Ischemia ReperfusionInduced Microvascular Inflammation

I/R Promotes Oxidative Stress and Microvascular Inflammation

The microvascular alterations associated with I/R include the following: (1) impaired endothelium-dependent vasodi-lation in arterioles, (2) increased capillary permeability as well as a decrease in the number of perfused capillaries, and (3) enhanced leukocyte trafficking in postcapillary venules and increased venular permeability. Considerable evidence supports the involvement of ROS in the pathogenesis of these microvascular alterations. During reperfusion after prolonged ischemia, the reintroduction of oxygen to tissues increases oxidant formation in endothelial cells of all vascular segments, but particularly so in venules. Throughout the ischemic period, XO activity progressively increases within endothelial cells. When tissue O2 levels increase during reperfusion, marked increases in oxidant generation occur via XO. The resulting oxidant stress at the onset of reperfusion causes rapid microvascular alterations through several actions, including local generation of lipid inflammatory mediators (i.e., platelet activating factor, leukotriene B4) as well as mobilization of preformed P-selectin to the endothe-lial surface (which promotes leukocyte rolling). In addition, ROS also activate genes leading to upregulation of other adhesion molecules, which serves to prolong the microvas-cular inflammatory responses to I/R.

Superoxide/NO Balance and I/R-Induced Microvascular Dysfunction

Granger and colleagues have provided compelling evidence implicating changes in the balance between superoxide and NO levels as a critical determinant of microvascular alterations after I/R. According to this view, under normal conditions, NO production exceeds ROS generation such that NO can effectively scavenge superoxide, yet NO levels remain sufficient to maintain the endothelium in an antiinflammatory state (Figure 2, upper panel). When superoxide generation increases markedly upon reperfusion, the balance shifts in favor of ROS: NO levels are no longer able to effectively scavenge superoxide, resulting in a progressive decrease in NO levels and corresponding increase in ROS. This shift initiates a proinflammatory state within the microcirculation, leading to the microvascular dysfunction associated with I/R (Figure 2, lower panel). In support of this view, interventions which reduce ROS levels or increase NO levels (i.e., XO inhibitors, antioxidants, NO donors) attenuate the severity of microvascular dysfunction after I/R.

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