Wednesday, February 5, 2025
2/5/2025
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.
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