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TAT-BH4 and TAT-Bcl-x_L Peptides Protect against Sepsis-Induced Lymphocyte Apoptosis In Vivo¹

Richard S. Hotchkiss^2,*,,, Kevin W. McConnell, Kristin Bullok, Christopher G. Davis^*, Katherine C. Chang^*, Steven J. Schwulst, Jeffrey C. Dunne^*, Gunnar P. H. Dietz^||, Mathias Bähr^||, Jonathan E. McDunn, Irene E. Karl, Tracey H. Wagner^*, J. Perren Cobb, Craig M. Coopersmith and David Piwnica-Worms^,||

Departments of ^* Anesthesiology, Medicine, Surgery, Radiology, and ^¶ Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110; and ^|| Department of Neurology, University of Göttingen, Göttingen, Germany

Apoptosis is a key pathogenic mechanism in sepsis that induces extensive death of lymphocytes and dendritic cells, thereby contributing to the immunosuppression that characterizes the septic disorder. Numerous animal studies indicate that prevention of apoptosis in sepsis improves survival and may represent a potential therapy for this highly lethal disorder. Recently, novel cell-penetrating peptide constructs such as HIV-1 TAT basic domain and related peptides have been developed to deliver bioactive cargoes and peptides into cells. In the present study, we investigated the effects of sepsis-induced apoptosis in Bcl-x_L transgenic mice and in wild-type mice treated with an antiapoptotic TAT-Bcl-x_L fusion protein and TAT-BH4 peptide. Lymphocytes from Bcl-x_L transgenic mice were resistant to sepsis-induced apoptosis, and these mice had a 3-fold improvement in survival. TAT-Bcl-x_L and TAT-BH4 prevented Escherichia coli-induced human lymphocyte apoptosis ex vivo and markedly decreased lymphocyte apoptosis in an in vivo mouse model of sepsis. In conclusion, TAT-conjugated antiapoptotic Bcl-2-like peptides may offer a novel therapy to prevent apoptosis in sepsis and improve survival.

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