Mechanisms of PMN and Endothelial-Mediated Lung Inflammation and Injury

Summary

Principal Investigator: Asrar B Malik
Abstract: 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.
Funding Period: 2004-07-01 - 2015-07-31
more information: NIH RePORT

Top Publications

  1. pmc Jmjd3-mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages
    Qian Yan
    School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P R China
    Cell Signal 26:1783-91. 2014
  2. pmc Transgenic expression of FoxM1 promotes endothelial repair following lung injury induced by polymicrobial sepsis in mice
    Xiaojia Huang
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, United States of America
    PLoS ONE 7:e50094. 2012
  3. pmc A critical role for phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac exchanger 1 in endothelial junction disruption and vascular hyperpermeability
    Ram P Naikawadi
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
    Circ Res 111:1517-27. 2012
  4. pmc Sphingosine kinase 1 mediation of expression of the anaphylatoxin receptor C5L2 dampens the inflammatory response to endotoxin
    Kurt Bachmaier
    Department of Pharmacology, College of Medicine, Center of Lung and Vascular Biology, University of Illinois, Chicago, Illinois, United States of America
    PLoS ONE 7:e30742. 2012
  5. pmc Map kinase phosphatase 5 protects against sepsis-induced acute lung injury
    Feng Qian
    Dept of Pharmacology, Univ of Illinois at Chicago, Chicago, IL 60612, USA
    Am J Physiol Lung Cell Mol Physiol 302:L866-74. 2012
  6. pmc Identification of a nuclear localization sequence in β-arrestin-1 and its functional implications
    Crystal Zoe Hoeppner
    Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 287:8932-43. 2012
  7. pmc The Ca(2+) sensor stromal interaction molecule 1 (STIM1) is necessary and sufficient for the store-operated Ca(2+) entry function of transient receptor potential canonical (TRPC) 1 and 4 channels in endothelial cells
    Premanand C Sundivakkam
    Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    Mol Pharmacol 81:510-26. 2012
  8. pmc Role for the guanine nucleotide exchange factor phosphatidylinositol-3,4,5-trisphosphate-dependent rac exchanger 1 in platelet secretion and aggregation
    Feng Qian
    Department of Pharmacology, University of Illinois College of Medicine, 835 S Wolcott Ave, Chicago, IL 60612, USA
    Arterioscler Thromb Vasc Biol 32:768-77. 2012
  9. pmc The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation
    Anke Di
    Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, Illinois, USA
    Nat Immunol 13:29-34. 2012
  10. pmc Delivery of nanoparticle: complexed drugs across the vascular endothelial barrier via caveolae
    Zhenjia Wang
    Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, USA
    IUBMB Life 63:659-67. 2011

Research Grants

  1. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
  2. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
  3. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
  4. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
  5. Rebuilding the Failing Heart
    Piero Anversa; Fiscal Year: 2013
  6. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
  7. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
  8. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
  9. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
  10. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013

