IMMUNOCHEMISTRY--ENDOTOXIN UNRESPONSIVE C3H/HEJ RODENTS

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。从以下位置释放 在细菌感染过程中的有机体，这些有效 细菌产品具有几乎无限的相互作用能力。 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 弥漫性血管内凝血。这些特征 严重革兰氏阴性感染的表现定义了一种临床状态 称为内毒素休克。在这方面，内毒素已被建议 是导致高死亡率的主要因素之一 在革兰氏阴性菌血症和败血症中，估计高达20 仅在美国每年就有数千人。 在过去的几十年里，密集的调查发现 内毒素的脂多糖成分，更具体地说 脂类：脂多糖的一个区域，是重要的生化成分 用于表达内毒素活性。然而，广泛性的 内毒素/内毒素的生物学活性已经排除了 精确描述对以下各项至关重要的交互作用 宿主组织损伤的表现。此外，在那些细胞中， 已被证明识别和响应脂多糖，如 作为淋巴细胞和巨噬细胞，这些细胞被 由脂多糖引发的是完全未知的。实验 这份提案中概述的内容旨在探讨 这种细胞膜上的特定内毒素受体。为了这些 我们将广泛利用一种突变的小鼠品系，称为 C3H/HeJ株，对几乎所有的 内毒素的免疫刺激和病理生理作用 在活体内。拟议的研究将同时使用生化和 确定内毒素分子基础的免疫学技术 C3H/HeJ小鼠在细胞水平上的无反应。这些 研究将有助于我们理解分子间的相互作用 哺乳动物细胞的内毒素。

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.