Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mo1, anti-CD11b) that inhibits leukocyte adhesion.

Abstract

A monoclonal antibody (904) that binds to a leukocyte cell adhesion-promoting glycoprotein, (Mol; CD11b/CD18) was administered (1 mg/kg, iv.) to open chest anesthetized dogs 45 min after the induction of regional myocardial ischemia. Ischemia was produced by occluding the left circumflex coronary artery (LCX) for 90 min and then reperfusing for 6 h. There was no difference between control and antibody treated groups with respect to arterial blood pressure, heart rate, or LCX blood flow. Administration of antibody produced no observable effect on circulating neutrophil counts, suggesting that antibody-bound neutrophils were not cleared from the circulation. The mean size of myocardial infarct expressed as percentage of the area at risk of infarction that resulted was reduced by 46% with anti-Mol treatment (25.8±4.7%, n = 8) compared to control (47.6±5.7%, n = 8; P < 0.01). The area at risk of infarction was similar between groups. Circulating (serum) antibody excess was confirmed in all 8 anti-Mol treated dogs by immunofluorescence analysis. Analysis of ST segment elevation on the electrocardiogram as an indicator of the severity of ischemia suggests that the anti-Mol reduces infarct size independent of the severity of ischemia. An additional group of dogs (n = 5) was tested with a control monoclonal antibody of the same subtype (murine IgGI) and was found to produce no significant reduction in myocardial infarct size. Accumulation of neutrophils within the myocardium was significantly attenuated with 904 treatment when analyzed by histological methods. These data demonstrate that administration of anti-Mol monoclonal antibody after the induction of regional myocardial ischemia results in reduced myocardial reperfusion injury as measured by ultimate infarct size.

Up‐Regulation of Endothelial Cell Adhesion Molecules Characterizes Disease Activity in Systemic Lupus Erythematosus

“…It is important to note that, regardless of the mechanism which leads to their production, the complement-derived anaphylatoxins generated in the plasma of patients with active SLE are potential inflammatory mediators: C3a des Arg and C5a desArg activate platelets (29) and neutrophils (30), respectively. Aggregation of these cells in small vessels following exposure to C3a desArg and C5a desArg has been invoked as a cause of vascular injury in diverse clinical syndromes including the adult respiratory distress syndrome (3 l), cerebral injury following extracorporeal circulation (32,33), reperfusion injury of the myocardium (34,35), and endotoxic shock (36). We have recently provided serologic and histologic evidence which suggests that syndromes of reversible hypoxemia and cerebritis in SLE may have a similar pathogenic mechanism (37).…”

Tumor-Necrosis-Factor-.ALPHA.-Gene-Deficient Mice Have Improved Cardiac Function Through Reduction of Intercellular Adhesion Molecule-1 in Myocardial Infarction

“…21 The systemic administration of an anti-CD11 monoclonal antibody significantly reduced infarct size in a dog model, 26,27 and CD18 or ICAM-1 KO mice show a reduced infarct size in ischemia-reperfusion injury. 28 Postischemic cardiac lymph can induce expression of both ICAM-1 and interleukin-6, and treatment with anti-TNF-antibody inhibits its ability to do so.…”

Retroinfusion of NFκB decoy oligonucleotide extends cardioprotection achieved by CD18 inhibition in a preclinical study of myocardial ischemia and retroinfusion in pigs

“…Accordingly, early bolus application of adhesion antagonists, eg CD18 antibodies or selectin antagonists, reduces myocardial detriment after 3-6 h of reperfusion. 4,5 However, improvement of myocardial function after anti-adhesive therapy fades over time, and is maintained only in animals receiving continuous antiadhesive treatment. 6,7 Consistent with these observations, postischemic PMN adhesion occurs in an immediate or delayed manner:…”