Detail Information

Publications57

  1. pmc Jmjd3-mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages
    Qian Yan
    School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P R China
    Cell Signal 26:1783-91. 2014
    ..This mechanism may be subject to therapeutic intervention for sterile inflammation and atherosclerosis...
  2. pmc Transgenic expression of FoxM1 promotes endothelial repair following lung injury induced by polymicrobial sepsis in mice
    Xiaojia Huang
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, United States of America
    PLoS ONE 7:e50094. 2012
    ..Together, these data suggest FoxM1 expression in endothelial cells is necessary and sufficient to mediate endothelial repair and thereby promote survival following sepsis challenge...
  3. pmc A critical role for phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac exchanger 1 in endothelial junction disruption and vascular hyperpermeability
    Ram P Naikawadi
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
    Circ Res 111:1517-27. 2012
    ..Understanding the upstream pathway may delineate Rac activation mechanisms and its role in maintaining vascular endothelial barrier integrity...
  4. pmc Sphingosine kinase 1 mediation of expression of the anaphylatoxin receptor C5L2 dampens the inflammatory response to endotoxin
    Kurt Bachmaier
    Department of Pharmacology, College of Medicine, Center of Lung and Vascular Biology, University of Illinois, Chicago, Illinois, United States of America
    PLoS ONE 7:e30742. 2012
    ..S1P-mediated up-regulation of C5L2 is a novel therapeutic target for mitigating endotoxin-induced lung inflammatory injury...
  5. pmc Map kinase phosphatase 5 protects against sepsis-induced acute lung injury
    Feng Qian
    Dept of Pharmacology, Univ of Illinois at Chicago, Chicago, IL 60612, USA
    Am J Physiol Lung Cell Mol Physiol 302:L866-74. 2012
    ..Taken together, these results suggest that MKP5 is crucial to homeostatic regulation of MAPK activation in inflammatory responses...
  6. pmc Identification of a nuclear localization sequence in β-arrestin-1 and its functional implications
    Crystal Zoe Hoeppner
    Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 287:8932-43. 2012
    ..These results demonstrate a critical role for β-arrestin-1 nuclear localization in scaffolding and transcriptional regulation...
  7. pmc The Ca(2+) sensor stromal interaction molecule 1 (STIM1) is necessary and sufficient for the store-operated Ca(2+) entry function of transient receptor potential canonical (TRPC) 1 and 4 channels in endothelial cells
    Premanand C Sundivakkam
    Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    Mol Pharmacol 81:510-26. 2012
    ..Thus, TRPC1 and TRPC4 can interact with STIM1 to form functional store-operated Ca(2+)-entry channels, which are essential for mediating Ca(2+) entry-dependent disruption of the endothelial barrier...
  8. pmc Role for the guanine nucleotide exchange factor phosphatidylinositol-3,4,5-trisphosphate-dependent rac exchanger 1 in platelet secretion and aggregation
    Feng Qian
    Department of Pharmacology, University of Illinois College of Medicine, 835 S Wolcott Ave, Chicago, IL 60612, USA
    Arterioscler Thromb Vasc Biol 32:768-77. 2012
    ..Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) was originally identified in neutrophils that regulates phagocyte functions. We sought to examine whether P-Rex1 plays a role in platelet activation...
  9. pmc The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation
    Anke Di
    Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, Illinois, USA
    Nat Immunol 13:29-34. 2012
    ..As ROS also activate TRPM2, our findings establish a negative feedback mechanism for the inactivation of ROS production through inhibition of the membrane potential-sensitive NADPH oxidase...
  10. pmc Delivery of nanoparticle: complexed drugs across the vascular endothelial barrier via caveolae
    Zhenjia Wang
    Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, USA
    IUBMB Life 63:659-67. 2011
    ..Here, we will review the current concepts and state of development for delivering engineered nanoparticles across the endothelium via the caveolae-mediated pathway...
  11. pmc Src phosphorylation of endothelial cell surface intercellular adhesion molecule-1 mediates neutrophil adhesion and contributes to the mechanism of lung inflammation
    Guoquan Liu
    Department of Pharmacology, University of Illinois, Chicago, IL, USA
    Arterioscler Thromb Vasc Biol 31:1342-50. 2011
    ....
  12. pmc Akt isoforms differentially regulate neutrophil functions
    Jia Chen
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
    Blood 115:4237-46. 2010
    ..These results demonstrate a predominant role of Akt2 in regulating neutrophil functions and provide evidence for differential activation of the 2 Akt isoforms in neutrophils...
  13. pmc A novel function of sphingosine kinase 1 suppression of JNK activity in preventing inflammation and injury
