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Ischemia/reperfusion-induced microvascular dysfunction: role of oxidants and lipid mediators
I Kurose1, L W Argenbright, R Wolf
1Department of Physiology, Louisiana State University Medical Center, Shreveport 77130-3932, USA.
Abstract:
The objective of this study was to define the role of oxidants and lipid mediators in the leukocyte-endothelial cell adhesion and albumin leakage elicited in rat mesenteric venules by ischemia-reperfusion (I/R). Intravital fluorescence microscopy was used to monitor leukocyte adherence and emigration, platelet-leukocyte aggregation, mast cell degranulation, and albumin leakage after release of a 20-min arterial occlusion. I/R elicited large increases in leukocyte-endothelial cell adhesion and albumin leakage. These responses were significantly attenuated in venules treated with either superoxide dismutase, oxypurinol (an inhibitor of xanthine oxidase), lodoxamide (a mast cell stabilizer), WEB-2086 (a platelet-activating factor antagonist), or SC-41930 (a leukotriene B4-receptor antagonist) but not by U-74006F (an inhibitor of lipid peroxidation). Platelet-leukocyte aggregates and mast cell degranulation induced by I/R were also attenuated by administration of either superoxide dismutase or lodoxamide. These results support the hypothesis that oxidants produced, in part, by xanthine oxidase promote the formation (by mast cells and endothelial cells) of platelet-activating factor and leukotriene B4, which recruit and activate leukocytes in postischemic venules. The adherent and emigrated leukocytes then mediate the increased albumin extravasation observed in the postcapillary venules.
Insights
Oxidants and lipid mediators drive leukocyte adhesion and albumin leakage after ischemia-reperfusion (I/R). Inhibiting oxidants, platelet-activating factor, and leukotriene B4 significantly reduced these damaging I/R responses.
Area of Science:
- Physiology
- Pathophysiology
- Inflammation Research
Background:
- Ischemia-reperfusion (I/R) injury involves complex inflammatory responses.
- Leukocyte-endothelial cell interactions and vascular permeability are key features of I/R.
Purpose of the Study:
- To elucidate the roles of oxidants and lipid mediators in I/R-induced leukocyte adhesion and albumin leakage.
- To investigate the involvement of xanthine oxidase, mast cells, platelet-activating factor, and leukotriene B4 in I/R.
Main Methods:
- Utilized intravital fluorescence microscopy in a rat mesenteric venule model.
- Monitored leukocyte adherence, emigration, platelet-leukocyte aggregation, mast cell degranulation, and albumin leakage.
- Administered various inhibitors including superoxide dismutase, oxypurinol, lodoxamide, WEB-2086, SC-41930, and U-74006F.
Main Results:
- I/R significantly increased leukocyte-endothelial cell adhesion and albumin leakage.
- Superoxide dismutase, oxypurinol, lodoxamide, WEB-2086, and SC-41930 attenuated these I/R-induced responses.
- Platelet-leukocyte aggregates and mast cell degranulation were reduced by superoxide dismutase and lodoxamide.
Conclusions:
- Oxidants, partly from xanthine oxidase, contribute to the formation of platelet-activating factor and leukotriene B4 during I/R.
- These mediators recruit and activate leukocytes, leading to increased albumin extravasation in postischemic venules.
- Targeting these pathways may offer therapeutic strategies for I/R injury.
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