Mechanisms of neutrophil-mediated injury.

The interaction of neutrophils with endothelial cells results in damage or killing of the latter. This outcome requires alteration of the endothelial cells such thatadhesive interactions betweenncutrophils and endothelia! cells are enhanced. In addition, neutrophil stimulation must also occur. To date, the most important adhesion promoting molecules appear to involve either P-selectiii or E-selectin as vv-ell as intercellular adhesion molecule-1 (lCAM-1). The 'counter-receptors' for these endothelial adhesion molecules are oligosaccharides {sialyl Lewis") presumably present on neutrophils in some sort of glycoconjugate as well as the P2 integrins of the neutrophil (CDlla/CD18, CDllb/CDl8, CDllc/ CD18). Engagement of these adhesion molecules results in close physical contact between neutrophils and their targets, the endothelial cells. Activated neutrophils release two important types of products involved in endothelial cell injury: proteases and oxygen products. With respect to the former, human leukocy ticelastase apparently gains entry to the endothelial cell cytoplasm where it induces hmited cleavage of xanthine dehydrogenase, converting this enzyme to xanthine oxidase (x.o.) [1]. The major oxygen product from the activated neutrophil is H^O ,̂ which readily diffuses into the endothelial cells. In turn, HjO, causes breakdown of endothelial ceil ATP, ultimately to form xanthine and hypoxanthine. substrates for x.o. [2]. Interactions of these substrates with x.o. results in generation of superoxide anion (Oj). The availability of iron in the endothelial ceil appears to be critical to the outcome of endothetial cell injury, since inadequate availability of iron will block neutrophil-mediated injury of endothehal cells [3]. The requirement for iron has been shown by the use of iron chelators (deferroxamine) or by the use of late passage endothelial cells which show iron depletion [4). In vitro repletion of intracellular iron by exogenously administered iron restores susceptibility to neutrophil-mediatedkilling.Itappears that the key roleofiiUracellularly generated O^ is to reduce the storage form of iron. Fe**, to its transition state, Fe^^ The latter then reacts with H,O^ to cause a single electron addition, producing the hydroxyl radical (HO*). HO* appears to be the toxic oxygen product responsible for endothelial cell injury [3]. The requirement for intracellular O " in neutrophil mediated killing of endothelial cells has been shown by causing the endothelial cell levels of superoxide dismutase (SOD) to increase approximately 10 fold by exogenous addition of SOD [5]. Under these conditions, neutrophilmediated killing of endothelial cells is greatly attenuated. Thus, the ability of neutrophils to kill endothelial cells requires products both from neutrophils as well as from endothelial cells.