    Anke Di
    Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 285:15848-57. 2010
    ..Therefore, SphK1-mediated down-regulation of JNK activity serves to dampen inflammation and tissue injury...
  14. pmc Role of nicotinamide adenine dinucleotide phosphate-reduced oxidase proteins in Pseudomonas aeruginosa-induced lung inflammation and permeability
    Panfeng Fu
    Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA
    Am J Respir Cell Mol Biol 48:477-88. 2013
    ..aeruginosa-induced lung inflammation. These data show that P. aeruginosa lung infection up-regulates NOX2 and NOX4 expression and ROS generation, which play distinct roles in regulating lung inflammation, apoptosis, and permeability...
  15. pmc Therapeutic administration of the chemokine CXCL1/KC abrogates autoimmune inflammatory heart disease
    Kurt Bachmaier
    Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Center for Lung and Vascular Biology, Chicago, Illinois, United States of America
    PLoS ONE 9:e89647. 2014
    ..These findings reveal a novel function of CXCL1/KC in the context of organ-specific autoimmune disease that may prove useful for the treatment of inflammatory conditions that underlie human heart disease. ..
  16. ncbi Endothelial FoxM1 mediates bone marrow progenitor cell-induced vascular repair and resolution of inflammation following inflammatory lung injury
    Yidan D Zhao
    Department of Pharmacology, The University of Illinois College of Medicine, Chicago, Illinois, USA Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, Illinois, USA
    Stem Cells 32:1855-64. 2014
    ....
  17. pmc Human CD34+ progenitor cells freshly isolated from umbilical cord blood attenuate inflammatory lung injury following LPS challenge
    Xiaojia Huang
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, United States of America Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, United States of America Department of Pharmacology, School of Medical Sciences and Laboratory Medicine, Jiangsu University, Zhenjiang, China
    PLoS ONE 9:e88814. 2014
    ....
  18. pmc The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation
    Chinnaswamy Tiruppathi
    Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA
    Nat Immunol 15:239-47. 2014
    ..Targeting of DREAM to induce USF1-mediated A20 expression is therefore a potential anti-inflammatory strategy for the treatment of diseases associated with unconstrained NF-κB activity, such as acute lung injury. ..
  19. pmc Loss of caveolin-1 and adiponectin induces severe inflammatory lung injury following LPS challenge through excessive oxidative/nitrative stress
    Lei Cai
    Dept of Pharmacology, Univ of Illinois College of Medicine, 835 South Wolcott Ave, E403 MSB, M C 868, Chicago, IL 60612
    Am J Physiol Lung Cell Mol Physiol 306:L566-73. 2014
    ..Thus oxidative/nitrative stress collectively modulated by Cav1 and ADPN signalings is a critical determinant of inflammatory lung injury in response to LPS challenge. ..
  20. pmc Cooperative interaction of trp melastatin channel transient receptor potential (TRPM2) with its splice variant TRPM2 short variant is essential for endothelial cell apoptosis
    Claudie M Hecquet
    From the Department of Pharmacology and the Center for Lung and Vascular Biology C M H, M Z, M M, S M V, A D, X G, M G B, A B M and Section of Cardiology M G B, College of Medicine, University of Illinois, Chicago
    Circ Res 114:469-79. 2014
    ....
  21. pmc Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration
    Xiaowu Gu
    Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
    Am J Pathol 184:541-55. 2014
    ..Our results are relevant to clinically significant retinal disorders with vascular pathologies, including diabetic retinopathy, uveoretinitis, and primary open-angle glaucoma. ..
  22. pmc Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands
    Hui Qiong He
    From the School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
    J Biol Chem 289:2295-306. 2014
    ..These results indicate that different structural determinants are used by FPR1 and FPR2 to interact with formyl peptides. ..
  23. pmc Transcriptional regulation of endothelial cell and vascular development
    Changwon Park
    Department of Pharmacology, Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL 60612, USA
    Circ Res 112:1380-400. 2013
    ..We also discuss recent progress on reprogramming of somatic cells toward distinct endothelial cell lineages and its promise in regenerative vascular medicine...
  24. pmc Store-operated Ca2+ entry (SOCE) induced by protease-activated receptor-1 mediates STIM1 protein phosphorylation to inhibit SOCE in endothelial cells through AMP-activated protein kinase and p38β mitogen-activated protein kinase
    Premanand C Sundivakkam
    Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, Illinois 60612 7343, USA
    J Biol Chem 288:17030-41. 2013
