Neutrophils are required for endotoxin-induced myocardial cross-tolerance to ischemia-reperfusion injury
D. R. Meldrum, B. C. Sheridan, J. C. Cleveland Jr, D. A. Fullerton, A. Banerjee and A. H. Harken
Department of Surgery, University of Colorado Health Sciences Center, Denver, USA.
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.
