Neutrophils are required for endotoxin-induced myocardial cross-tolerance to ischemia-reperfusion injury
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D R Meldrum1, B C Sheridan, J C Cleveland
1Department 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.
Insights
Sublethal endotoxin protects the heart against ischemia-reperfusion injury by inducing polymorphonuclear neutrophils (PMNs). Depleting PMNs before endotoxin administration blocks this protective effect, indicating PMN induction is essential for endotoxin-mediated myocardial resistance.
Area of Science:
- Cardiovascular Physiology
- Immunology
- Cellular Biology
Background:
- Polymorphonuclear neutrophilic leukocytes (PMNs) are known to contribute to oxidative stress following endotoxemia.
- The role of pre-ischemic PMN induction in endotoxin-mediated myocardial resistance to ischemia-reperfusion (I/R) injury remains unclear.
Purpose of the Study:
- To investigate whether neutrophils mediate endotoxin-induced myocardial cross-tolerance to I/R.
- To elucidate the mechanism of endotoxin's protective effect on the heart during I/R.
Main Methods:
- Rats were administered sublethal endotoxin 24 hours before inducing global myocardial I/R.
- Neutrophil depletion was achieved using anti-PMN antibody, with absolute neutrophil counts monitored.
- Myocardial function (developed pressure, coronary flow) and injury markers (creatine kinase leakage) were assessed.
Main Results:
- Sublethal endotoxin preconditioning significantly improved recovered cardiac function and reduced I/R injury markers.
- Administration of anti-PMN antibody prior to endotoxin abolished these protective effects.
- Neutrophil depletion alone did not alter the severity of I/R injury, but prevented endotoxin-induced tolerance.
Conclusions:
- Sublethal endotoxin induces myocardial cross-tolerance to I/R.
- PMN induction is a critical requirement for endotoxin-mediated myocardial resistance to I/R.
- Endotoxin-induced tolerance to I/R does not occur in a neutropenic state.