    ..Thus, our findings demonstrate that SOCE activates CaMKKβ-AMPKα1-p38β MAPK signaling to phosphorylate STIM1, thereby suppressing endothelial SOCE and permeability responses...
  25. ncbi Bioluminescent detection of peroxynitrite with a boronic acid-caged luciferin
    Nathan A Sieracki
    Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA
    Free Radic Biol Med 61:40-50. 2013
    ..Thus, the PCL-1 method for measuring peroxynitrite generation shows superior selectivity over other oxidants under in vivo conditions. ..
  26. pmc Dentin phosphophoryn activates Smad protein signaling through Ca2+-calmodulin-dependent protein kinase II in undifferentiated mesenchymal cells
    Asha Eapen
    Department of Oral Biology, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 288:8585-95. 2013
    ..These findings suggest that DPP is capable of triggering commitment of pluripotent stem cells to the osteogenic lineage...
  27. pmc Characterization of P-Rex1 for its role in fMet-Leu-Phe-induced superoxide production in reconstituted COS(phox) cells
    Baoming Nie
    Department of Pharmacology, University of Illinois, Chicago, 60612, United States
    Cell Signal 22:770-82. 2010
    ..These results demonstrate that in COS(phox) cells, P-Rex1 is a critical component for FPR1-mediated signaling leading to NADPH oxidase activation, and there is a crosstalk between the P-Rex1-Rac pathway and Akt in superoxide generation...
  28. ncbi TRP channels and the control of vascular function
    Anke Di
    Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL 60612, USA
    Curr Opin Pharmacol 10:127-32. 2010
    ..This diversity of activating mechanisms could be consistent with the potential multiple functions of the TRP superfamily. This review summarizes the burgeoning understanding of these cation channels in the control of vascular function...
  29. pmc Ca2+ influx via TRPC channels induces NF-kappaB-dependent A20 expression to prevent thrombin-induced apoptosis in endothelial cells
    Prabhakar B Thippegowda
    Dept of Pharmacology, College of Medicine, Univ of Illinois, 835 South Wolcott Ave, Chicago, IL 60612, USA
    Am J Physiol Cell Physiol 298:C656-64. 2010
    ..These results suggest that Ca(2+) influx via TRPC channels plays a critical role in the mechanism of cell survival signaling through A20 expression in ECs...
  30. ncbi A critical role of protein kinase C delta activation loop phosphorylation in formyl-methionyl-leucyl-phenylalanine-induced phosphorylation of p47(phox) and rapid activation of nicotinamide adenine dinucleotide phosphate oxidase
    Ni Cheng
    Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL 60612, USA
    J Immunol 179:7720-8. 2007
    ..We conclude that agonist-induced PKCdelta phosphorylation is a novel mechanism for NADPH oxidase activation. The ability to induce PKCdelta phosphorylation may distinguish a full agonist from a partial agonist for superoxide production...
  31. ncbi Characterization of a mutation in the Phox homology domain of the NADPH oxidase component p40phox identifies a mechanism for negative regulation of superoxide production
    Jia Chen
    Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 282:30273-84. 2007
    ..Both functions require the association of p40(phox) with p67(phox)...
  32. ncbi E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury
    Kurt Bachmaier
    Department of Pharmacology, College of Medicine, University of Illinois, E403, Medical Science Building, M C 868, 835 S Wolcott Avenue, Chicago, Illinois 60612, USA
    Nat Med 13:920-6. 2007
    ..The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis...
  33. ncbi Interrelations/cross talk between transcellular transport function and paracellular tight junctional properties in lung epithelial and endothelial barriers
    Willy Van Driessche
    Laboratory of Physiology, Campus Gasthuisberg O and N, K U Leuven, Leuven, Belgium
    Am J Physiol Lung Cell Mol Physiol 293:L520-4. 2007
    ..Mechanistic (e.g., signaling cascades) information on such cross talk remain to be determined...
  34. ncbi Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation
    Xiao Pei Gao
    Department of Pharmacology and Center of Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA
    J Biol Chem 282:6116-25. 2007
    ....
  35. ncbi Ca2+ signaling, TRP channels, and endothelial permeability
    Chinnaswamy Tiruppathi
    Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    Microcirculation 13:693-708. 2006
    ..These results indicate that endothelial TRP channels such as TRPC1 and TRPC4 play an important role in signaling agonist-induced increases in endothelial permeability...
  36. ncbi Caveolin-1 regulates NF-kappaB activation and lung inflammatory response to sepsis induced by lipopolysaccharide
    Sean Garrean
    Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, 835 South Wolcott Avenue, Chicago, IL 60612, USA
    J Immunol 177:4853-60. 2006
    ..Thus, caveolin-1, through its ability to regulate eNOS-derived NO production, is a crucial determinant of NF-kappaB activation and the lung inflammatory response to LPS...
