MODULATION OF P-SELECTIN EXPRESSION IN THE POSTISCHEMIC INTESTINAL MICROVASCULATURE

The dual radiolabeled monoclonal antibody technique was used to 1) def ine the magnitude and kinetics of P-selectin expression in murine smal l intestine exposed to ischemia-reperfusion (I/R), and 2) determine th e factor(s) responsible for initiating this response. Within 10 min af ter release of a 20-min arterial occlusion, intestinal P-selectin expr ession increased two-to threefold compared with control values. Peak ( 4-fold) expression of P-selectin was noted at 5 h after reperfusion, r eturning to the control value at 24 h. The early (10-30 min) I/R-induc ed upregulation of P-selectin appears to reflect mobilization of a pre formed pool of the adhesion molecule, whereas the later(5 h) rise appe ars to be transcription dependent. The early increase in P-selectin ex pression was not inhibited by pretreatment with either oxypurinol (inh ibits xanthine oxidase), diphenhydramine (H-1-receptor antagonist), or MK-571 (leukotriene C-4/D-4 antagonist), nor was it blunted in transg enic mice expressing three times the normal level of copper-zinc super oxide dismutase or in mast cell-deficient mice. However, significant i nhibition was noted after treatment with either MK-886 (5-lipoxygenase inhibitor) or a nitric oxide (NO) donor (diethylenetriamine/NO). Thes e findings indicate that the early I/R-induced increase in intestinal P-selectin expression is mediated by a 5-lipoxygenase-dependent NO-inh ibitable mechanism.