Syndecan-1 suppression of lung inflammation

项目摘要/摘要 急性呼吸窘迫综合征(ARDS)是由一些肺和肺外的损伤引起的。 然而，尽管对潜在的病因进行了治疗，肺损伤仍会持续存在。因此，失败 炎症消退是推动ARDS发生的一种潜在的异常。多条路径 已经被证实会导致炎性细胞死亡。然而，细胞凋亡的能力还没有得到充分认识。 引起炎症。事实上，肺上皮细胞的凋亡性死亡是ARDS和 在各种ARDS模型中，阻断细胞凋亡已被证明是有益的。 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， 只有当细胞通过一种叫做胞泡吞噬的过程移除时，细胞死亡才是静止的。通关效率低 增加炎症损伤组织，导致进一步的凋亡死亡，创造一个正反馈循环 持续的炎症，就像我们在ARDS中看到的那样。我们发现Syndecan-1调节肺部炎症 在流感感染后，通过促进凋亡上皮的胞吐作用。因此，核心假说是 这一建议认为，肺上皮细胞表达Syndecan-1通过以下方式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。 这一多PI建议将研究Syndecan-1角色的两个长期合作者聚集在一起 在肺损伤中。陈博士有一个主要基于了解上皮免疫的研究计划 损伤后肺部的反应，而帕克斯博士的项目侧重于巨噬细胞生物学。正在合并 这两个绩效指标的专业知识将提供一个独特的机会，对以下方面进行高度影响的研究 上皮细胞：肺损伤中巨噬细胞的相互作用。具体来说，调查小组将评估Syndecan如何- 1在肺上皮细胞中的表达促进巨噬细胞对凋亡细胞的清除(即胞吐)以解决 流感感染后肺部发炎。

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.