TY - JOUR
T1 - Evaluation of the role of polymorphonuclear leukocytes on contractile function in myocardial reperfusion injury
T2 - Evidence for plasma-mediated leukocyte activation
AU - Shandelya, Suresh M.L.
AU - Kuppusamy, Periannan
AU - Weisfeldt, Myron L.
AU - Zweier, Jay L.
PY - 1993/2
Y1 - 1993/2
N2 - Background. It has been hypothesized that chemotaxis and activation of polymorphonuclear leukocytes (PMNs) occur upon reperfusion of ischemic myocardium. Questions remain, however, regarding the mechanisms by which PMNs are chemotaxed and activated and how this process causes contractile failure. Methods and Results. Studies were performed in an isolated rat heart model in which the effects of isolated cellular or humoral factors could be studied. Isolated rat hearts were perfused by the method of Langendorff, subjected to 20 minutes of global ischemia, and reperfused with perfusate alone or with perfusate containing PMNs, plasma, PMNs plus plasma, or PMNs plus inactivated plasma (preheated to 56°C for 30 minutes to denature complement) (n=10 in each group). Left ventricular developed pressure (LVDP) was measured during 1 minute of preischemic control infusion and on reflow after a 20-minute period of global ischemia. Additional measurements of free-radical generation were also performed on the coronary effluent by electron paramagnetic resonance spectroscopy (EPR) with the spin trap 5,5′-dimethyl-1-pyrroline-N-oxide (DMPO). During control infusion, no significant alterations in LVDP were observed, and there was no measurable free-radical generation. Reperfusion with plasma or PMNs alone did not alter postischemic LVDP, whereas plasma and PMNs together caused marked injury. LVDP after 45 minutes of reflow with PMNs plus plasma was 31.9±6.1% of control compared with 60.6±9.9% with plasma, 64.5±8.8% with PMNs, and 63.6±7.2% with perfusate alone (p<0.01). With plasma, which was preheated to deplete complement, this injury was not seen; LVDP was 70.8±10.9%. EPR measurements with the spin trap DMPO in the absence of PMNs demonstrated that oxygen free-radical generation is observed only during the first 1-2 minutes of reflow. Upon reperfusion with PMNs and plasma, however, radical generation persisted for more than 10 minutes. Increased neutrophil accumulation was observed in the postischemic heart in the absence of plasma; however, plasma factors were required for neutrophil-mediated contractile failure. C5a alone did not cause significant injury, but in the presence of PMNs it effectively substituted for plasma, causing marked injury. Conclusions. Thus, plasma factors, most likely complement, are required for neutrophil activation with oxygen free-radical generation and secondary contractile dysfunction.
AB - Background. It has been hypothesized that chemotaxis and activation of polymorphonuclear leukocytes (PMNs) occur upon reperfusion of ischemic myocardium. Questions remain, however, regarding the mechanisms by which PMNs are chemotaxed and activated and how this process causes contractile failure. Methods and Results. Studies were performed in an isolated rat heart model in which the effects of isolated cellular or humoral factors could be studied. Isolated rat hearts were perfused by the method of Langendorff, subjected to 20 minutes of global ischemia, and reperfused with perfusate alone or with perfusate containing PMNs, plasma, PMNs plus plasma, or PMNs plus inactivated plasma (preheated to 56°C for 30 minutes to denature complement) (n=10 in each group). Left ventricular developed pressure (LVDP) was measured during 1 minute of preischemic control infusion and on reflow after a 20-minute period of global ischemia. Additional measurements of free-radical generation were also performed on the coronary effluent by electron paramagnetic resonance spectroscopy (EPR) with the spin trap 5,5′-dimethyl-1-pyrroline-N-oxide (DMPO). During control infusion, no significant alterations in LVDP were observed, and there was no measurable free-radical generation. Reperfusion with plasma or PMNs alone did not alter postischemic LVDP, whereas plasma and PMNs together caused marked injury. LVDP after 45 minutes of reflow with PMNs plus plasma was 31.9±6.1% of control compared with 60.6±9.9% with plasma, 64.5±8.8% with PMNs, and 63.6±7.2% with perfusate alone (p<0.01). With plasma, which was preheated to deplete complement, this injury was not seen; LVDP was 70.8±10.9%. EPR measurements with the spin trap DMPO in the absence of PMNs demonstrated that oxygen free-radical generation is observed only during the first 1-2 minutes of reflow. Upon reperfusion with PMNs and plasma, however, radical generation persisted for more than 10 minutes. Increased neutrophil accumulation was observed in the postischemic heart in the absence of plasma; however, plasma factors were required for neutrophil-mediated contractile failure. C5a alone did not cause significant injury, but in the presence of PMNs it effectively substituted for plasma, causing marked injury. Conclusions. Thus, plasma factors, most likely complement, are required for neutrophil activation with oxygen free-radical generation and secondary contractile dysfunction.
KW - Free radicals
KW - Leukocytes
KW - Myocardial reperfusion injury
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U2 - 10.1161/01.CIR.87.2.536
DO - 10.1161/01.CIR.87.2.536
M3 - Review article
C2 - 8381059
AN - SCOPUS:0027392825
SN - 0009-7322
VL - 87
SP - 536
EP - 546
JO - Circulation
JF - Circulation
IS - 2
ER -