Immunoinflammatory cascade activation may be either a cellular response to injury (the acute phase response) or the cause of cellular injury if the degree of activation is severe and prolonged, as in the systemic inflammatory response syndrome. Leukocyte and endothelial activation and neutrophil migration are central to this process. Cytokines and other cellular chemoattractants activate leukocytes and promote their adhesion to vascular (particularly venous) endothelium, with subsequent migration into the tissues. The specific site of attachment may be determined by the volume of endothelium available, local cytokine signaling from tissue macrophages, and local tissue injury. Neutrophils cannot re-enter the circulation, and remain trapped within the tissues discharging their contents until they are phagocytosed. Not only are neutrophils activated by the cellular response to ischemia-reperfusion and membrane oxidation, but they themselves also cause oxidative damage by generating reactive oxygen species, including nitric oxide. Thus there are considerable similarities between the precipitants of, and the host response to, cell injury. The cytokine network is a complex and very sensitive system for controlling host defenses, but once widely activated it has limited powers of expression and may be poorly targeted.
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