Despite recent advances in understanding of the many aspects of the pathogenesis of acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS), there are currently no effective pharmacological or cell-based treatments for the disease. Employing novel animal models and integrated pharmacological and molecular and cellular biological approaches, the focus of Project 3 in the context of the Program Project will be to define for the first time the reprogramming of lung macrophages (M?) to the M2 lineage as regulated by the interaction of endothelial cell (EC)-expressed Jagged1 (Jag1, a Notch ligand) with M?- expressed Notch. We will determine whether these ?instructed? cells have the potential to resolve inflammatory lung injury. We hope through these studies to develop novel therapeutics to promote resolution of inflammatory lung injury and enhance lung?s tolerance to injury. Our Supporting Data show that disruption of Jag1 in EC induces reprogramming of M? towards the M2-like anti-inflammatory phenotype and resolution of lung inflammation. Thus, in Project 3, we will test the hypothesis that the interaction of M? with lung EC-expressed Jag1 mediates Notch signaling in M? and thereby determines their polarity and their ability to resolve inflammatory lung injury. The proposed studies will address the following Specific Aims.
In Aim 1, we will determine the regulation of polarization of M? by EC-expressed Jag1 and its role in resolving inflammatory lung injury and promoting tolerance to injury induced by secondary infection.
In Aim 2, we will define the signaling mechanisms activated in M? that mediate EC Jag1-induced M? polarization and the therapeutic potential of strategies of specifically targeting Jag1 in resolving inflammatory lung injury. Upon completion of these studies, we will identify not only the fundamental role of lung EC Jag1 in mediating M? polarization via interaction with Notch signaling and its significance in resolving inflammatory lung injury but also novel therapeutic approaches and targets for the treatment of ALI/ARDS.
The focus of Project 3 in the context of the Program Project is to delineate key mechanisms involving the resolution of inflammatory lung injury and enhancing lung tolerance to subsequent infection via the interaction of the regulatory proteins Jag1 in lung endothelial cells and Notch in macrophages. We will thereby develop novel therapeutic strategies for treatment of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).
|Lv, Yang; Kim, Kyungho; Sheng, Yue et al. (2018) YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. Circ Res 123:43-56|
|Di, Anke; Xiong, Shiqin; Ye, Zhiming et al. (2018) The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation. Immunity 49:56-65.e4|
|Dai, Zhiyu; Zhu, Maggie M; Peng, Yi et al. (2018) Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension. Am J Respir Crit Care Med 198:788-802|
|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|
|Evans, Colin E; Zhao, You-Yang (2017) Impact of thrombosis on pulmonary endothelial injury and repair following sepsis. Am J Physiol Lung Cell Mol Physiol 312:L441-L451|
|Mittal, Manish; Nepal, Saroj; Tsukasaki, Yoshikazu et al. (2017) Response by Mittal et al to Letter Regarding Article, ""Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury"". Circ Res 121:e87|
|Soni, Dheeraj; Regmi, Sushil C; Wang, Dong-Mei et al. (2017) Pyk2 phosphorylation of VE-PTP downstream of STIM1-induced Ca2+ entry regulates disassembly of adherens junctions. Am J Physiol Lung Cell Mol Physiol 312:L1003-L1017|
|Di, Anke; Kiya, Tomohiro; Gong, Haixia et al. (2017) Role of the phagosomal redox-sensitive TRP channel TRPM2 in regulating bactericidal activity of macrophages. J Cell Sci 130:735-744|
|Reddy, Sekhar P; Mehta, Dolly (2017) Lung Interstitial Macrophages Redefined: It Is Not That Simple Anymore. Am J Respir Cell Mol Biol 57:135-136|
|Cheng, Kwong Tai; Xiong, Shiqin; Ye, Zhiming et al. (2017) Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest 127:4124-4135|
Showing the most recent 10 out of 103 publications