Our current work in our unanesthetized resuscitated model of hemorrhagic shock in the rat indicates that there is a prompt bacteremia and endotoxemia which occurs during and after hemorrhagic shock. Enteric organisms migrate promptly to the lungs in the first four hours and are found in the liver, kidney, spleen and heart in lesser but significant amounts. Elimination of this major autoinvasion by bacteria by shocking germ-free rats improves survival in our model by 20% but 70% of these animals still succumb to shock. About half of these animals show endotoxemia (at low levels) absorbed from their germ free diet. There is now considerable evidence that the lethal effects of shock are the result of mediated phenomena which may be generated by endotoxin or tissue ischemia or both. Endotoxin and/or ischemia induces the production and release of the following endogenous mediators: anaphylatoxins, interleukins, leukotrienes, prostaglandins, free O2- radicals, cachectin and interferon. This complex host response to endotoxin/ischemia makes it unlikely that any single treatment will be successful. Clinically, the characterization of the interactions between endotoxin/ischemia and mediators and the time course of these interactions is of the utmost importance for the development of a rational treatment regimen. Using an endotoxin-depleted, germ-free rat model of treated hemorrhagic shock we propose to examine the individual and synergistic roles of endotoxin/ischemia, ischemia alone and their associated mediators in terms of their effect on the following physiological parameters: lipid peroxidation, cachectin and other products of endotoxemia/ischemia, bone marrow proliferation, histology, wbc count, various shock parameters (shock time, body temperature, blood pressure) and survival. The following specific aims are proposed: 1. To define the role of endotoxin in hemorrhagic shock in terms of survival in the endotoxin depleted-germ-free rat. 2. To determine the profile and time course of endotoxin/ischemia- induced mediators vs. ischemia-induced mediators in our proposed models. 3. To determine the effect on mortality and the profile of shock mediators produced by blocking individual mediators in our proposed models.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Medicine & Dentistry of NJ
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Schmidt, H; Rush, B; Simonian, G et al. (1996) Thalidomide inhibits TNF response and increases survival following endotoxin injection in rats. J Surg Res 63:143-6
Ferraro, F J; Rush Jr, B F; Simonian, G T et al. (1995) A comparison of survival at different degrees of hemorrhagic shock in germ-free and germ-bearing rats. Shock 4:117-20
Livingston, D H; Wang, M T; Hsieh, J et al. (1992) Hemorrhagic shock inhibits lipopolysaccharide-induced myelopoiesis in both germ-free and conventional rats. Surgery 112:773-9;discussion 779-80
Rush Jr, B F (1992) The bacterial factor in hemorrhagic shock. Surg Gynecol Obstet 175:285-92
Redan, J A; Rush, B F; McCullough, J N et al. (1990) Organ distribution of radiolabeled enteric Escherichia coli during and after hemorrhagic shock. Ann Surg 211:663-6;discussion 666-8
Redan, J A; Rush Jr, B F; Lysz, T W et al. (1990) Organ distribution of gut-derived bacteria caused by bowel manipulation or ischemia. Am J Surg 159:85-9;discussion 89-90
Rush Jr, B F; Redan, J A; Flanagan Jr, J J et al. (1989) Does the bacteremia observed in hemorrhagic shock have clinical significance? A study in germ-free animals. Ann Surg 210:342-5;discussion 346-7
Rush Jr, B F (1989) Irreversibility in hemorrhagic shock is caused by sepsis. Am Surg 55:204-8
Rush Jr, B F; Sori, A J; Murphy, T F et al. (1988) Endotoxemia and bacteremia during hemorrhagic shock. The link between trauma and sepsis? Ann Surg 207:549-54
Sori, A J; Rush Jr, B F; Lysz, T W et al. (1988) The gut as source of sepsis after hemorrhagic shock. Am J Surg 155:187-92