Sepsis is a major cause of mortality and morbidity in the critically ill. We have been studying the disorder using a murine model (cecal ligation and puncture or CLP) for some time and have uncovered some important abnormalities in several organ systems, notably liver, lung and heart. Key among our findings is a loss in the activity of an important inflammatory mediator, the cytokine interleukin (IL) - 6. We have extended our investigations to mice with a congenital absence of IL-6 (IL-6 -/- or """"""""knockout"""""""" mice). All the abnormalities we observed in wild type (IL-6 +/+) mice were worse in IL-6 -/- animals. However, in IL-6 -/- mice, the knockout is generated at conception. Therefore, compensatory pathways can develop. In addition, the loss of IL-6 in IL-6 -/- mice does not truly mimic what occurs in sepsis in wild types. The ability to acutely eliminate IL- 6 would be extremely useful in studying sepsis. Unfortunately, current techniques to eliminate IL-6 have significant drawbacks. Use of IL-6 -/- mice is limited by an inability to extrapolate findings in animals with a congenital, in-born error to the acute situation. Use of antibodies directed at IL-6 is effective in eliminating IL-6 from the circulation but not from tissues, where most of the damage in sepsis occurs. In this grant, we propose another approach. We will generate and breed a mouse from which IL-6 can be acutely eliminated. This will be accomplished by creating an IL-6 construct gene that is flanked by two sites that can be cleaved by an enzyme called cre-recombinase. This construct will be introduced into germ tissue and a mouse containing this sequence will be bred. Once we have established a line of animals, we will be able to eliminate IL-6 from lung and liver by administering an adenoviral vector expressing cre-recombinase into the trachea or the bloodstream. This will allow acute elimination of IL-6 from lung and liver. The availability of such a tool will allow us to better investigate that role of IL-6 in the pathogenesis of sepsis-induced changes in these organs. This will provide increased understanding op septic pathophysiology. Sepsis is an important cause of mortality and morbidity. It has been estimated that in excess of $16 billion are spent each year in the use to treat this disorder. As such, sepsis constitutes a major public health problem. . Unfortunately, the pathophysiology of the disease is poorly understood. A better understanding of this disease is extremely relevant to the care of the citizens of the United States. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SBIB-D (02))
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Dong, Gang
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University of Pennsylvania
Schools of Medicine
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Deutschman, Clifford S (2018) Translational Research: The Model Matters. Crit Care Med 46:835-837
Lyons, M Melanie; Raj, Nichelle N; Chittams, Jesse L et al. (2015) TAT-HSP70 Attenuates Experimental Lung Injury. Shock 43:582-8
Deutschman, Clifford S; Raj, Nichelle R; McGuire, Erin O et al. (2013) Orexinergic activity modulates altered vital signs and pituitary hormone secretion in experimental sepsis. Crit Care Med 41:e368-75