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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Harabin, Andrea L
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University of Illinois at Chicago
Schools of Medicine
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Yan, Qian; Sun, Lei; Zhu, Ziyan et al. (2014) Jmjd3-mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages. Cell Signal 26:1783-91
Huang, Xiaojia; Sun, Kai; Zhao, Yidan D et al. (2014) Human CD34+ progenitor cells freshly isolated from umbilical cord blood attenuate inflammatory lung injury following LPS challenge. PLoS One 9:e88814
He, Hui-Qiong; Troksa, Erica L; Caltabiano, Gianluigi et al. (2014) Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands. J Biol Chem 289:2295-306
Gu, Xiaowu; Fliesler, Steven J; Zhao, You-Yang et al. (2014) Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration. Am J Pathol 184:541-55
Zhou, Jun-xian; Liao, Dan; Zhang, Shuo et al. (2014) Chemerin C9 peptide induces receptor internalization through a clathrin-independent pathway. Acta Pharmacol Sin 35:653-63
Bachmaier, Kurt; Toya, Sophie; Malik, Asrar B (2014) Therapeutic administration of the chemokine CXCL1/KC abrogates autoimmune inflammatory heart disease. PLoS One 9:e89647
DebRoy, Auditi; Vogel, Stephen M; Soni, Dheeraj et al. (2014) Cooperative signaling via transcription factors NF-?B and AP1/c-Fos mediates endothelial cell STIM1 expression and hyperpermeability in response to endotoxin. J Biol Chem 289:24188-201
Hecquet, Claudie M; Zhang, Min; Mittal, Manish et al. (2014) Cooperative interaction of trp melastatin channel transient receptor potential (TRPM2) with its splice variant TRPM2 short variant is essential for endothelial cell apoptosis. Circ Res 114:469-79
Cai, Lei; Yi, Fan; Dai, Zhiyu et al. (2014) Loss of caveolin-1 and adiponectin induces severe inflammatory lung injury following LPS challenge through excessive oxidative/nitrative stress. Am J Physiol Lung Cell Mol Physiol 306:L566-73
Zhao, Yidan D; Huang, Xiaojia; Yi, Fan et al. (2014) Endothelial FoxM1 mediates bone marrow progenitor cell-induced vascular repair and resolution of inflammation following inflammatory lung injury. Stem Cells 32:1855-64

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