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1 Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA
2 Department of Surgery, University of Texas Southwestern, Dallas, TX, USA; Department of Pathology, University of Texas Southwestern, Dallas, TX, USA
3 Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA; Department of Surgery, University of Texas Southwestern, Dallas, TX, USA
4 Departmet of Cardiothoracic Surgery, University of Texas Southwestern, Dallas, TX, USA
5 Department of Surgery, University of Texas Southwestern, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: BRETT.GIROIR{at}childrens.com.
Macrophage migration inhibitory factor (MIF) is a pluripotent, pro-inflammatory cytokine, which is ubiquitously expressed in organs, including the heart. However, no specific role for MIF in modulating cardiac performance has yet been described. Therefore, we examined cardiac MIF expression in mice following LPS challenge (4 mg/kg), and tested the hypothesis that MIF is a mediator of LPS-induced cardiac dysfunction. Western blots of whole heart lysates, as well as immunohistochemisty, documented constitutive MIF protein expression in the heart. Cardiac MIF protein levels significantly decreased after LPS challenge, reaching a nadir at 12 hours, and then returned to baseline by 24 hours. This pattern was consistent with MIF release from cytoplasmic stores following endotoxin challenge. Following release of protein, MIF mRNA levels increased 24-48 hours post challenge. To determine the functional consequences of MIF release, we treated LPS-challenged mice with anti-MIF neutralizing antibodies, or isotype control antibodies. Anti-MIF treated animals had significantly improved cardiac function, as evidenced by significant improvement in left ventricular fractional shortening percentage (FS%) at 8, 12, 24, and 48 hours following endotoxin challenge. In support of these findings, perfusion of isolated beating mouse hearts (Langendorff preparation) with recombinant MIF (20ng/ml) led to a significant decrease in both systolic and diastolic performance (LVP, ±dP/dt, dp40). This study demonstrates that MIF mediates LPS induced cardiac dysfunction, and suggests that MIF should be considered a pharmacologic target for the treatment of cardiac dysfunction in sepsis and potentially other cardiac diseases.
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