Inhibition of TNF-alpha reduces myocardial injury and proinflammatory pathways following ischemia-reperfusion in the dog.
We examined whether tumor necrosis factor-alpha (TNF-alpha) promotes postischemic inflammation and myocardial injury via activation of nuclear factor kappa B (NFkappaB) in an in vivo canine model. Isoflurane-anesthetized dogs underwent closed-chest balloon occlusion of the anterior descending coronary artery for 90 minutes, followed by reperfusion for 3 hours. Dogs randomly received a soluble TNF inhibitor (etanercept, 0.5 mg/kg intravenously) or saline before occlusion. Collateral blood flow and risk region size (RISK) were measured with radioactive microspheres, infarct size (INF) was measured by triphenyltetrazolium chloride staining, inflammation was measured by tissue myeloperoxidase (MPO) activity, intercellular adhesion molecular-1 (ICAM-1) messenger ribonucleic acid (mRNA) was measured by Northern blotting, and ICAM-1 protein expression was measured by Western blotting. NFkappaB activation was measured in nuclear extracts by electrophoretic mobility shift assays. INF/RISK was significantly smaller in the etanercept group than in the saline control group after adjusting for collateral flow (P < 0.009 by analysis of covariance, mean reduction in INF/RISK = 40%, 0.32 +/- 0.09 versus 0.53 +/- 0.09). MPO activity, ICAM-1 mRNA and protein expression, and NFkappaB binding activity were all significantly reduced in the etanercept group. Administration of a soluble TNF-alpha inhibitor reduced NFkappaB activation, ICAM-1 upregulation, and myocardial injury following ischemia-reperfusion. TNF-alpha appears to play a significant role in vivo in the genesis of postischemic inflammation.
Gu
Qiuping
Q
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Yang
Xiao Ping
XP
Bonde
Pramod
P
DiPaula
Anthony
A
Fox-Talbot
Karen
K
Becker
Lewis C
LC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D001831:Body Temperature / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D024202:Electrophoretic Mobility Shift Assay; D000068800:Etanercept; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007120:Immunochemistry; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control*; D007275:Injections, Intravenous; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D016328:NF-kappa B; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000068800:Etanercept