In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury.

Abstract

The cardioprotective effects of an mAb to P-selectin designated mAb PB1.3 was examined in a feline model of myocardial ischemia (MI) and reperfusion. PB1.3 (1 mg/kg), administered after 80 min of ischemia (i.e., 10 min before reperfusion), significantly attenuated myocardial necrosis compared to a nonblocking mAb (NBP1.6) for P-selectin (15±3 vs 35±3% of area at risk, P < 0.01). Moreover, endothelial release of endothelium derived relaxing factor, as assessed by relaxation to acetylcholine, was also significantly preserved in ischemic-reperfused coronary arteries isolated from cats treated with mAb PB1.3 compared to mAb NBP1.6 (67±6 vs 11±3, P < 0.01). This endothelial preservation was directly related to reduced endothelial adherence of PMNs in ischemic-reperfused coronary arteries. Immunohistochemical localization of P-selectin was significantly upregulated in the cytoplasm of endothelial cells that lined coronary arteries and veins after 90 min of ischemia and 20 min of reperfusion. The principal site of intracytoplasmic expression was in venous vessels. mAb PB1.3 significantly decreased (P < 0.01 ) adherence of unstimulated PMNs to thrombin and histamine stimulated endothelial cells in a concentration-dependent manner in vitro. These results demonstrate that PMN adherence to endothelium by P-selectin is an important early consequence of reperfusion injury, and a specific monoclonal antibody to P-selectin exerts significant endothelial preservation and cardioprotection in myocardial ischemia and reperfusion. (J. Clin. Invest. 1993. 91:2620-2629

Lipoxin A4stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

“…Both the superior mesenteric artery and superior mesenteric vein then were rapidly cannulated for perfusion fixation of the small bowel. The ileum was first washed free of blood by perfusion with Krebs-Henseleit buffer warmed to 37°C, bubbled with 95% O 2 and 5% CO 2 , and fixed in 4% paraformaldehyde for 90 min at 4°C as previously described (25).…”

“…Immunohistochemical localization of P-selectin was accomplished using the avidin-biotin immunoperoxidase technique (Vectastain ABC Reagent, Vector Laboratories) as previously described by Weyrich et al (25). Positive staining was defined as a venule displaying brown reaction product on greater than 50% of the circumference of its endothelium.…”

The immune system and cardiac repair

“…It is stored in the Weibel-Palade bodies and is rapidly translocated to the endothelial surface in response to thrombin and/or oxidative stress, both of which would be likely to be found in the ischemic myocardium, and to histamine, which is rapidly released in the injured myocardium by degranulating mast cells. Experimental studies have suggested that monoclonal antibodies against L-selectin and P-selectin [183,184] reduced myocardial necrosis, preserving coronary endothelial function and attenuating neutrophil accumulation in the ischemic and reperfused feline myocardium. In addition, P-selectin deficient mice showed decreased infarct size after 30 min of coronary occlusion and 2 h of reperfusion [185].…”

Relationship of admission hematological indexes with myocardial reperfusion abnormalities in acute ST segment elevation myocardial infarction patients treated with primary percutaneous coronary interventions

“…We might speculate that patients with a higher MPV have a higher potential for platelet-leukocyte interaction and thus, are more prone to platelet-activated, leukocyte-mediated reperfusion injury. Accordingly, in experimental models, interfering with P-selectin function, which is supposed to be the key linking molecule between platelets and leukocytes, has been shown to reduce neutrophil infiltration and subsequent myocardial damage after reperfusion (29).…”