Mechanisms responsible for enhanced inflammatory response to ischemia-reperfusion in diabetes

Abstract

The objective of the present study was to assess the role of lipid mediators and adhesion molecule expression in exacerbation of ischemia-reperfusion-induced inflammatory response in diabetes. Leukocyte-endothelial cell interactions were studied in mesenteric venules by intravital microscopy. Endothelial expression of intercellular adhesion molecule (ICAM)-1 was measured by the double-radiolabeled monoclonal antibody technique, and β2-integrin expression was measured by flow cytometry. Ischemia-reperfusion elicited significantly larger increases in leukocyte adhesion and emigration in diabetic rats that were prevented by a platelet-activating factor (PAF)-receptor antagonist or a leukotriene synthesis inhibitor. Leukotriene B4(LTB4) superfusion induced similar leukocyte recruitment in diabetic and control rats, whereas PAF elicited larger increases in diabetic rats. CD11a, but not CD11b, expression was higher in leukocytes from diabetic animals. Endothelial ICAM-1 in mesentery and in intestine did not differ between diabetic and control rats. These results indicate that diabetes is associated with an enhanced response to ischemia-reperfusion that depends on both PAF and leukotrienes. An increased sensitivity to PAF, along with an increased CD11a expression, may account for the exaggerated inflammatory response to ischemia-reperfusion in diabetes.

Reperfusion-induced oxidative stress in diabetes: cellular and enzymatic sources

“…The results of this study confirm that the diabetic state induces an exaggerated inflammatory response to I/R in the mesenteric microcirculation, which is manifested as a greater accumulation of adherent and emigrated leukocytes within the postcapillary venules [15,16]. Our studies also provide novel in vivo data that bear on the sequence and mechanisms involved in oxidative changes that occur in the microvasculature during reperfusion, and demonstrate that an enhanced oxidative stress accompanies the exacerbated inflammatory response to I/R in the diabetic state.…”

“…As we previously described in an animal model, the increased microvascular dysfunction induced by ischemia in the diabetic state is associated with an exaggerated inflammatory response during reoxygenation [15,16]. Although neutrophils in diabetes have been reported to produce enhanced amounts of ROMs in unstimulated conditions [17,18], oxidant production during reoxygenation of ischemic tissues has not yet been monitored and compared with the non-diabetic situation.…”

Role of P‐selectin in radiation‐induced intestinal inflammatory damage

“…To measure endothelial E-selectin expression, a mixture of 10 g of 125 I-anti-E-selectin MAb (RME-1) and 10 g of 131 I-nonbinding MAb (P23) was used. This dose of anti-P-selectin MAb has been shown to be saturating in previous assays [19]. The dose of anti-E-selectin MAb that has been shown to be saturating in previous assays in our laboratory was 10 g (data not shown).…”

Estrogen Replacement Treatment in Diabetic Ovariectomized Female Rats Potentiates Postischemic Leukocyte Adhesion in Cerebral Venules

“…6 In nonbrain models of ischemia/reperfusion, diabetic (chronically hyperglycemic) animals versus nondiabetics show a more intense postischemic inflammatory response. 7,8 There is currently no information regarding chronic hyperglycemia and postischemic inflammatory activity in cerebral ischemia/reperfusion models. In acutely hyperglycemic rats subjected to forebrain ischemia/reperfusion, Lin et al 9,10 reported a substantial increase (at 24 to 72 hours) in the numbers of adherent and infiltrated leukocytes in and around pial vessels, as well as parenchymal vessels in vulnerable brain regions.…”