Which of the following statement(s) is/are true concerning ischemia reperfusion injury?

a. During ischemia, ATP degradation results in increased plasma and intracellular levels of hypoxanthine and xanthene

b. Oxygen free radicals such as the superoxide radical are involved in the expression of the proinflammatory phenotype of endothelial cells, macrophages and neutrophils

c. The intracellular adhesion molecule-1 (ICAN-1) contributes to injury and disruption of the endothelial lining, with extensive capillary leak and resultant interstitial edema

d. Animal models have demonstrated that passive immunization with antibodies to neutrophil adhesive complex lessen the ischemic/reperfusion microvascular injury

During the ischemia and hypoperfusion phase, degradation of ATP stores essential to maintain cell integrity and significant loss of diffusible intracellular adenine neuclotides occurs. As ATP further degrades there is an elevation in plasma and intracellular levels of hypoxanthine and xanthene which upon restoration of perfusion and reoxygenation are catalyzed by xanthine oxidase resulting in the formation of superoxide radicals. These radicals plus others such as hydrogen peroxide and hydroxyl radical are generated and lead to endothelial and parenchymal cell injury through membrane lipid peroxidation and activation of critical enzymes. These radicals have also been shown to be involved in the expression of proinflammatory phenotype endothelial cells and on macraphages and neutrophils. The proinflammatory phenotype of the endothelium includes procoagulant activity and the expression of adhesion molecules on the membrane surface, including the intercellular adhesion molecule-1 (ICAN-1) and the selectins. The subsequent adhesion of activated neutrophils to the endothelial leads to an explosive oxidative burst producing additional radicals and extensive release of proteolytic enzymes leading to injury and disruption of the endothelial lining, extensive capillary leak, and massive interstitial edema. Passive immunization of animals with monoclonal antibodies to either the neutrophil adhesive complex or the endothelial selectins dramatically lessens ischemia/reperfusion microvascular injury.