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Neutrophils Are Required for Endotoxin-Induced Myocardial Cross-Tolerance to Ischemia-Reperfusion Injury

Daniel R. Meldrum, MD; Brett C. Sheridan, MD; Joseph C. Cleveland Jr, MD; David A. Fullerton, MD; Anirban Banerjee, PhD; Alden H. Harken, MD
Arch Surg. 1996;131(11):1203-1208. doi:10.1001/archsurg.1996.01430230085015.
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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/μL) 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.Arch Surg. 1996;131:1203-1208


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