic O2 metabolites to cerebral ischemia reperfusion injury has not been determined. We found that gerbils subjected to temporary unilateral carotid artery occlusion (ischemia) consistently developed neurologic deficits during ischemia with severities that correlated with increasing degrees of brain edema and brain H2O2 levels after reperfusion. In contrast, gerbils treated just before reperfusion (after ischemia) with dimethylthiourea (DMTU), but not urea, had decreased brain edema and brain H2O2 levels. In addition, gerbils fed a tungsten-rich diet for 4, 5, or 6 wk developed progressive decreases in brain xanthine oxidase (XO) and brain XO + xanthine dehydrogenase (XD) activities, brain edema, and brain H2O2 levels after temporary unilateral carotid artery occlusion and reperfusion. In contrast to tungsten-treated gerbils, allopurinol-treated gerbils did not have statistically significant decreases in brain XO or XO + XD levels, and reduced brain edema and brain H2O2 levels occurred only in gerbils developing mild but not severe neurologic deficits during ischemia. Finally, gerbils treated with DMTU or tungsten all survived, while greater than 60% of gerbils treated with urea, allopurinol, or saline died by 48 h after temporary unilateral carotid artery occlusion and reperfusion. Our findings indicate that H2O2 from XO contributes to reperfusion-induced edema in brains subjected to temporary ischemia.

Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic, isolated, perfused rat hearts.

Three lines of investigation indicated that hydrogen peroxide (H2O2) from xanthine oxidase (XO) contributes to cardiac dysfunction during reperfusion after ischemia. First, addition of dimethylthiourea (DMTU), a highly permeant O2 metabolite scavenger (but not urea) simultaneously with reperfusion improved recovery of ventricular function as assessed by ventricular developed pressure (DP), contractility (+dP/dt), and relaxation rate (-dP/dt) in isolated Krebs-Henseleit-perfused rat hearts subjected to global normothermic ischemia. Second, hearts from rats fed tungsten or treated with allopurinol had negligible XO activities (less than 0.5 mU/g wet myocardium compared with greater than 6.0 mU/g in control hearts) and increased ventricular function after ischemia and reperfusion. Third, myocardial H2O2-dependent inactivation of catalase occurred after reperfusion following ischemia, but not after ischemia without reperfusion or perfusion without ischemia. In contrast, myocardial catalase did not decrease during reperfusion of ischemic hearts treated with DMTU, tungsten, or allopurinol.

Extra-anatomic bypass: A closer view

The results of 60 femorofemoral, 27 axillobifemoral, and 15 axillounifemoral bypasses were analyzed. Considered in this order, the operative mortality rate was zero, 11%, and 13%, respectively; initial hemodynamic failure was 7%, 13%, and 9%, respectively; 5-year overall primary patency rate was 67%, 62%, and 19%, respectively; and the secondary patency rate was 74%, 82%, and 37%, respectively. However, axillobifemoral patency was made to seem better by including six cases (12 graft limbs) performed because of nonocclusive disease (aneurysm or failure of graft performed for aneurysm). Excluding these, axillobifemoral primary and secondary patency decreased to 47% and 69%, respectively. Femorofemoral bypass results were made worse by cases performed because of unilateral failure of an aortic bifurcation graft. Exclusion of these bypasses increased primary and secondary patency rates to 74% and 82%, respectively. Occlusion of the major outflow artery (superficial femoral) markedly affected long-term patency of all three bypasses. Thus, good and poor runoff primary patencies were, respectively, for femorofemoral bypass 79% and 53%, for axillobifemoral bypass 92% and 41%, respectively (occlusive disease only), and for axillounifemoral bypass 54% and zero, respectively. This detailed breakdown of results explains the wide variances in the reported results for these extra-anatomic bypasses and provides a better perspective for their application in different clinical settings.

