Extracellular Matrix in the Innate Immune Response in Lung Inflammation

肺部感染给公共卫生带来的负担高于其他主要疾病，如艾滋病毒/艾滋病、癌症、冠心病和中风（世卫组织数据）。先天性免疫系统是身体抵抗肺部感染的第一道防线，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和活化。关于特异性细胞外基质（ECM）组分在先天性免疫应答中的作用的信息很少。我们的初步数据表明，非常少的多功能蛋白聚糖，ECM蛋白聚糖，存在于健康的肺，但TLR 4激动剂，脂多糖（LPS），以及铜绿假单胞菌和呼吸道合胞病毒（RSV）迅速增加多功能蛋白聚糖积累在细胞外空间的小鼠肺。多功能蛋白聚糖的这种增加发生在肺部炎症的早期阶段，并与白细胞浸润相一致。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，其与另一种细胞外大分子透明质酸形成大分子复合物，以促进单核细胞以多功能蛋白聚糖依赖性方式粘附于ECM。我们的初步结果和已发表的工作表明，多功能蛋白聚糖积累是重要的先天性免疫反应，肺部感染，并导致我们制定我们的中心假说，这是多功能蛋白聚糖起着关键作用，在先天性免疫反应，肺部感染，促进粘附，保留，和激活单核细胞，巨噬细胞和中性粒细胞。本研究拟通过以下四个方面的研究来确定多功能蛋白聚糖在肺部感染的先天性免疫应答中的作用：（1）确定铜绿假单胞菌和呼吸道合胞病毒（RSV）感染小鼠肺中富含多功能蛋白聚糖的ECM的组成和区室化，并确定其在白细胞粘附中的作用;（2）确定多功能蛋白聚糖在铜绿假单胞菌和呼吸道合胞病毒感染小鼠肺中聚集的TLR及其信号通路;（三）确定多功能蛋白聚糖对巨噬细胞表型和功能的影响，并确定肺巨噬细胞产生的多功能蛋白聚糖在先天性免疫应答中的作用，肺部感染;和（4）确定在感染铜绿假单胞菌和RSV的小鼠的肺中的先天免疫应答中对多功能蛋白聚糖的需要。

Lung infections 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 infection, includes pathogen recognition receptors such as Toll-like receptors (TLRs), production of inflammatory mediators such as cytokines and chemokines, and leukocyte recruitment and activation. 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 early 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 mimetic, 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 accumulation 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 completion of the following four Aims: (1) Define the composition and compartmentalization of the versican-enriched ECM that accumulates in the lungs of mice exposed to Pseudomonas aeruginosa and respiratory syncytial virus (RSV) Infection and determine its role in leukocyte adhesion; (2) Determine the TLRs and the TLR signaling pathways responsible for the accumulation 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 infection; and (4) Determine the requirement for versican in the innate immune response in the lungs of mice infected with P. aeruginosa and RSV.