Gastric ulceration: critical events at the neutrophil--endothelium interface

Neutrophil adherence to the vascular endothelium and the subsequent release of oxygen-derived free radicals and proteolytic enzymes has been implicated as a critical event in the pathogenesis of various forms of gastrointestinal ulceration. This paper reviews the evidence that events at the neutrophil-endothelium interface are important in the pathogenesis of gastric ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Endothelial injury occurs within minutes of NSAID administration and appears to be attributable to neutrophil adherence and activation. Neutrophil adherence in response to NSAIDs may occur as a consequence of inhibition of endothelial prostaglandin synthesis, but it appears to involve a lipoxygenase product, such as leukotriene B4. Prevention of neutrophil adherence to the vascular endothelium results in near-complete prevention of experimental NSAID gastropathy. Depletion of circulating neutrophils also results in reduced susceptibility to NSAID-induced mucosal injury. As prostaglandins are potent inhibitors of neutrophil adherence and activation, it is possible that the neutrophil--endothelium interface represents one of the most important targets of action of these compounds in terms of their ability to prevent or reduce the severity of NSAID-induced ulceration.