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.


METHODS
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).


METHODS
The University of Colorado Surgical Research Laboratories, Denver.


METHODS
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.
Meldrum
D R
DR
Department of Surgery, University of Colorado Health Sciences Center, Denver, USA.
Sheridan
B C
BC
Cleveland
J C
JC
Fullerton
D A
DA
Banerjee
A
A
Harken
A H
AH
D000818:Animals; D001794:Blood Pressure; D003326:Coronary Circulation; D003402:Creatine Kinase / Q000032:analysis; D003971:Diastole; D004198:Disease Susceptibility / Q000276:immunology; D004731:Endotoxins / Q000276:immunology*; D006324:Heart Arrest, Induced; D007958:Leukocyte Count; D008297:Male; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000276:immunology*; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000276:immunology*; D009206:Myocardium / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology*; D018384:Oxidative Stress / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004731:Endotoxins; D003402:Creatine Kinase