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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL104092-10
Application #
9959490
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Aggarwal, Neil R
Project Start
2010-08-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Zhang, Yuehui; Wang, Lijun; Lv, Yang et al. (2018) The GTPase Rab1 Is Required for NLRP3 Inflammasome Activation and Inflammatory Lung Injury. J Immunol :
Lv, Yang; Kim, Kyungho; Sheng, Yue et al. (2018) YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. Circ Res 123:43-56
Du, Xueke; Jiang, Chunling; Lv, Yang et al. (2017) Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated ADAM17/Mer signaling. PLoS One 12:e0180213
Jiang, Chunling; Liu, Zheng; Hu, Rong et al. (2017) Inactivation of Rab11a GTPase in Macrophages Facilitates Phagocytosis of Apoptotic Neutrophils. J Immunol 198:1660-1672
Wu, Chaomin; Evans, Colin E; Dai, Zhiyu et al. (2017) Lipopolysaccharide-induced endotoxemia in corn oil-preloaded mice causes an extended course of lung injury and repair and pulmonary fibrosis: A translational mouse model of acute respiratory distress syndrome. PLoS One 12:e0174327
Yan, Zhibo; Wang, Zhen-Guo; Segev, Nava et al. (2016) Rab11a Mediates Vascular Endothelial-Cadherin Recycling and Controls Endothelial Barrier Function. Arterioscler Thromb Vasc Biol 36:339-49
Piegeler, Tobias; Dull, Randal O; Hu, Guochang et al. (2014) Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling. BMC Anesthesiol 14:57
Yang, Zhiyong; Sun, Dong; Yan, Zhibo et al. (2014) Differential role for p120-catenin in regulation of TLR4 signaling in macrophages. J Immunol 193:1931-41
Zhang, Yang; Liu, Gongjian; Dull, Randal O et al. (2014) Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 307:L173-85
Hu, Guochang (2014) Recombinant human annexin A5: a novel drug candidate for treatment of sepsis? Crit Care Med 42:219-20

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