Therapeutic strategies to reduce TNF-alpha mediated cardiac contractile depression following ischemia and reperfusion.
Recent evidence has implicated proinflammatory mediators such as TNF- alpha in the pathophysiology of ischemia-reperfusion (I/R) injury. Clinically, serum levels of TNF-alpha are increased after myocardial infarction and after cardiopulmonary bypass. Each of these represent clinically relevant instances of cardiac I/R injury. We and others have recently reported that TNF-alpha is produced by the heart following experimental I/R in animals and that TNF-alpha directly decreases animal and human myocardial contractility in a dose dependent fashion. Thus, strategies to reduce or neutralize myocardial TNF- alpha production should conceptually decrease myocardial contractile dysfunction following I/R. The purposes of this manuscript are: 1) to explore the clinical and experimental instances of I/R injury in which TNF-alpha is elevated, 2) to review the molecular mechanisms of TNF- alpha induced contractile dysfunction, 3) to examine both experimental and clinical strategies of reducing myocardial TNF-alpha production, and 4) to determine the influence of reducing post-I/R TNF-alpha on cardiac contractile function in both animals and man.
Cain
B S
BS
Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Harken
A H
AH
Meldrum
D R
DR
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D013110:Sphingosine / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013110:Sphingosine