Extracellular Matrix in the Innate Response in Lung Inflammation

肺部炎症先天反应中的细胞外基质

• 批准号: 8005411
• 负责人: Thomas N Wight
• 金额: $ 51.49万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8005411
• 关键词: AIDS/HIV problem; Adhesions; Agonist; Alveolar Macrophages; Coronary heart disease; Data; Disease; Extracellular Matrix; Extracellular Space; Fibroblasts; Human; Hyaluronan; Immune response; Immune system; Infection; Infectious Agent; Infiltration; Inflammatory; Inflammatory Response; Leukocytes; Lipopolysaccharides; Lung; Lung Inflammation; Lung diseases; Macromolecular Complexes; Malignant Neoplasms; Mediator of activation protein; Mus; Phase; Phenotype; Play; Production; Proteoglycan; Pseudomonas aeruginosa; Public Health; Publishing; Receptor Signaling; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Role; Series; Signal Pathway; Stroke; TLR3 gene; TLR4 gene; Toll-like receptors; Viral; Work; chemokine; cytokine; extracellular; macromolecule; macrophage; mimetics; monocyte; neutrophil; pathogen; prevent; receptor; research study; response; versican

Lung infecfions place a higher burden on public health than other major diseases such as HIV/AIDS, cancer coronary heart disease, and strokes (WHO data).^ The innate immune system, which is the body's first line of defense against lung infecfion, includes pathogen recognition receptors such as Toll-like receptors (TLRs), producfion of infiammatory mediators such as cytokines and chemokines, and leukocyte recruitment and acfivafion. There is a paucity of information available with regard to the role of specific extracellular matrix (ECM) components in the innate immune response. Our preliminary data show that very little versican, an ECM proteoglycan, is present in healthy lungs but that the TLR4 agonist, lipopolysaccharide (LPS), as well as Pseudomonas aeruginosa and respiratory syncytial virus (RSV) rapidly increase versican accumulation in the extracellular space in the lungs of mice. This increase in versican occurs during the eariy phases of lung inflammation and coincides with leukocyte infiltration. Furthermore, our preliminary experiments show that human lung fibroblasts treated with the TLR3 agonist and viral mimefic, poly l:C produce a versican-enriched ECM that forms a macromolecular complex with another extracellular macromolecule, hyaluronan, to promote monocyte adhesion to the ECM in a versican-dependent manner. Our preliminary results and published work suggest that versican accumulafion is important in the innate immune response to lung infection and have led us to formulate our Central Hypothesis, which is that versican plays a key role in the innate immune response to lung infection by promoting the adhesion, retention, and activation of monocytes, macrophages and neutrophils. We propose to determine the role of versican in the innate immune response to lung infection through complefion of the following four Aims: (1) Define the composifion and compartmentalization of the versican-enriched ECM that accumulates in the lungs of mice exposed to Pseudomonas aeruginosa and respiratory syncytial virus (RSV) Infecfion and determine its role in leukocyte adhesion; (2) Determine the TLRs and the TLR signaling pathways responsible for the accumulafion of versican in the lungs of mice infected with P. aeruginosa and RSV; (3) Define the impact of versican on macrophage phenotype and function and determine the role of versican produced by pulmonary macrophages in the innate immune response to lung infecfion; and (4) Determine the requirement for versican in the innate immune response in the lungs of mice infected with P. aeruginosa and RSV.

肺部感染给公共卫生带来的负担比其他主要疾病，如艾滋病毒/艾滋病、癌症 冠心病和中风（WHO数据）。先天免疫系统是人体的第一道防线 包括病原体识别受体如Toll样受体（TLR）， 炎症介质如细胞因子和趋化因子的产生，以及白细胞募集， acfivafion。关于特异性细胞外基质的作用， (ECM)先天免疫反应的组成部分。我们的初步数据显示，很少有全能， ECM蛋白聚糖存在于健康的肺中，但TLR 4激动剂脂多糖（LPS）也存在于健康的肺中。 由于铜绿假单胞菌和呼吸道合胞病毒（RSV）快速增加多功能蛋白聚糖在 小鼠肺部的细胞外空间。多功能蛋白聚糖的这种增加发生在肺损伤的早期阶段， 炎症，并符合白细胞浸润。此外，我们的初步实验表明， 用TLR 3激动剂和病毒模拟物poly I：C处理的人肺成纤维细胞产生富含多功能蛋白聚糖的 ECM与另一种细胞外大分子透明质酸形成大分子复合物， 以多功能蛋白聚糖依赖性方式促进单核细胞粘附于ECM。我们的初步结果和 已发表的工作表明，多功能蛋白聚糖的积累在对肺的先天性免疫应答中是重要的， 感染，并导致我们制定了我们的中心假设，这是多能蛋白聚糖发挥了关键作用， 通过促进单核细胞的粘附、滞留和活化，对肺部感染的先天免疫应答， 巨噬细胞和嗜中性粒细胞。我们建议确定多功能蛋白聚糖在先天免疫反应中的作用 通过以下四个方面的研究，达到治疗肺部感染的目的：（1）明确药物的组成， 富集versican的ECM的区室化，所述ECM在暴露于 铜绿假单胞菌和呼吸道合胞病毒（RSV）的鉴定及其在白细胞中的作用 （2）确定TLR和TLR信号通路负责的积累， 多能蛋白聚糖在感染铜绿假单胞菌和RSV的小鼠的肺中的作用;（3）定义多能蛋白聚糖对 巨噬细胞的表型和功能，并确定多能蛋白聚糖的作用， 巨噬细胞在肺部感染的先天免疫反应中的作用;以及（4）确定 多功能蛋白聚糖在感染铜绿假单胞菌和RSV的小鼠肺中的先天免疫应答中的作用。