ENDOTOXIN AND SUSCEPTIBILITY TO TRICHOTHECENE MYCOTOXINS

描述：（改编自研究者摘要）“越来越多的证据表明，人类暴露于细菌内毒素（脂多糖，LPS）是常见的，并且LPS暴露可能增加个体对各种化学试剂造成的组织损伤的易感性。在这项提议中，研究人员试图通过确定LPS和一类免疫毒物（毛霉毒素）相互作用导致淋巴组织耗竭的机制来检验这一范式。毛霉烯是食物和室内空气污染物，其中包括一些已知的最有效的蛋白质合成抑制剂。研究人员观察到，与单独接受LPS或VT的小鼠相比，小鼠同时暴露于小剂量的LPS和毛霉烯呕吐毒素（VT）后，mRNA表达和血清tnf - α浓度大大升高。随后，淋巴组织的细胞凋亡被观察到是最早和最突出的组织学病变。研究人员假设LPS和毛霉烯共同暴露诱导淋巴细胞凋亡是由tnf - α表达升高和tnf - α介导的后遗症介导的。为了验证这一假设，研究人员提出在小鼠模型中实现三个特定目标。在目的1中，我们将描述和测量体内暴露于LPS和VT后淋巴细胞凋亡的剂量、时间和易感表型。在Aim 2中，研究人员将把TNF- α和TNF- α介导的后遗症（即皮质酮、前列腺素E2 [PG E2]）的表达升高与体内暴露于LPS和VT后发生的淋巴细胞凋亡联系起来。在Aim 3中，研究人员将确定体外暴露于VT可在多大程度上直接诱导细胞凋亡，或在选定的淋巴细胞表型中增强tnf - α、皮质酮、PGE2和其他apogenic信号的作用。人类遇到的常见毛霉烯之间的结构-活性关系将使用相关的Aim 1和3端点进行检查。该项目的直接结果将提高对脂多糖和毛鞘蛋白如何相互作用导致淋巴细胞死亡以及tnf - α在这一过程中的作用的机制理解。从长远来看，这项研究将为暴露于环境毒物的lps暴露个体可能发生的不良免疫后果提供见解。”

DESCRIPTION: (Adapted from the Investigator's Abstract) "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."