Much effort has been expended to understanding the mechanisms of lung inflammation and injury of lung vascular and alveolar epithelial barriers, the hallmarks of the acute lung injury (ALI) syndrome. However, the primary approach to treatment of these patients remains optimizing the mechanical ventilation and administering antibiotics. Attempts to treat ALI with drugs and cell-based therapies have thus far been unsuccessful. The central research focus of this renewal application for years 11 to 15 will be on defining the resolution phase of inflammatory lung injury and approaches that activate the intrinsic resolution pathways and promote tolerance to injury occurring as a consequence of secondary infection. The innovative hypotheses outlined in each project will define the pro-resolution pathways in macrophages at the molecular and signaling levels. In Project 1, Dr. Asrar Malik, PI, will test the fundamental hypothesis that macrophage phagosomal acidification is regulated through the activation of the cation channel TRPM2 in the phagosomal membrane. Studies will be carried out to determine the function of TRPM2 in regulating the pH in phagosomes and determine its role in promoting resolution and generating tolerance. In Project 2, Dr. Dolly Mehta, PI, will test the hypothesis that a subpopulation of macrophages capable of generating sphingosine-1-phosphate are induced during the resolution phase, are essential for tissue repair, and have the capacity to induce tolerance. In Project 3, Dr. YouYang Zhao, PI, will test the hypothesis that Jag1 expressed in ECs through binding to Notch receptors in macrophages skews lung macrophages towards the pro-inflammatory M1-like phenotype whereas inhibiting Jag1 has the potential to re-program macrophages towards pro-resolving cells that promote the resolution of inflammatory lung injury and enhance the lung's tolerance to injury induced by secondary infection. This concerted effort using novel and rigorous approaches described in each project of the Program will lead to a new overall understanding of the signaling mechanisms responsible for resolving lung inflammatory injury, and potential therapeutic strategies to accelerate and enhance the pro-resolution mechanisms and increase the resilience of lungs. (End of Abstract) PROJECT 1: TRPM2 REGULATION OF PHAGOCYTE BACTERICIDAL ACTIVITY AND RESOLUTION OF LUNG INJURY (Malik, Asrar)

Public Health Relevance

Program Narrative Acute lung injury (ALI) is caused by an unchecked inflammatory response to bacteria such as Pseudomonas aeruginosa which for reasons currently unknown compromises host-defense leading to the breakdown of vascular and alveolar barrier functions, neutrophil sequestration, excessive activation of coagulation pathways, and protein-rich pulmonary edema. This Program Project renewal application seeks to identify signaling pathways that promote resolution of inflammatory lung injury by inducing the generation of bactericidally-competent phagocytic cells and promoting their interaction with lung endothelial and epithelial barriers to re-establish lung integrity and normal lung function. We will identify key therapeutic targets for drug discovery and the treatment of ALI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL077806-11A1
Application #
8935121
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Harabin, Andrea L
Project Start
2004-07-01
Project End
2020-03-31
Budget Start
2015-08-01
Budget End
2016-03-31
Support Year
11
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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