PNEUMOCYTE DERIVED HOST DEFENSE LECTINS

肺细胞衍生的宿主防御凝集素

• 批准号: 6202219
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6202219
• 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剂相关蛋白A（SP-A）和 D（SP-D）介导宿主和吸入微生物之间的相互作用。 这些胶原凝集素（collectins）显示出与 表达的保守结构成分和毒力因子 各种微生物的表面。配体包括克- 阴性脂多糖（LPS），荚膜多糖（CPS） 肺炎克雷伯氏菌（Kp）的特异性包囊菌株，以及 甲型流感病毒（IAV）血凝素。肺聚集蛋白还调节 白细胞的功能，无论是通过直接相互作用与特定的 受体，并通过改变微生物作为一种 微生物聚集的结果。我们假设SP-A和SP-D 由于它们相互作用的能力， 不同的结构在颗粒表面呈现不同的形状， 阴性细菌，它们的组合相互作用影响 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， 间接调节这些细胞对LPS的反应。因为特定 Kp菌株已被证明与SP-A和SP-D相互作用，我们 建议检查人SP-D和SP-A与菌株的相互作用 Kp和Kp LPS，以表征SP-D介导的Kp调理作用， 研究LPS和CPS表达的环境调节对 收集素与这些生物体的相互作用，并检查 可溶性Kp CPS对SP-A寄主防御活性的影响。我们 还建议审查SP-D对生产选定的 细胞因子（例如，TNF-α）和金属蛋白酶 为了评估GP-340（一种假定的SP-D受体）对 调节改变的细胞因子和金属蛋白酶的产生， 细菌调理作用，并确定肺聚集蛋白是否可以 调节LPS对巨噬细胞细胞因子产生的影响， LPS与LPS结合蛋白（LBP）或LPS受体的相互作用 （CD14）。最后，我们建议进一步界定 吞噬细胞聚集依赖性调节所需的SP-D 功能我们预计，拟议的研究将产生重要的新成果， 与肺凝集素生物活性的信息关系， 肺对革兰氏阴性微生物，革兰氏阴性LPS， 和呼吸道病毒。