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.

与艾滋病毒/艾滋病、癌症等其他主要疾病相比，肺部感染对公共卫生造成的负担更大