Syndecan-1 suppression of lung inflammation

项目总结/摘要 急性呼吸窘迫综合征（ARDS）是由多种肺和肺外损伤引起的。 然而，尽管治疗了潜在病因，肺损伤仍会持续。因此，失败 炎症消退的持续时间是驱动ARDS发展的潜在异常。多种途径 已经建立了驱动炎性细胞死亡的机制。然而，细胞凋亡的能力被低估， 引起炎症事实上，肺上皮细胞的凋亡性死亡是ARDS的一个突出特征， 在各种ARDS模型中已经证明阻断细胞凋亡是有益的。 凋亡细胞必须被吞噬细胞有效地清除，以防止死亡细胞的继发性坏死。因此，在本发明中， 凋亡性死亡只有在细胞被称为细胞增生的过程去除时才是静止的。无效清除 增加炎症损伤组织，导致进一步的凋亡性死亡， 持续的炎症，就像我们在ARDS中看到的我们发现syndecan-1调节肺部炎症 流感病毒感染后，通过促进凋亡上皮细胞的细胞增殖。因此， 该建议是肺上皮的多配体蛋白聚糖-1表达促进凋亡细胞的清除， 巨噬细胞，从而促进流感损伤后肺部炎症的消退。 这个多PI的建议汇集了两个长期的合作者，他们研究了syndecan-1的作用 在肺损伤中。陈博士有一个研究计划，主要是基于了解上皮免疫 帕克斯博士的项目侧重于巨噬细胞生物学。合并 这两个PI的专业知识将提供一个独特的机会，进行高影响力的研究， 肺损伤中的上皮细胞：巨噬细胞相互作用。具体来说，调查小组将评估syndecan- 1在肺上皮中的表达促进凋亡细胞的巨噬细胞清除（即，红细胞增多症）至消退 流感感染后的肺部炎症。

Project Summary/Abstract Acute respiratory distress syndrome (ARDS) is initiated by a number of pulmonary and extra-pulmonary insults. However, the lung damage becomes persistent despite treatment of the underlying etiology. Therefore, failure of inflammation resolution is an underlying abnormality that drives the development of ARDS. Multiple pathways have been established that drive inflammatory cell death. However, apoptosis is under recognized in its ability to cause inflammation. Indeed, apoptotic death of the lung epithelium is a prominent feature in ARDS and blocking apoptosis has proven beneficial in various models of ARDS. Apoptotic cells must be efficiently cleared by phagocytes to prevent secondary necrosis of the dying cell. Thus, apoptotic death is quiescent only when the cell is removed by a process called efferocytosis. Inefficient clearance augments inflammation damages tissue leading to further apoptotic death creating a positive feedback loop of unrelenting inflammation, such as we see in ARDS. We have found that syndecan-1 regulates lung inflammation after influenza infection by promoting efferocytosis of apoptotic epithelium. Therefore, the central hypothesis of this proposal is that syndecan-1 expression by the lung epithelium facilitates apoptotic cells clearance by macrophages thereby promoting the resolution of lung inflammation after influenza injury. This multi-PI proposal brings together two longstanding collaborators that have studied the role of syndecan-1 in lung injury. Dr. Chen has a research program primarily based on understanding the epithelial immune response in the lungs after injury whereas Dr. Parks' program focuses on macrophage biology. Merging the expertise from these two PIs will provide an unique opportunity to conduct high impact studies on epithelial:macrophage interactions in lung injury. Specifically, the investigative team will evaluate how syndecan- 1 expression in lung epithelium promotes macrophage clearance of apoptotic cells (i.e., efferocytosis) to resolve lung inflammation after influenza infection.