The central objective of the Program Project renewal is to define critical mechanisms mediating neutrophil (PMN) and endothelial activation that induce lung inflammation and vascular injury and lead to protein-rich pulmonary edema and acute lung injury (ALI) and specific mechanisms that lead to recovery. The Program Project is based on the premise that activation of specific signaling pathways in the PMN and the endothelium set into motion events that produce inflammation and, if left unchecked, lead to endothelial injury and tissue edema. In Project 1 Dr. Asrar Malik, P.I., and colleagues will address the concept that cross-talk between PMNs and ECs via NADPH oxidase-derived oxidants is critical in signaling the gating of the novel, oxidant-sensitive transient receptor potential melastatin (TRPM)-2, a Ca++-permeable channel abundant in lung endothelial cells. They will test the postulate that this channel is critical in the mechanism of lung injury. In Project 2 the P.I., Dr. Richard Ye, together with his colleagues, will explore their recent discovery that MAP kinase phosphatase 5 (MKP5) is required for the negative regulation of the phagocyte NADPH oxidase, and thereby modulation of lung injury. This project will test the postulate of this pathway in lung injury. In Project 3 Dr. C. Tiruppathi, P.I. will study the currently uncharacterized but potentially significant role of the transcriptional repressor protein, Dream, as a negative master regulator of the dual function deubiquitinating/E3 ligase enzyme A20, which has a central role in preventing NF-kappaB activation. In Project 4, Dr. Y. Y. Zhao, P.I. will address the role of the Forkhead transcription factor FoxM1 in the repair of endothelial adherens junctions and in the regeneration of the endothelial monolayer after lung vascular injury. We are convinced that a concerted effort as described in this program will lead to a new understanding of the signaling mechanisms responsible for lung inflammatory injury and recovery, which is essential for developing more rational therapeutic strategies based on the underlying pathobiology of lung inflammatory injury and ALI.

Public Health Relevance

This Program Project seeks to identify important signaling pathways that cause and those that reverse activation of inflammatory cells and their interaction with and activation of cells in lung blood vessels. These interactions can lead to lung inflammation and acute lung injury (ALI). Our group will study how the cells signal each other so that we may identify 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 #
5P01HL077806-07
Application #
8097444
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Moore, Timothy M
Project Start
2004-07-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2011
Total Cost
$1,832,559
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
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
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
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
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
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
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
Li, Liping; Sheng, Yue; Li, Wenshu et al. (2017) ?-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q). Cancer Res 77:4116-4126
Evans, Colin E; Zhao, You-Yang (2017) Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension. Adv Exp Med Biol 967:33-45
Tsang, Kit Man; Hyun, James S; Cheng, Kwong Tai et al. (2017) Embryonic Stem Cell Differentiation to Functional Arterial Endothelial Cells through Sequential Activation of ETV2 and NOTCH1 Signaling by HIF1?. Stem Cell Reports 9:796-806
Zhang, Chongxu; Adamos, Crystal; Oh, Myung-Jin et al. (2017) oxLDL induces endothelial cell proliferation via Rho/ROCK/Akt/p27kip1 signaling: opposite effects of oxLDL and cholesterol loading. Am J Physiol Cell Physiol 313:C340-C351

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