  37. pmc Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury
    You Yang Zhao
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA
    J Clin Invest 116:2333-43. 2006
    ..These data suggest that impairment in FoxM1 activation may be an important determinant of the persistent vascular barrier leakiness and edema formation associated with inflammatory diseases...
  38. ncbi Caveolin-1 regulates store-operated Ca2+ influx by binding of its scaffolding domain to transient receptor potential channel-1 in endothelial cells
    Angela M Kwiatek
    Department of Pharmacology M C868, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Avenue, Chicago, IL 60612, USA
    Mol Pharmacol 70:1174-83. 2006
    ..We identified the interaction between biotin-labeled AP-TRPC1 C terminus peptide and caveolin-1. Thus, these results demonstrate a crucial role of caveolin-1 scaffolding domain interaction with TRPC1 in regulating Ca2+ influx via SOC...
  39. pmc Activation state-dependent interaction between Galphai and p67phox
    Caroline Marty
    Department of Pharmacology, University of Illinois at Chicago, 835 S Wolcott Avenue, Chicago, IL 60612, USA
    Mol Cell Biol 26:5190-200. 2006
    ..These results provide the first evidence for an interaction between p67phox and an alpha subunit of heterotrimeric G proteins, suggesting a potential role for Galphai in the regulation or activation of NADPH oxidase...
  40. ncbi Regulation of lung neutrophil recruitment by VE-cadherin
    Janie Orrington-Myers
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
    Am J Physiol Lung Cell Mol Physiol 291:L764-71. 2006
    ..These results suggest that disassembly of VE-cadherin junctions serves as a negative signal for limiting transendothelial PMN migration secondary to decreased ICAM-1 expression in the mouse model of LPS-induced sepsis...
  41. ncbi Ca2+ influx induced by protease-activated receptor-1 activates a feed-forward mechanism of TRPC1 expression via nuclear factor-kappaB activation in endothelial cells
    Biman C Paria
    Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, 60612, USA
    J Biol Chem 281:20715-27. 2006
    ..Thus, Ca(2+) influx via TRPC1 is a critical feed-forward pathway responsible for TRPC1 expression. The NF-kappaB-regulated TRPC1 expression may be an essential mechanism of vascular inflammation and, hence, a novel therapeutic target...
  42. pmc Role of NF-kappaB-dependent caveolin-1 expression in the mechanism of increased endothelial permeability induced by lipopolysaccharide
    Chinnaswamy Tiruppathi
    Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA
    J Biol Chem 283:4210-8. 2008
    ..Thus, LPS mediates NF-kappaB-dependent Cav-1 expression that results in increased caveolae number and thereby contributes to the mechanism of increased transendothelial albumin permeability...
  43. pmc Augmented inducible nitric oxide synthase expression and increased NO production reduce sepsis-induced lung injury and mortality in myeloperoxidase-null mice
    Viktor Brovkovych
    Department of Pharmacology, University of Illinois College of Medicine, 835 S Wolcott, Chicago, Illinois 60612, USA
    Am J Physiol Lung Cell Mol Physiol 295:L96-103. 2008
    ..Thus augmented iNOS expression and NO production in MPO(-/-) mice compensate for the lack of HOCl-mediated bacterial killing, and the absence of MPO-derived oxidants mitigates E. coli sepsis-induced lung inflammation and injury...
  44. pmc Size and dynamics of caveolae studied using nanoparticles in living endothelial cells
    Zhenjia Wang
    Department of Pharmacology, University of Illinois, Chicago, IL 60612, USA
    ACS Nano 3:4110-6. 2009
    ..Together, our results show the feasibility of tracking multicolored nanoparticles in living endothelial cells and potential usefulness for designing therapeutic nanoparticle cargo to cross the limiting vessel wall endothelial barrier...
  45. pmc A non-redundant role for MKP5 in limiting ROS production and preventing LPS-induced vascular injury
    Feng Qian
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA
    EMBO J 28:2896-907. 2009
    ..Collectively, these results show an earlier unrecognized and non-redundant function of MKP5 in restraining p38 MAPK-mediated neutrophil oxidant production, thereby preventing LPS-induced vascular injury...
  46. pmc Bone marrow progenitor cells induce endothelial adherens junction integrity by sphingosine-1-phosphate-mediated Rac1 and Cdc42 signaling
    Yidan D Zhao
    Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Ill 60612, USA
    Circ Res 105:696-704, 8 p following 704. 2009
    ..Little is known about the contribution of bone marrow-derived progenitor cells (BMPCs) in the regulation endothelial barrier function as defined by microvascular permeability alterations at the level of adherens junctions (AJs)...
  47. pmc LIM kinase 1 promotes endothelial barrier disruption and neutrophil infiltration in mouse lungs
