The role of tumor necrosis factor-α (TNF-α) and the sphingosine pathway in sepsis-induced myocardial dysfunction

Authors

  • Merilee F. Costello DVM, DACVECC,

    1. From the Section of Critical Care, School of Veterinary Medicine, University of Pennsylvania (Costello, Otto), and Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri–Columbia (Rubin).
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  • Cynthia M. Otto DVM, PhD, DACVECC,

    1. From the Section of Critical Care, School of Veterinary Medicine, University of Pennsylvania (Costello, Otto), and Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri–Columbia (Rubin).
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  • Leona J. Rubin PhD

    1. From the Section of Critical Care, School of Veterinary Medicine, University of Pennsylvania (Costello, Otto), and Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri–Columbia (Rubin).
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Merilee F. Costello, DVM, Section of Critical Care, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancy Street, Philadelphia, PA 19104-6010. Fax: (215) 573 6050. E-mail: merilee@vet.upenn.edu

Abstract

Objective: Myocardial dysfunction has been shown to play a major role in the mortality associated with sepsis. Tumor necrosis factor-α (TNF-α) has been implicated as a key factor in this dysfunction, and the sphingomyelin pathway is a membrane-signaling pathway by which TNF-α exerts many of its negative inotropic effects. The purpose of this manuscript is to review the physiology of TNF-α and sphingosine, etiology of increased levels of myocardial TNF-α and sphingosine, as well as the effects of these increased levels on the myocardium. In addition, both in vivo and in vitro studies looking at the effects of blocking TNF-α will be presented.

Data sources: Data sources included scientific reviews and original research publications.

Human data synthesis: It is well documented that levels of TNF-α are elevated in many human patients with sepsis. However, clinical trials evaluating the effects of blocking TNF-α have not shown a statistically significant decrease in the mortality of sepsis.

Veterinary data synthesis: No clinical research has been performed on TNF-α and myocardial dysfunction in veterinary medicine, although many of the research models may be relevant to our patient population. In these models, myocardial TNF-α and sphingosine are elevated in sepsis. Treatment of experimental animals with TNF-α antibodies has shown variable results, while blockage of sphingosine has been shown to completely reverse the myocardial effects of increased TNF-α.

Conclusions: Tumor necrosis factor-α and the sphingomyelin pathway are an important part of the myocardial compromise that accompanies sepsis. Further research into these pathways may provide new understandings and treatment options for veterinary patients.

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