Neutrophils are required for endotoxin-induced myocardial cross-tolerance to ischemia-reperfusion injury.

BACKGROUND

Although polymorphonuclear neutrophilic leukocytes (PMNs) contribute to oxidative stress after endotoxemia, it is unknown whether preischemic PMN induction is required for endotoxin-mediated myocardial resistance to ischemia-reperfusion (I/R).

OBJECTIVE

To determine whether neutrophils mediate endotoxin-induced myocardial cross-tolerance to I/R.

DESIGN AND INTERVENTIONS

Rats received sublethal endotoxin (0.5 mg/kg intraperitoneally) with and without rabbit anti-rat PMN antibody (anti-PMN antibody, 0.15 mL intravenously, to achieve an absolute neutrophil count of < 200/microL) or antibody alone, 24 hours prior to global myocardial I/R (20-40 minutes, Langendorff mode).

SETTING

The University of Colorado Surgical Research Laboratories, Denver.

MAIN OUTCOME MEASURES

Myocardial developed pressure, coronary flow, end diastolic pressure, and time to ischemic contracture were recorded with a pressure amplifier-digitizer (MacLab, AD Instruments Inc, Milford, Mass). Myocyte damage was assessed by determining creatine kinase leakage in the coronary flow effluent by creatine kinase assay.

RESULTS

Sublethal endotoxin induced cross-tolerance to I/R, as demonstrated by improved recovered developed pressure and coronary flow, and decreased time to ischemic contracture, end diastolic pressure, and creatine kinase leak (P < .05, analysis of variance and Bonferroni-Dunn). Anti-PMN antibody administered prior to sublethal endotoxin abolished these protective effects (P < .05). Polymorphonuclear neutrophil leukocyte depletion alone failed to abrogate the deleterious effects of I/R.

CONCLUSIONS

(1) Sublethal endotoxin induces myocardial cross-tolerance to I/R; (2) PMN induction is required for endotoxin-mediated myocardial resistance to I/R; and (3) while myocardial I/R injury is equally severe after antibody-mediated PMN depletion, endotoxin-induced tolerance to I/R does not occur in the neutropenic host.