    Matvey Gorovoy
    Department of Pharmacology, University of Illinois at Chicago, 909 S Wolcott Ave, Chicago, IL 60612, USA
    Circ Res 105:549-56. 2009
    ..Recently we reported that endotoxin induced activation of RhoA in mice lungs that led to the disruption of endothelial barrier and lung edema formation; however, the molecular mechanism of this phenomenon remained unknown...
  48. pmc NF-kappaB regulates thrombin-induced ICAM-1 gene expression in cooperation with NFAT by binding to the intronic NF-kappaB site in the ICAM-1 gene
    Jiaping Xue
    Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    Physiol Genomics 38:42-53. 2009
    ..Thus these results suggest that p65/RelA and NFATc1 bind to the intronic NF-kappaB site 1 sequence to induce optimal transcription of the ICAM-1 gene in response to thrombin in endothelial cells...
  49. pmc Role of H(2)O(2)-activated TRPM2 calcium channel in oxidant-induced endothelial injury
    Claudie M Hecquet
    Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA
    Thromb Haemost 101:619-25. 2009
    ....
  50. pmc Galpha13 regulates MEF2-dependent gene transcription in endothelial cells: role in angiogenesis
    Guoquan Liu
    Department of Pharmacology, University of Illinois, 835 S Wolcott Ave, Chicago, IL 60612, USA
    Angiogenesis 12:1-15. 2009
    ..Our studies suggest that MEF2 proteins are an important component in Galpha13-mediated angiogenesis...
  51. pmc Caveolin-1 scaffold domain interacts with TRPC1 and IP3R3 to regulate Ca2+ store release-induced Ca2+ entry in endothelial cells
    Premanand C Sundivakkam
    Dept of Pharmacology M C 868 College of Medicine, Univ of Illinois 835 South Wolcott Ave, Chicago, IL 60612, USA
    Am J Physiol Cell Physiol 296:C403-13. 2009
    ..These findings suggest that CSD interacts with TRPC1 and IP(3)R3 and thereby regulates Ca(2+) store release-induced Ca(2+) entry in endothelial cells...
  52. pmc Ca2+ entry via TRPC channels is necessary for thrombin-induced NF-kappaB activation in endothelial cells through AMP-activated protein kinase and protein kinase Cdelta
    Angela M Bair
    Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 284:563-74. 2009
    ....
  53. pmc Opposing effects of platelet-activating factor and lyso-platelet-activating factor on neutrophil and platelet activation
    Emily J Welch
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
    Mol Pharmacol 75:227-34. 2009
    ..These findings identify lysoPAF as a bioactive lipid with opposing functions of PAF and suggest a novel and intrinsic regulatory mechanism for balance of the potent activity of PAF...
  54. pmc Identification of formyl peptides from Listeria monocytogenes and Staphylococcus aureus as potent chemoattractants for mouse neutrophils
    Erica L Southgate
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
    J Immunol 181:1429-37. 2008
    ..aureus are approximately 100-fold more potent than fMLF in activating mouse neutrophils. The ability of mFPR1 to detect bacterially derived formyl peptides indicates that this important host defense mechanism is conserved in mice...
  55. pmc Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating beta2 integrins
    Jingsong Xu
    Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA
    Nat Immunol 9:880-6. 2008
    ..Our results demonstrate that MYLK-mediated activation of beta(2) integrins through Pyk2 links beta(2) integrin signaling to the actin motile machinery of neutrophils...
  56. ncbi Signaling mechanisms regulating endothelial permeability
    Dolly Mehta
    Center of Lung and Vascular Biology, Dept of Pharmacology M C 868, University of Illinois, 835 S Wolcott Avenue, Chicago, IL 60612, USA
    Physiol Rev 86:279-367. 2006
    ....

Research Grants30

  1. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  2. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  3. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  4. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
    ..abstract_text> ..
  5. Rebuilding the Failing Heart
    Piero Anversa; Fiscal Year: 2013
    ..abstract_text> ..
  6. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..
  7. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  8. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  9. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  10. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  11. Signaling of Endothelial Permeability and Lung Vascular Injury
    Asrar B Malik; Fiscal Year: 2013
    ..Moreover the depth of understanding to be gained of the signaling pathways mediating the increase in lung vascular permeability will provide novel insights into the mechanisms of protein-rich pulmonary edema and ARDS. ..
  12. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  13. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  14. Cell Adhesion Mechanisms in Vascular Disease &Thrombosis
    MARK HOWARD GINSBERG; Fiscal Year: 2013
    ..abstract_text> ..