Extracellular Matrix in the Innate Response in Lung Inflammation

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了更大的负担 冠心病和中风(世卫组织数据)。先天性免疫系统，这是人体的第一条线 对肺部感染的防御包括病原体识别受体，如Toll样受体(TLRs)， 炎症介质的产生，如细胞因子和趋化因子，以及白细胞的募集和 Acfivafion。关于特定的细胞外基质的作用，现有的信息很少。 (ECM)先天免疫反应中的成分。我们的初步数据显示，非常少的凡西嘉人，一个 ECM蛋白多糖存在于健康的肺中，但TLR4激动剂脂多糖(LPS)也存在 由于铜绿假单胞菌和呼吸道合胞病毒(RSV)迅速增加了金黄色葡萄球菌的聚集 小鼠肺内的细胞外间隙。这种变态的增加发生在肺的早期。 炎症，并与白细胞的渗出相吻合。此外，我们的初步实验表明， 人肺成纤维细胞经TLR3激动剂和病毒模拟物多聚L：C处理后产生富含万西康的 与另一种胞外大分子透明质酸形成大分子复合体的细胞外基质 以多种依赖方式促进单核细胞与细胞外基质的黏附。我们的初步结果和 已发表的研究表明，肺蓄积在肺的先天免疫反应中起着重要作用。 并导致我们形成了我们的中心假说，即Verscan在 通过促进单核细胞的黏附、滞留和激活对肺部感染的先天免疫反应， 巨噬细胞和中性粒细胞。我们建议确定变态反应在先天免疫反应中的作用。 通过完成以下四个目标来防治肺部感染：(1)确定肺感染的组成和 染毒小鼠肺内蓄积的富含维西康星的细胞外基质的区划 铜绿假单胞菌与呼吸道合胞病毒感染及其在白细胞中的作用 粘附性；(2)确定TLR和TLR信号通路，负责TLR的蓄积 在铜绿假单胞菌和呼吸道合胞病毒感染的小鼠的肺中；(3)确定万西康对 巨噬细胞的表型和功能及其在肺多糖酶产生中的作用 巨噬细胞在对肺部感染的先天免疫反应中的作用；以及(4)确定对 维西康在感染铜绿假单胞菌和呼吸道合胞病毒感染小鼠肺部的先天免疫反应。

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.