Mouse model for sepsis

描述（由申请人提供）： 小鼠是许多感染性疾病的初始研究中最常用的物种之一，包括宿主对细菌的反应的研究。然而，小鼠在对细菌脂多糖（LPS）和许多其他微生物毒素的影响的大多数生物反应中的抵抗力比人类高100至100，000倍。在文献中，在我们的手中，来自两个物种的巨噬细胞对LPS的敏感性通常相似，无论来源如何。我们的初步数据表明，在小鼠血清中存在一种可溶性物质，其强烈抑制由许多病原体相关分子模式分子（PAMP）刺激的小鼠和人巨噬细胞产生IL-6和TNF。这些数据提出了一种可能性，即小鼠对LPS和其他细菌毒素具有抵抗力的原因是其血液中存在这种因子。拟议工作的总体目标是了解小鼠对LPS具有抗性的机制。我们的第一个具体目标是系统研究来自小鼠和人（如可能）不同组织隔室的巨噬细胞和内皮细胞以及细胞系在LPS耐药动物（如啮齿动物、狒狒）和LPS敏感动物（如人、胎牛）血清存在下的敏感性。我们的第二个具体目标是从小鼠血清中纯化抑制小鼠巨噬细胞产生TNF的物质。我们的第三个具体目标是研究被抑制的信号传导的细胞水平。该项目具有广泛的意义，因为大多数使用小鼠细胞的实验目前使用补充有胎牛血清而不是小鼠血清的培养基进行，因为拟议的工作将进一步加深我们对细菌病原体引起的败血症的理解，并且因为这项工作最终可能导致更好的动物模型用于败血症的研究。

DESCRIPTION (provided by applicant): Mice are one of the most commonly utilized species for the initial study of many infectious diseases, including the study of the host response to bacteria. However, mice are 100 to 100,000- fold more resistant than humans in most biological responses to the effects of bacterial lipopolysaccharide (LPS), and to many other microbial toxins. In the literature, and in our hands, macrophages from the two species are generally similar in their sensitivity to LPS, regardless of source. Our preliminary data indicate that there is a soluble substance in the serum of mice that strongly suppresses the production of IL-6 and TNF from mouse and human macrophages that are stimulated with many pathogen associated molecular pattern molecules (PAMPs). These data raise the possibility that the reason that mice are resistant to LPS and other bacterial toxins is the presence of this factor in their blood. The overall goal of the proposed work is to understand the mechanism(s) by which mice are resistant to LPS. Our first specific aim is to systematically study the sensitivity of macrophages and endothelial cells from different tissue compartments from mice and humans (where possible), as well as in cell lines, in the presence of serum from LPS-resistant animals (eg rodent, baboon) and LPS-sensitive animals (eg human, fetal calf). Our second specific aim is to purify the material from mouse serum that inhibits the production of TNF from mouse macrophages. Our third specific aim is to study the cellular level of signaling that is inhibited. The project has broad significance because most experiments using mouse cells are currently performed using media supplemented with fetal calf serum rather than mouse serum, because the proposed work will further our understanding of sepsis caused by bacterial pathogens, and because the work could eventually lead to better animal models for the study of sepsis.