The primary purpose of this study is to compare the effects of chronic tumor necrosis factor (TNF) inhibition via gene deletion versus its acute inhibition with monoclonal antibodies (MAb), in a murine model of sepsis. Research has strongly suggested that activation of the host inflammatory response and release of host mediators, while important for host defense, if excessive could be important contributors to the pathogenesis of sepsis and septic shock. Based on preclinical sepsis models in which MAbs designed to inhibit specific host mediators like tumor necrosis factor (TNF) improved survival, similar MAbs have now been used in clinical sepsis trials. While the clinical experience with these agents has not been as successful as preclinical models suggested, studies we have done indicate that this approach is an effective one, if critical factors, importantly the severity of infection, are taken into account. Thus, use of MAbs in wild type animals appears to have been an effective approach for identifying critical host components in the pathogenesis of sepsis and septic shock. There is increasing interest in the use of murine knock-out models to also study the relevance of specific host protein products in the pathogenesis of acute diseases like sepsis. Whether the absence of a gene product since birth in an animal results in a similar response as its acute inhibition during a disease like sepsis is unclear. Lifetime absence related to gene deletion of a protein product protective under some circumstances may stimulate the growth of compensatory mechanisms during development. This compensation may confound studies assessing the influence the absence of the gene product has in question. The study will be executed in three parts: (1) Develop an antibiotic treated murine model of sepsis in wild type mice. (2) Test the susceptibility of TNF knock out mice to the model of sepsis developed for wild type mice. (3) Study the effects of TNF inhibition with anti-TNF MAbs during sepsis using doses of bacteria producing low, medium or high lethality rates in wild type versus TNF gene knock-out mice.
