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(Circulation Research. 2005;96:1095.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Endotoxin-Induced Myocardial Dysfunction

Effects of Macrophage Migration Inhibitory Factor Neutralization

Frederic Chagnon, Christine N. Metz, Richard Bucala, Olivier Lesur

From the Groupe de Recherche en Physiopathologie Respiratoire (F.C., O.L.), Centre de Recherche Clinique, Universite de Sherbrooke PQ, Canada; The Institute for Medical Research at North Shore-LIJ (C.N.M.), Manhasset, NY; the Department of Internal Medicine (R.B.), Section of Rhumatology, Yale University School of Medicine, New Haven, Conn; and Unite des Soins Intensifs Medicaux (O.L.), CHU Sherbrooke, PQ, Canada.

Correspondence to Olivier Lesur MD, PhD, Groupe de Recherche en Physiopathologie Respiratoire, Centre de Recherche Clinique, CHU Sherbrooke, Qc J1H 5N4 Canada. E-mail Olivier.Lesur{at}USherbrooke.ca

The pathophysiology of sepsis-induced myocardial dysfunction still remains controversial. Macrophage migration inhibitory factor (MIF) has recently been identified as a cardiac-derived myocardial depressant factor in septic shock. Putative mechanisms by which MIF affects cardiac function are unknown. In an investigation of possible mechanisms of action, a rat model of endotoxin toxicity was designed using intraperitoneal (I/P) injection of lipopolysaccharides (LPS) with or without coinfusion of neutralizing anti-MIF or isotypic-matched antibodies. Echocardiographic evaluation revealed that MIF neutralization reversed endotoxin-induced myocardial dysfunction at 24 hours after injection. RNase protection assay (RPA) and Western blot established that MIF neutralization prevented LPS-induced mRNA expression and production of heart-derived inflammatory paracrine and autocrine cytokines such as IL-1s and IL-6. Moreover, MIF immunoneutralization increased heart Bcl-2/Bax protein ratio and suppressed endotoxin-induced release of mitochondrial cytochrome-c, as demonstrated by Western blotting. Inhibition of mitochondrial loss of cytochrome-c decreased in heart caspase-3 activity at 6 and 24 hours after injection. MIF neutralization also restored the LPS-induced deficient nuclear translocation of phospho-Akt and consequently the expression of the heart survival nuclear factor GATA-4. The restoration of the translocation/expression of survival factors by MIF inhibition resulted in lowered endotoxin-induced DNA fragmentation at 24 hours, a hallmark of downstream cardiomyocyte apoptosis. Our data indicate that early inactivation of MIF significantly reverses the imbalance of proapoptotic to prosurvival pathways and reduces acute inflammation of the heart thereby improving myocardial dysfunction induced by endotoxin.

Key Words: sepsis • myocardial dysfunction • migration inhibitory factor neutralization • lipopolysaccharides

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