Role of p120-catenin in sepsis-induced lung injury The overarching theme of this project is the delineation of the novel immunomodulatory function of p120- catenin (p120) in resolving lung injury and inflammation. The crucial observations underpinning this renewal proposal (presented in Supporting Data) suggest an essential host-defense function of p120 expression in macrophages in regulating clearance of apoptotic neutrophils (efferocytosis). We observed that loss of p120 expression in macrophages severely impaired the ability of macrophages to phagocytose the apoptotic neutrophils. Specific p120 ablation in macrophages markedly delayed recovery of inflammatory lung injury in a murine model of sepsis. These results raise several fundamental questions central to lung?s host-defense function that will be addressed in this proposal, including: How does p120 regulate the phagocytosis of apoptotic neutrophils? Is this p120-mediated function required for resolving inflammatory lung injury? Can pulmonary transplantation of genetically engineered macrophage expressing p120 accelerate repair of lung injury? Although p120 is a well-described constituent of adherens junctions in epithelial and endothelial cells, our studies during the previous cycle of the grant have demonstrated that endothelial p120 protected the lungs from sepsis-induced injury by inhibiting Toll-like receptor 4 signaling. In this renewal proposal, we will focus on defining previously unrecognized function of p120 in pulmonary macrophages and whether it orchestrates resolution of inflammation and lung repair and, if so, the underlying mechanisms mediating this action of p120. Thus we will test the central hypothesis that p120 in pulmonary macrophages favors resolution of inflammatory lung injury by modulating efferocytosis-related signaling. This hypothesis will be tested by addressing the following Specific Aims.
In Aim 1, we will define the molecular mechanisms by which p120 regulates the ability of pulmonary macrophages to phagocytize apoptotic neutrophils.
In Aim 2, we will evaluate the functional significance of pulmonary macrophage p120 as an essential protein in the resolution mechanism of inflammatory lung injury. We hope through these studies to provide important and useful insights into the role of p120 in the pathogenesis of lung injury and in the repair processes. With the completion of these studies, we will have a more clear understanding of the role of pulmonary macrophage p120 as a potentially important and novel modulator of lung immune function and also as a potential therapeutic target to promote resolution of inflammatory lung injury.
Acute lung injury caused by widespread bacterial infection is a severe and life threatening condition that requires a mechanical breathing machine and other supportive care in hospital intensive care units. We have shown that protein p120 catenin in the lung plays an essential role in preventing severe lung inflammation that causes acute lung injury. The purpose of this research is to define the basic molecular mechanisms by which p120 catenin regulates inflammatory cell function and resolution of lung inflammation in order to design new and effective strategies for the treatment or prevention of acute lung injury.
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