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BIOCHEMICAL PARAMETERS OF LPS-INITIATED HOST RESPONSE

LPS 引发的宿主反应的生化参数

基本信息

批准号：
3134690
负责人：
DAVID C. MORRISON
金额：
$ 15.47万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-04-01 至 1992-05-31
项目状态：
已结题

项目摘要

The multiple physiological, pathological and immunological activities of bacterial endotoxins (lipopolysaccharides, LPS) have been well documented. A primary reason for this broad spectrum of activities is the almost ubiquitous capacity of these potent bacterial products to interact with host defense systems. There is now abundant evidence which indicates that the lipid A region of the LPS macromolecule is critical for the expression of biological activity of endotoxin. However, the complexity of the subunit structures which comprise the LPS maacromolecule has only recently been fully appreciated. Recent evidence from this laboratory has provided evidence for a dominant role for lipid A rich (R-LPS) subunits in mediating the effects of LPS and experiments are proposed to test the validity of this hypothesis by the preparation of LPS macromolecules with highly defined subunit composition. Studies are also proposed to examine the biochemical basis for the postulated requirement for R-LPS subunits as assessed by their interaction with mammalian cell membranes. We and others have postulated that non-specific hydrophobic interactions of LPS (lipid A) with cell membranes contributes to the activation of lymphoid cells and macrophages by LPS. Some recent experiments from this laboratory have demonstrated selective association of R-LPS subunits with lymphocytes. Finally, it is proposed to define an evaluate both biochemically and biologically the LPS macromolecules released from bacteria following their interaction with host defense systems, particularly the serum complement system and the phagocytic macrophage. Our experiments to date have suggested that, in both of these systems a selective release of LPS subunits is effected by these host defense systems which may well dictate their expression of biological activity. These collective experiments to define the interaction of bacterial endotoxins with host mediation systems will provide fundamental information on the contribution of these biologically active macromolecules to the hypotension and disseminated intravascular coagulation characteristic of patients with gram negative sepsis.

它具有多种生理、病理和免疫活性，细菌内毒素（脂多糖，LPS）已被充分记载。这种广泛活动的主要原因是，这些有效的细菌产物的普遍存在的能力，宿主防御系统现在有大量的证据表明， LPS大分子的脂质A区对于表达内毒素的生物活性。然而，包括LPS大分子的亚基结构最近才被发现，得到了充分的赞赏。该实验室的最新证据提供了有证据表明富含脂质A（R-LPS）的亚单位在介导 LPS的影响和实验提出了测试的有效性，这一假设通过制备LPS大分子，确定的亚基组成。还建议进行研究， R-LPS亚基的假定需求的生化基础，通过它们与哺乳动物细胞膜的相互作用来评估。我们和其他人已经假设LPS（脂质A）的非特异性疏水相互作用与细胞膜的结合有助于淋巴样细胞的活化，巨噬细胞LPS。这个实验室最近的一些实验证明了R-LPS亚单位与淋巴细胞的选择性缔合。最后，建议定义一个生物化学和在生物学上，细菌释放的LPS大分子，与宿主防御系统，特别是血清补体的相互作用系统和吞噬巨噬细胞。我们迄今为止的实验这表明，在这两种系统中，LPS的选择性释放亚单位受到这些宿主防御系统的影响，这些防御系统很可能决定它们的生物活性的表达。这些集体实验确定细菌内毒素与宿主介导系统的相互作用将提供有关这些贡献的基本信息，生物活性大分子对低血压和弥漫性革兰氏阴性菌患者血管内凝血特点败血症