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1 Pathology, University of Texas Southwestern, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: monte_willis{at}med.unc.edu.
We have recently demonstrated that macrophage migration inhibitory factor (MIF) is a myocardial depressant protein, and that MIF mediates late, prolonged cardiac dysfunction following endotoxin challenge in mice. Since many factors, including endotoxin, have been implicated in the pathogenesis of cardiac dysfunction following burn injury, we tested the hypothesis that MIF might also be the mediator of prolonged cardiac dysfunction in this model. At 4 hours following 40% total body surface area (TBSA) burn in anesthetized mice, serum MIF levels increased significantly compared to baseline (2.2 fold). This increase was accompanied by a significant decrease in cardiac tissue MIF levels (2.1 fold decrease compared to controls). This pattern was consistent with MIF release from pre-formed cytoplasmic stores in the heart and other organs. To determine whether MIF mediates cardiac dysfunction following burn injury, mice were pre-treated with anti-MIF neutralizing monoclonal antibodies or isotype control antibodies. Beginning 4 hours after burn injury (and continuing through 48 hours), burned mice demonstrated a significantly depressed left ventricular fractional shortening (FS%) of 38.6+/-1.8%, compared to the normal controls (FS% 56.0 +/-2.6%). Mice treated with anti-MIF displayed an intitial depression of cardiac function similar to nontreated animals, but then showed rapid restoration of cardiac function with complete recovery by 24 hours, which persisted for the duration of the protocol. This study is the first to demonstrate that MIF mediates late, prolonged cardiac dysfunction following burn injury, and suggests that MIF blockade should be considered a therapeutic target for the treatment of burn injury.
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