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CD18 antibody treatment limits early myocardial reperfusion injury after initial leukocyte deposition
P F McDonagh1, D S Wilson, H Iwamura
1Department of Surgery, College of Medicine, University of Arizona, Tucson, USA.
Insights
Treating reperfusion blood with a CD18 antibody improved heart function recovery after ischemia. This suggests blocking leukocyte adhesion may reduce reperfusion injury by modulating inflammation, not just leukocyte retention.
Area of Science:
- Cardiovascular Science
- Immunology
- Ischemia-Reperfusion Injury
Background:
- Myocardial ischemia followed by reperfusion can impair ventricular function.
- Leukocytes play a significant role in early myocardial reperfusion injury, but mechanisms remain unclear.
Purpose of the Study:
- To investigate if a monoclonal antibody (CL26) against leukocyte adhesion protein CD18 reduces leukocyte contribution to early reperfusion injury.
- To determine if blocking CD18 alters leukocyte retention and subsequent inflammatory responses.
Main Methods:
- Isolated rat hearts underwent normothermic ischemia followed by reperfusion with diluted whole blood (DWB) treated with either vehicle or CL26 antibody.
- Ventricular function, coronary flow, and leukocyte retention were measured during reperfusion.
- Hearts were subsequently reperfused with a red cell-rich solution (K2RBC).
Main Results:
- Leukocyte retention in the heart was similar between vehicle and CL26-treated groups.
- While initial ventricular function recovery was not different, later recovery (+dP/dt) was significantly improved in the CL26 group.
- Hearts treated with CL26 required less voltage for pacing, indicating better functional recovery.
Conclusions:
- Blocking CD18 with CL26 antibody improved ventricular function recovery post-ischemia, independent of reduced leukocyte retention or improved coronary flow.
- The findings suggest that CD18 antibody treatment attenuates inflammatory responses occurring after initial leukocyte deposition, thereby mitigating reperfusion injury.
Abstract:
Following myocardial ischemia, initial reperfusion with whole blood impairs the recovery of ventricular function. The exact mechanisms underlying early myocardial reperfusion injury are not clear, but leukocytes play an important role. In this study, we tested if treating the initial blood reperfusate with a monoclonal antibody (CL26) against the leukocyte adhesion protein (CD18 would reduce the leukocyte contribution to early reperfusion injury. We reasoned that blocking CD18 would reduce the initial retention of leukocytes in the heart and thereby limit the inflammatory response. Rat hearts were isolated and perfused at constant flow with a red cell-rich solution (K2RBC). The perfusate was not recirculated. Baseline measures were made of coronary flow, perfusion pressure, and ventricular pump function. No-flow, normothermic ischemia was induced for 30 min, followed immediately by reperfusion, at the preischemic flowrate, with diluted whole blood (DWB, treated with either vehicle or CL26). Reperfusion was continued with K2RBC for 40 min more, during which postischemic measures were made. We found that the cardiac retention of leukocytes was not significantly different for the two groups, nor were the recoveries of ventricular function. Later in reperfusion (R35), the coronary blood flowrate and the coronary vascular resistances were not different; however, the recoveries of ventricular pump function were significantly different (+dP/dt @ R35 (%Pre-I): Vehicle: 27 +/- 9% (n = 8); CL26: 51 +/- 6% (n = 7); P < 0.05). Also, at R35, the voltage required to capture and pace the vehicle-treated hearts was significantly greater than the voltage required to pace the CL26 hearts (P < 0.05). Because the coronary flowrate and leukocyte retention were similar for both groups, the improved recovery observed in the CL26-treated group was not due to either improved flow or to reduced leukocyte retention. Rather, the findings suggest that the beneficial effect of antibody treatment was to attenuate step(s) in the acute inflammatory response that occurred after the initial deposition of leukocytes in the heart.