PMN ENHANCEMENT OF ENDOTHELIAL RESPONSE TO CANDIDA

PMN 增强内皮细胞对念珠菌的反应

• 批准号: 2005200
• 负责人: Scott G Filler
• 金额: $ 9.87万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2005200
• 关键词: Candida albicans; blood toxicology; cell adhesion molecules; cytokine; host organism interaction; immunocytochemistry; immunomodulators; laboratory mouse; leukocyte activation /transformation; leukocyte adhesion molecules; mycosis; neutrophil; selectins; tissue /cell culture; vascular endothelium

DESCRIPTION (Adapted from the applicant's abstract): The incidence of bloodstream infections caused by Candida species has increased dramatically, so that these organisms now account for 10% of all bloodstream isolates. During the process of hematogenous dissemination, it is likely that blood-borne organisms must adhere to and penetrate the endothelial lining of the vasculature to invade the tissue parenchyma. Thus, a potential method to prevent or treat hematogenously disseminated candidal infections is to augment the combined response of neutrophils and endothelial cells against this organism while it is within the intravascular compartment. We have shown that adding neutrophils to Candida-infected endothelium prevents endothelial cell injury in vitro. Also, we have found that Candida albicans by itself can stimulate endothelial cells to express leukocyte adhesion molecules and proinflammatory cytokines. The expression of these factors is greatly increased when neutrophils are added to endothelium infected with C. albicans. Together, these results suggest that there is a two-way exchange of signals between endothelial cells and neutrophils during their response to intravascular infection. The experiments outlined in this proposal are designed to elucidate the mechanisms that mediate this neutrophil amplification of the endothelial cell proinflammatory response to C. albicans. The influence of the microbial target (C. albicans) on the neutrophil enhancement of the endothelial cell response will be evaluated first. Based on these results, the immunomodulatory substances that mediate this neutrophil amplification will be identified. The expression of the leukocyte adhesion molecules, E-selectin and VCAM-1, will be used as a marker of endothelial cell activation in these experiments. Next, the activities of the immunomodulatory substances identified by the above experiments will be inhibited to determine if theses substances also influence the ability of neutrophils to kill C. albicans and protect endothelial cells from candidal injury. Finally, the results of these in vitro experiments will be evaluated in vivo. Both immunocompetent and neutropenic mice will be infected with C. albicans and immunohistochemistry will be used to detect the local expression of leukocyte adhesion molecules and cytokines at sites of candidal infection. Investigating the interactions between endothelial cells, neutrophils and C. albicans will enable us to determine the mechanism by which endothelial cells are activated in response to infection. The long-range goal of these studies is to devise endothelial cell-based strategies to enhance the host inflammatory response to blood-borne microbial pathogens.

描述（改编自申请人的摘要）： 由念珠菌引起的血液感染急剧增加， 因此，这些生物现在占所有血液分离株的10％。 在血源传播过程中，很可能 血源性生物必须粘附并穿透 脉管系统侵入组织实质。 因此，潜在方法 预防或治疗血源性传播的候选感染是 增强中性粒细胞和内皮细胞的综合反应 该生物在血管内室内。 我们有 表明将中性粒细胞添加到念珠菌感染的内皮中可防止 体外内皮细胞损伤。 另外，我们发现白色念珠菌 本身可以刺激内皮细胞表达白细胞粘附 分子和促炎细胞因子。 这些因素的表达是 当将中性粒细胞添加到感染C.的内皮时，大大增加了。 白色唱片。 这些结果在一起表明有双向交流 内皮细胞和中性粒细胞在反应过程中的信号 血管内感染。 本提案中概述的实验旨在阐明 介导这种内皮的这种中性粒细胞扩增的机制 细胞促炎对白色念珠菌的反应。 影响 微生物靶（白色念珠菌）在增强中性粒细胞 内皮细胞反应将首先评估。 基于这些结果， 介导这种中性粒细胞扩增的免疫调节物质 将被确定。 白细胞粘附分子的表达， E-选择素和VCAM-1将用作内皮细胞的标记 这些实验中的激活。 接下来， 上述实验确定的免疫调节物质将是 被抑制以确定这些物质是否也影响 中性粒细胞杀死白色念珠菌并保护内皮细胞免受候选 受伤。 最后，这些体外实验的结果将是 在体内评估。 免疫能力和中性粒细胞减少小鼠都将 被白色念珠菌感染和免疫组织化学将用于检测 白细胞粘附分子和细胞因子位点的局部表达 候选感染。 研究内皮之间的相互作用 细胞，中性粒细胞和白色念珠菌将使我们能够确定机制 通过该感染，内皮细胞被激活。 这 这些研究的远程目标是设计基于内皮细胞 增强宿主对血液炎症反应的策略 微生物病原体。