Iron depletion or chelation reduces ischemia/reperfusion-induced edema in gerbil brains☆

Since hydrogen peroxide (H2O2) can react with ferrous iron (FE++) to form the more toxic hydroxyl radical (OH) in vitro, and since H2O2 is generated brain xanthine oxidase (XO) during ischemia/reperfusion (I/R), we hypothesized that gerbils depleted of iron by dietary restriction or treated with iron chelators would be less susceptible to I/R injury. We found that gerbils fed a low iron diet for 8 weeks had decreased brain and serum iron levels, less neurologic deficits, and decreased brain edema after temporary unilateral carotid ligation (ischemia) and then reperfusion than gerbils fed a control standard iron diet. In addition, brains from gerbils treated with iron-free deferoxamine (an iron chelator), but not iron-loaded deferoxamine, had decreased (P less than .05) brain edema following ischemia and reperfusion. The results indicate that iron may contribute to cerebral ischemia/reperfusion damage.

Aortobifemoral bypass: The operation of choice for unilateral iliac occlusion? *

Aortobifemoral bypass (ABF) is the preferred operation for patients with bilateral aortoiliac occlusive disease, but for those with unilateral occlusion without significant stenosis of the contralateral iliac artery, alternative reconstructions, such as femorofemoral (FF) or iliofemoral (IF) bypass have been advocated. We compared the surgical outcome in 96 such patients after ABF (n = 32), FF (n = 47), or IF (n = 17) bypasses, with biplane arteriography and noninvasive laboratory testing used to assess the contralateral iliac artery and runoff status, in particular, patency of the superficial femoral artery (SFA). Graft patencies were assessed by noninvasive criteria and analyzed by the life-table method. The only death occurred after ABF bypass (3.1%). Primary patency rates at 1, 3, and 5 years with an open SFA were 100%, 89% and 89%, respectively, for ABF; 92%, 92%, and 92% for FF; and 71%, 71%, and 36% for IF. When the SFA was occluded, the primary patency rates at 1, 3, and 5 years were 100%, 100%, and 72%, respectively, for ABF; 72%, 53%, and 35% for FF; and 56%, 56%, and 56% for IF bypasses. There were no later occlusions on the contralateral (good) side after ABF. Significant progression of atherosclerosis in donor iliac artery was observed in 6% of both FF and IF bypasses. We conclude that ABF is the preferred operation for extensive iliac artery occlusive disease that is hemodynamically significant only on the symptomatic side unless specifically contraindicated by prohibitive risk or abdominal disease. This is particularly true in the face of SFA occlusion.

Hydrogen peroxide mediates reperfusion injury in the isolated rat heart

In an isolated, normothermic rat heart model (Langendorff, 37 °C), dimethylthiourea (DMTU) infusion only during reperfusion reduced both injury and measurable hydrogen peroxide (H2O2) concentrations after global ischemia. Cardiac function was assessed by measurement of ventricular developed pressure (DP). H2O2 was assessed using H2O2 dependent aminotriazole inactivation of myocardial catalase. Depletion of xanthine oxidase by two methods (tungsten or allopurinol inhibition) also improved recovery of function and H2O2 production. The results indicate that XO derived H2O2 contributes to myocardial reperfusion injury.

Xanthine oxidase contributes to lung leak in rats subjected to skin burn

We found that rats subjected to thermal skin injury (skin burn) had increased serum xanthine oxidase (XO) activities, increased serum complement activation (decreased serum CH50 levels), increased erythrocyte (RBC) fragility, increased lung neutrophil accumulation, and increased lung leak compared to sham-treated rats. Treatment of rats with allopurinol (an XO inhibitor) not only decreased serum XO activity, but also decreased complement activation, RBC fragility, lung neutrophil accumulation, and lung leak abnormalities in rats subjected to skin burn. We conclude that XO may contribute to acute lung injury and a number of events associated with the development of acute lung leak following skin burn.

Cerebral ischemia-reperfusion injury in the gerbil

Gerbils subjected to cerebral ischemia (unilateral carotid occlusion for 6 hr) were either asymptomatic or developed increasingly severe neurologic deficits which correlated with degrees of brain swelling (weights of ischemic hemisphere versus the contralateral control hemispheres) following 3 hr of reperfusion. Asymptomatic gerbils or gerbils suffering only mild deficits survived for 1 week following reperfusion while gerbils suffering moderate to severe deficits had a poor survival rate with only 22% remaining alive after 1 week.