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Postischemic Leukocyte/Endothelial Cell Interactions and Microvascular Barrier Dysfunction in Skeletal Muscle: Cellular Mechanisms and Effect of Daflon® 500 mgKorthuis R.J. · Gute D.C.
Department of Physiology, Louisiana State University Medical Center, School of Medicine in Shreveport, La., USA
A growing body of evidence indicates that neutrophils play a critical role in disrupting the microvascular barrier in skeletal muscle. Recent studies from our laboratory and by others indicate that administration of antibodies directed against P-selectin, ICAM-1, or the common subunit (CD 18) of CD 11/CD 18 was as effective as neutrophil depletion in attenuating ischemia/ reperfusion (I/R)-induced microvascular barrier disruption and edema formation in skeletal muscle. These studies have important implications with regard to the pathogenesis of leg ulceration in view of our more recent work indicating that the increase in tissue pressure induced by edema formation secondary to microvascular barrier disruption may lead to the development of capillary no-reflow. The resulting maldistribution of blood flow during reperfusion exacerbates muscle injury induced by ischemia. Daflon® 500 mg is a purified, micronized flavonoid fraction that exhibits a number of anti-inflammatory properties and is used clinically to treat venous insufficiency. In view of these actions and the demonstrated role of neutrophil adhesion in the pathogenesis of I/R, we sought to determine whether this agent would prevent leukocyte adhesion and microvascular barrier disruption in postischemic rat cremaster muscles and small bowel. Rats were treated with Dafion 500 mg (80 mg/kg/ day by gavage) or its vehicle for 2 (cremaster studies) or 10 (mesenteric studies) days prior to the experiments. Leukocyte/endothelial cell interactions and venular protein leakage were quantitated using intravital microscopic techniques in rat cremaster muscles and mesenteries subjected to ischemia (60 min for cremaster, 20 min for mesentery) and reperfusion (60 min). The results indicated that Dafion 500 mg was as effective as the anti-adhesive monoclonal antibodies in reducing postischemic leukocyte adhesion and emigration and venular protein leakage in these models.
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