XOR and Models of Injury

Ischemia-Reperfusion Injury

Because of its ability to generate potentially noxious ROS, XOR has long been suspected to be involved in ischemia-reperfusion injury (IRI). Conversion of XOR from the dehydrogenase to the oxidase form was at the heart of a hypothesis proposed by Granger et al. and others to explain the specific involvement of XOR in IRI. In that scheme, ischemia causes an increase in intracellular calcium, stimulating a calcium-activated neutral protease [9] that irreversibly converts xanthine dehydrogenase to the oxidase form. Concomitantly, ischemia depletes intracellu-

lar ATP and leads to the accumulation of the XOR substrate hypoxanthine. With reoxygenation, xanthine oxidase converts molecular oxygen to superoxide and hydrogen peroxide, causing oxidative damage [9]. Although data from several studies indeed support a role for XOR in IRI, the hypothesis is challenged by the finding that conversion of XOR from the dehydrogenase to the oxidase form is either too slow or not significant during IRI. Furthermore, the beneficial effects on IRI of so-called specific XOR inhibitors, such as allopurinol, may be questioned since these compounds exert other effects on cellular metabolism and have anti-oxidant properties unrelated to their XOR inhibitory activity. However, as mentioned earlier, the conversion of XOR to the oxidase form is not necessary for ROS generation by the enzyme (see "Biology and Function of Xanthine Oxidoreductase").

Two lines of evidence that implicate XOR in IRI are of particular relevance to the microvasculature. The first is circulating XOR, which interacts with glycosaminoglycans on endothelial cells. Several studies have indicated that although normal plasma XOR levels are low, they increase in disease conditions such as IRI. Circulating XOR derived from XO-rich organs such as the liver has been proposed to cause damage to a variety of distant organs, particularly the lung. Such effect might explain multiorgan dysfunction in response to ischemia in a single organ such as the liver. The second line of evidence comes from studies that propose a role for XOR in mediating interactions between neutrophils and microvascular endothelial cells. Neutrophils have a significant role in tissue injury including IRI. Since interaction of neutrophils with endothelial cells involves upregula-tion of adhesion molecules by ROS, it is possible that, in addition to ROS generated by neutrophil NADH oxidase, XOR-derived ROS contribute to IRI by enhancing neutrophil-endothelial interactions.

XOR and Acute Lung Injury

The concept of injury related to XOR-derived ROS was originally promoted by McCord [10] and others in disease processes of the heart, kidney, lung, liver, and intestine. In animal models of acute lung injury (ALI), XOR is increased in lung parenchyma and bronchoalveolar lavage (about four-hundredfold). In humans, increased hypoxanthine and XOR levels have been demonstrated in the epithelial lining fluid from premature neonates with bronchopulmonary dysplasia, and in the serum of patients with the acute respiratory distress syndrome (ARDS), as compared to normal controls or critical-care patients with other organ diseases. Furthermore, plasma hypoxanthine levels are highest in nonsur-vivors of ARDS, implicating oxidative damage (and presumably XOR) as a determinant of mortality in these mechanically ventilated patients. It is also possible that, in ARDS and ALI, XOR-derived superoxide and nitric oxide (NO) generated from inducible nitric oxide synthase (iNOS) react to form the highly toxic oxidant peroxynitrite, result ing in lung protein nitrotyrosine formation and oxidative damage. In support of oxidant-mediated toxicity by perox-ynitrite is the demonstration of nitrotyrosine residues in the vascular endothelium and subendothelial tissues in patients with sepsis-induced ALI, and in the bronchoalveolar lavage of patients with ARDS. Whether the source of superoxide in this case is XOR or other lung oxidases, such as NAD(P)H oxidase, remains to be determined. Likewise, the specific source of NO may indeed be iNOS but potentially other oxidases, such as the neutrophil myeloperoxidase (through its NO oxidase activity), may also be involved.

XOR and Cardiovascular Diseases

The role of endothelial dysfunction and production of ROS in the pathogenesis of cardiovascular diseases has long been recognized. There has been renewed interest in the specific role of XOR in models of vascular diseases such as atherosclerosis and cardiomyopathy. Indeed, the endothelium has an important role in regulating local vasomotor tone. This is achieved through production of vasodilator (e.g., nitric oxide and prostacyclin) and vasoconstrictive substances (e.g., endothelin and superoxide). Therefore, tissue perfusion is quite dependent on a functional endothelium and a balance between these opposing endothelium-derived factors. An example of such imbalance is impaired flow-dependent, endothelium-mediated vasodilation in congestive heart failure (CHF), which appears to be secondary to reduced NO availability. The latter is dependent on production by endothelial nitric oxide synthase (NOS) but also on NO degradation by oxygen radicals, and in particular superoxide. Recent studies suggest that XOR is an important generator of superoxide in human vessels and may be one of the main sources of decreased NO availability, specifically through production of superoxide. Enhanced endothelium-bound XOR activity, in conjunction with decreased extracellular superoxide dismutase activity, has recently been associated with vascular oxidative stress in patients with CHF. A role for XOR in vascular oxidative stress is also suggested by reports of elevated myocardial XOR levels found in experimental heart failure and in patients with CHF, and identification of XOR in atherosclerotic plaques. Finally, an imbalance between NOS and XOR signaling pathways has been proposed in the regulation of myocardial mechanical efficiency, with upregulation of XOR relative to NOS as a leading factor in mechanoenergetic uncoupling in heart failure.

XOR and Lactation

The presence of XOR in cow and human milk has been long recognized; however, the exact function of the enzyme in the mammary gland has been unclear. The expression of XOR appears to be restricted to the mammary epithelium, and targeted disruption of XOR in mice revealed that XOR is important in the secretion of fat droplets in milk and, therefore, in maintaining lactation. In XOR +/- females, the mammary gland undergoes premature involution due to collapse of the mammary epithelium. In the secretion of the milk fat droplet, XOR translocates from a cytoplasmic position to an apical membrane location through structural interaction with two other milk fat globule proteins, butyrophilin and adipophilin. Whether this unique feature of XOR in secretory processes is also operative in the endothelium and in tissues other than the mammary gland is unclear at this time.

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