bof-4272 and Ischemia

We investigated the effects of the xanthine oxidase inhibitor, BOF-4272, on the production of cytokine-induced neutrophil chemoattractant (CINC) following reperfusion injury in rat liver. Ischemia was induced for 30 minutes by portal vein occlusion. Animals were pretreated with intravenous injection of BOF-4272 (1 mg/kg) or heparin (50 U/kg) 5 minutes before vascular clamp. Both BOF-4272 and heparin limited increases in the chemoattractant compared with nonpretreated rats. Pretreatment with BOF-4272 plus heparin resulted in an additive effect. Most cells immunostained for chemoattractant were macrophages in sinusoids. In vitro chemoattractant production by Kupffer cells isolated from animals pretreated with heparin or BOF-4272 was significantly lower than by Kupffer cells from nonpretreated animals. Expression of transcripts in liver for chemoattractant peaked 3 hours after reperfusion in nonpretreated animals, while pretreatment with heparin or BOF-4272 significantly decreased chemoattractant mRNA levels. In vitro chemoattractant transcription and production could be induced in naive Kupffer cells by hypoxanthine and xanthine oxidase, but BOF-4272 prevented these increases. We conclude that Kupffer cells release chemoattractant in response to oxygen radicals reducible by xanthine oxidase inhibition.

Topics: Animals; Chemokines, CXC; Chemotactic Factors; Enzyme Inhibitors; Growth Substances; Heparin; Intercellular Signaling Peptides and Proteins; Ischemia; Kupffer Cells; Liver; Liver Circulation; Male; Neutrophils; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; RNA, Messenger; Triazines; Xanthine Oxidase

Although leukocyte adhesion and capillary plugging are postulated to play a role in postischemic tissue injury, there is only limited evidence demonstrating the relationship between tissue leukocyte accumulation and cell injury in terms of their temporal sequence and spatial distribution.. This study was designed to study in vivo neutrophil behavior and its correlation with cell injury in postischemic skeletal muscle microcirculation. The microcirculation of the rat spinotrapezius muscle was observed in vivo using dual-color digital microfluorography to simultaneously visualize leukocyte traffic and cell death (irreversible nuclear damage) on the basis of carboxyfluorescein diacetate succinimidyl ester and propidium iodide, respectively. A 1-hour period of hemorrhagic hypotension (40 mm Hg) followed by reperfusion was carried out to induce muscle injury.. Hypotension was followed by an increase in leukocyte recruitment in two different ways: capillary obstruction and venular adhesion. Upon reperfusion, a majority of the leukocytes were initially dispersed from the muscle capillaries and venules, but then the number of leukocytes plugging capillaries and adherent to venules increased again in a time-dependent manner. The number of leukocytes obstructing capillaries was closely correlated with the postischemic systemic blood pressure. The cell injury became detectable initially at the end of the hypotensive period and then increased explosively after reperfusion before a significant leukocyte accumulation. Reperfusion-induced early nuclear injury was seen predominantly in reperfused capillaries without plugging leukocytes. A majority of the initially damaged nuclei were those of myocytes in the pericapillary space, but no nuclei of capillary endothelium was involved. Sodium (-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a]-1,3,5-triazine-4-olate monohydrate, a novel inhibitor of xanthine oxidase, significantly attenuated the early increase in muscle injury and subsequent venular leukocyte adhesion after reperfusion.. These results suggest the involvement of an endothelium-dependent mechanism involving xanthine oxidase in postischemic irreversible myocyte injury. It is conceivable that leukocytes adherent to venules as well as those plugging capillaries play only minor roles in the initial mechanism of reperfusion injury.

Topics: Animals; Antibodies, Monoclonal; Antigens, CD; Blood Pressure; Capillaries; CD18 Antigens; Ischemia; Leukocytes; Male; Microcirculation; Microscopy, Fluorescence; Muscles; Rats; Rats, Wistar; Reperfusion; Time Factors; Triazines; Venules; Xanthine Oxidase