ENDOTOXIN AND SUSCEPTIBILITY TO TRICHOTHECENE MYCOTOXINS

内毒素和对单端孢霉烯真菌毒素的敏感性

• 批准号: 6178513
• 负责人: James J Pestka
• 金额: $ 18.06万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178513
• 关键词: apoptosis; bacterial toxicology; bacterial toxins; chemical structure function; corticosterone; dosage; gene expression; genetic susceptibility; host organism interaction; laboratory mouse; lipopolysaccharides; lymphatic disorder; lymphocyte; mycotoxins; phenotype; prostaglandin E; tumor necrosis factor alpha

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."

描述：(改编自《调查人员摘要》)“越来越多的证据表明，人类暴露在细菌内毒素(脂多糖)中是很常见的，而且暴露于内毒素可能会增加个人对各种化学物质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内毒素和一种免疫毒素--毛霉菌毒素--相互作用导致淋巴组织耗尽的机制来检验这一范式。三氯乙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，与单独接受内毒素或三环烯呕吐毒素(VT)的小鼠相比，小剂量的内毒素和三环烯呕吐毒素(VT)联合暴露后，小鼠的mRNA表达和血清中肿瘤坏死因子-α的浓度大大增加。随后，淋巴组织中的细胞凋亡被观察到是最早和最显著的组织学损害。研究人员假设，脂多糖和三氯乙烯联合暴露诱导淋巴细胞凋亡是由升高的肿瘤坏死因子-α表达和肿瘤坏死因子-α介导的后遗症所介导的。为了验证这一假设，研究人员建议在小鼠模型中实现三个特定目标。在目标1中，我们将从剂量、时间和易感表型方面对体内暴露于内毒素和维生素T后的淋巴细胞凋亡进行表征和测量。在目标2中，研究人员将在体内将肿瘤坏死因子-α和肿瘤坏死因子-α介导的后遗症(即皮质酮、前列腺素E_2[PG_2])的高表达与体内暴露于脂多糖和维生素T后发生的淋巴细胞凋亡联系起来。在目标3中，研究人员将确定在体外暴露于VT可以在多大程度上直接诱导选定淋巴细胞表型中的细胞凋亡或增强肿瘤坏死因子-α、皮质酮、前列腺素E_2和其他非致细胞信号的作用。将使用相关的目标1和3终点来研究人类遇到的常见三氯乙烯之间的结构-活性关系。该项目的直接结果将提高对脂多糖和毛霉菌如何相互作用导致淋巴细胞死亡以及肿瘤坏死因子-α在这一过程中的作用的机械理解。从长远来看，这项研究将为暴露在环境毒物中的脂多糖暴露个人可能产生的不良免疫后果提供洞察力。