IMMUNOCHEMISTRY OF ENDOTOXIN UNRESPONSIVE C3H/HEJ MICE

细菌内毒素已被定义为外毒素的组成部分， 几乎所有革兰氏阴性细菌的细胞膜。 当从 在细菌感染的过程中，这些有效的 细菌产物几乎有无限的能力与 哺乳动物细胞和组织。 这些相互作用的后果可能是 对宿主极其有害，可导致发烧、低血压和 弥散性血管内凝血 这些特征 严重革兰氏阴性菌感染的临床表现定义为 称为内毒素休克。 在这方面，内毒素被认为 是造成高死亡率的主要因素之一 在革兰氏阴性菌血症和脓毒症中，估计高达20 仅在美国每年就有数千人死亡。 过去几十年的深入调查发现， 内毒素的脂多糖成分，更具体地， 脂多糖的类脂A区，作为一种重要的生化成分 用于表达内毒素活性。 然而， 脂多糖/内毒素的生物活性已经排除了 这些相互作用的精确描述是至关重要的 宿主组织损伤的表现。 此外，在这些细胞中， 已经被证明可以识别并对脂多糖做出反应， 如淋巴细胞和巨噬细胞，这些细胞的机制是 是完全未知的 实验 本提案中概述的各项建议旨在探讨 这些细胞膜上的特异性内毒素受体。 为这些 研究中，我们将广泛使用一种突变小鼠品系，称为 C3 H/HeJ菌株，其对几乎所有的 内毒素的免疫刺激和病理生理作用， 和体内。 拟议的研究将采用生物化学和 免疫学技术确定内毒素的分子基础 在细胞水平上观察到该C3 H/HeJ小鼠的无反应性。 这些 研究将有助于我们理解分子间的相互作用， 内毒素与哺乳动物细胞。

Bacterial endotoxins have been defined as integral components of the outer cell membrane of virtually all gram negative bacteria. When released from the organism during the course of bacterial infections, these potent bacterial products have an almost unlimited capacity to interact with mammalian cells and tissues. The consequences of these interactions may be extremely deleterious to the host and can result in fever, hypotension and disseminated intravascular coagulation. These characteristic manifestations of severe gram negative infections define a clinical state termed endotoxin shock. In this respect, endotoxin has been suggested to be one of the major contributing factors to the high incidence of mortality in gram negative bacteremia and sepsis, estimated to be as high as twenty thousand individuals annually in the United States alone. Intensive investigations during the past several decades have identified the lipopolysaccharide component of endotoxin, and more specifically the lipid A region of lipopolysaccharide, as an important biochemical element for the expression of endotoxin activity. However, the broad spectrum of biological activities of lipopolysaccharide/endotoxin has precluded a precise delineation of those interactions which are critical for manifestation of host tissue injury. In addition, in those cells which have been documented to recognize and respond to lipopolysaccharide, such as lymphocytes and macrophages, the mechanism by which these cells are triggered by lipopolysaccharide is completely unknown. Experiments outlined in this proposal have been designed to explore the concept of specific endotoxin receptors on the membranes of such cells. For these studies we will utilize extensively a mutant mouse strain, termed the C3H/HeJ strain, which is refractory to virtually all of the immunostimulatory and pathophysiologic effects of endotoxin, both in vitro and in vivo. The proposed research will employ both biochemical and immunologic techniques to define the molecular basis for endotoxin unresponsiveness of this C3H/HeJ mouse at the cellular level. These studies will contribute to our understanding of molecular interactions of endotoxin with mammalian cells.