Locations and mechanisms of leukocyte accumulation in the coronary microcirculation during reperfusion following ischemia

Abstract

Restoration of blood flow to the ischemic myocardium is the most effective approach to limit necrosis. However, it appears that the act of reperfusion causes additional tissue damage, and this condition is known as myocardial reperfusion injury. It is well established that leukocytes contribute to additional myocyte and vascular injury during reperfusion, and that this injury occurs within the first minutes of flow restoration. A great deal is known about the leukocyte contribution to myocardial reperfusion injury. However, the mechanisms under which leukocytes accumulate in the coronary microcirculation during early reperfusion are unclear. The purpose of these studies was to identify the mechanisms of leukocyte accumulation in the coronary microcirculation during early reperfusion following ischemia. Using direct visualization techniques, it was observed that leukocyte accumulation in coronary capillaries and venules during the first minutes of reperfusion differs with respect to the magnitude and persistence of accumulation. During reperfusion, significant leukostasis in coronary capillaries occurs in the absence of blood activation, and is significantly enhanced when the blood is activated and when the reperfusion blood flow is moderately reduced. Also, the results indicate that postischemic capillary leukostasis can be attenuated by increasing leukocyte deformability and by inhibition of P- and L-selectin adhesion molecules. In contrast, leukocyte adhesion to the coronary venules during reperfusion is not significantly increased when the blood is not activated and returned at full flow. However, leukocyte adhesion to the venules is enhanced when the blood is activated or when reperfusion blood flow is severely reduced. In addition, under conditions of low reperfusion blood flow, leukocyte adhesion to the venules is attenuated by P- and L-selectin adhesion molecule inhibition. In these experiments, leukocytes remained in the capillaries longer than they remained in the venules during reperfusion. These results indicate that the degree to which leukocyte accumulation occurs in postischemic capillaries and venules is dependent upon the conditions of reperfusion. The results of this study also suggest that attempts to limit early myocardial leukocyte-mediated reperfusion injury should consider leukocyte deformability, the state of activation of the leukocyte, reperfusion blood flow, and selectin-mediated adhesion events.