""""""""There is increasing evidence that human exposure to bacterial endotoxin (lipopolysaccharide, LPS) is common and that LPS exposure may increase the susceptibility of individuals to tissue injury by a variety of chemical agents. In this proposal, the investigators seek to examine this paradigm by determining the mechanisms by which LPS and one class of immunotoxicants, the trichothecene mycotoxins, interact to cause depletion of lymphoid tissue. Trichothecenes are food and indoor air contaminants that include some of the most potent protein synthesis inhibitors known. The investigators have observed that, following co-exposure of mice to small doses of LPS and the trichothecene vomitoxin (VT), mRNA expression and serum concentrations of TNF-alpha are greatly elevated as compared to mice receiving LPS or VT alone. Subsequently, apoptosis in lymphoid tissue is observed as the earliest and most prominent histologic lesion. The investigators hypothesize that induction of lymphocyte apoptosis by LPS and trichothecene co-exposure is mediated by elevated TNF-alpha expression and TNF-alpha mediated sequelae. To test this hypothesis, the investigators propose to achieve three Specific Aims in a murine model.
In Aim 1, we will characterize and measure lymphocyte apoptosis following exposure to LPS and VT in vivo with respect to dose, timing and susceptible phenotypes.
In Aim 2, the investigators will relate elevated expression of TNF-alpha and TNF- alpha mediated sequelae (i.e. corticosterone, prostaglandin E2 [PG E2]) to lymphocyte apoptosis that occurs following exposure to LPS and VT in vivo.
In Aim 3, the investigators will determine the extent to which in vitro exposure to VT can directly induce apoptosis or augment the action of TNF-alpha, corticosterone, PGE2, and other apogenic signals in selected lymphocyte phenotypes. Structure-activity relationships among common trichothecenes encountered by humans will be examined using relevant Aim 1 and 3 endpoints. The immediate outcomes of this project will improve mechanistic understanding of how LPS and trichothecens interacts to cause lymphocyte death and the role of TNF-alpha in the process. Over the long term, this research will provide insight into adverse immunologic consequences that may occur in LPS-exposed individuals who are exposed to environmental toxicants.""""""""
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