PNEUMOCYTE DERIVED HOST DEFENSE LECTINS

肺细胞衍生的宿主防御凝集素

• 批准号: 6347586
• 负责人: ERIKA Christine CROUCH
• 金额: $ 20.75万
• 依托单位: BARNES-JEWISH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347586
• 关键词: animal tissue; bacteria infection mechanism; bactericidal immunity; binding proteins; cell adhesion; cell aggregation; collagen; cytokine; endotoxins; gene expression; human tissue; in situ hybridization; inflammation; lectin; lipopolysaccharides; lung injury; metalloendopeptidases; opsonin; posttranslational modifications; protein structure function; pulmonary surfactants; respiratory epithelium; tissue /cell culture; tumor necrosis factor alpha

There is growing evidence that surfactant-associated proteins A (SP-A) and D (SP-D) mediate interactions between the host and inhaled microorganisms. These collagenous lectins (collectins) show specific interactions with conserved structural components and virulence factors expressed on the surfaces of a wide variety of microorganisms. The ligands include gram- negative lipopolysaccharides (LPS), the capsular polysaccharides (CPS) of specific encapsulated strains of Klebsiella pneumoniae (Kp), and the hemagglutinin of influenza A virus (IAV). Lung collectins also modulate the function of leukocytes, both through direct interactions with specific receptors and by altering the presentation of microorganisms as a consequence of microbial aggregation. We hypothesize that SP-A and SP-D are functionally complementary by virtue of their capacity to interact with different structures variably displayed on the surface of gram- negative bacteria, and that their combined interactions influence the responses of phagocytic cells. We further hypothesize that SP-D directly modulates the phenotype of macrophages and that the lung collectins indirectly modulate the response of these cells to LPS. Because specific strains of Kp have been shown to interact with both SP-A and SP-D, we propose to examine the interactions of human SP-D and SP-A with strains of Kp and Kp LPS, to characterize the SP-D mediated opsonization of Kp, to study the effects of environmental modulation of LPS and CPS expression on the interactions of the collectins with these organisms, and to examine the effects of soluble Kp CPS on the host defense activities of SP-A. We also propose to examine the effects of SP-D on the production of selected cytokines (e.g., TNF-alpha) and metalloproteinases by monocyte/macrophages to evaluate the contribution of GP-340 (a putative SP-D receptor) to the regulation of altered cytokine and metalloproteinase production and bacterial opsonization, and to determine whether lung collectins can modulate the effects of LPS on macrophage cytokine production by altering the interactions of LPS with LPS binding protein (LBP) or LPS receptor (CD14). Finally, we propose to further define the structural features of SP-D required for the aggregation dependent modulation of phagocyte function. We anticipate that the proposed studies will yield important new information relation to the biologic activities of lung collectins and the response of the lung to gram-negative organisms, gram-negative LPS, and respiratory viruses.

越来越多的证据表明，表面活性物质相关蛋白A(SP-A)和 D(SP-D)调节宿主和吸入微生物之间的相互作用。 这些胶原性凝集素(集合素)显示与 表达的保守结构成分和毒力因子 各种各样的微生物的表面。配体包括革兰氏- 阴性脂多糖(LPS)、衣壳多糖(CPS) 肺炎克雷伯氏菌(Kp)的特定囊化菌株，以及 甲型流感病毒血凝素(IAV)。肺集合素也能调节 白细胞的功能，既是通过与特定的 受体和通过改变微生物作为一种 微生物聚集的后果。我们假设SP-A和SP-D 由于它们的互动能力，它们在功能上是互补的 不同的结构可变地显示在革兰氏表面- 负性细菌，它们的联合作用影响了 吞噬细胞的反应。我们进一步假设SP-D直接 调节巨噬细胞的表型和肺集合素 间接调节这些细胞对内毒素的反应。因为具体来说 Kp菌株已被证明与SP-A和SP-D都有相互作用，我们 建议研究人SP-D和SP-A与沙门氏菌株的相互作用 Kp和Kp-LPS，以表征SP-D介导的Kp、TO的调变 环境调控对脂多糖和环磷酰胺表达的影响 收集素与这些生物的相互作用，并检查 可溶性KP CPS对SP-A寄主防御活性的影响。我们 还建议研究SP-D对精选玉米生产的影响 单核/巨噬细胞的细胞因子(如肿瘤坏死因子-α)和金属蛋白酶 目的：探讨GP-340(一种可能的SP-D受体)在大鼠脑缺血再灌注中的作用。 改变的细胞因子和金属蛋白酶的产生和调节 细菌调理，并确定肺集合素是否可以 通过改变内毒素对巨噬细胞产生细胞因子的影响 脂多糖与脂多糖结合蛋白及其受体的相互作用 (CD14)。最后，我们建议进一步定义结构特征 吞噬细胞聚集性调节所需的SP-D 功能。我们预计拟议的研究将产生重要的新的 与肺集合素生物活性有关的信息和 肺对革兰氏阴性菌、革兰氏阴性内毒素、 和呼吸道病毒。