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.
