application): Acute lung injury is frequently associated with sepsis or blood loss. In preliminary studies, The investigators found that hemorrhage or endotoxemia cause rapid increases in the expression of proinflammatory cytokines IL-1, TNF, and MIP-2, and in activation of the transcriptional regulatory factors NF-kB and CREB in lung neutrophils. After endotoxemia, but not hemorrhage, adrenergic blockade increases expression of proinflammatory cytokines by lung neutrophils, adrenergic blockade increased CREB and decreased NF-kB activation after hemorrhage, but decreased CREB and increased NF-kB activation after endotoxemia. After hemorrhage, but not endotoxemia, the increased expression of proinflammatory cytokines by lung neutrophils was inhibited by blockade of xanthine oxidase. After hemorrhage, but not endotoxemia, blockade of xanthine oxidase increases CREB activation, but does not prevent NF-kB activation in lung neutrophils. They hypothesize that distinct mechanisms lead to activation of activation of NF-kB and CREB in lung neutrophils after hemorrhage or endotoxemia, modulating their ability to affect subsequent transcription of proinflammatory cytokines involved in the development of acute lung injury.
The specific aims are to determine: 1) the mechanisms involving alterations in nuclear and cytoplasmic I-kBs, NF-kB relevant kinases, and NF-kB subunit composition, which lead to hemorrhage or endotoxemia-induced activation of NF-kB in lung neutrophils; 2) the mechanisms involving CREB relevant kinases, CREB phosphorylation, CREM and ICER expression, which lead to hemorrhage or endotoxemia-induced activation of CREB in lung neutrophils; 3) the effects of hemorrhage or endotoxemia on binding interactions between CREB, NF-kB, and CBP in lung neutrophils; and 4) the mechanisms by which reactive oxygen intermediates or catecholamines modulate NF-kB and CREB activations as well as their interactions with CBP in lung neutrophils after hemorrhage or endotoxemia, and the effects of such modulation of NF-kB and CREB activity on the development of acute lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062221-03
Application #
6537528
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Harabin, Andrea L
Project Start
2000-07-10
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$290,021
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Deshane, Jessy S; Redden, David T; Zeng, Meiqin et al. (2015) Subsets of airway myeloid-derived regulatory cells distinguish mild asthma from chronic obstructive pulmonary disease. J Allergy Clin Immunol 135:413-424.e15
Deshane, J; Zmijewski, J W; Luther, R et al. (2011) Free radical-producing myeloid-derived regulatory cells: potent activators and suppressors of lung inflammation and airway hyperresponsiveness. Mucosal Immunol 4:503-18
Zmijewski, Jaroslaw W; Banerjee, Sami; Bae, Hongbeom et al. (2010) Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J Biol Chem 285:33154-64
Banerjee, Sami; Zmijewski, Jaroslaw W; Lorne, Emmanuel et al. (2010) Modulation of SCF beta-TrCP-dependent I kappaB alpha ubiquitination by hydrogen peroxide. J Biol Chem 285:2665-75
Zmijewski, Jaroslaw W; Lorne, Emmanuel; Zhao, Xia et al. (2009) Antiinflammatory effects of hydrogen peroxide in neutrophil activation and acute lung injury. Am J Respir Crit Care Med 179:694-704
Lorne, Emmanuel; Zhao, Xia; Zmijewski, Jaroslaw W et al. (2009) Participation of mammalian target of rapamycin complex 1 in Toll-like receptor 2- and 4-induced neutrophil activation and acute lung injury. Am J Respir Cell Mol Biol 41:237-45
Zmijewski, Jaroslaw W; Banerjee, Sami; Abraham, Edward (2009) S-glutathionylation of the Rpn2 regulatory subunit inhibits 26 S proteasomal function. J Biol Chem 284:22213-21
Liu, Gang; Park, Young-Jun; Tsuruta, Yuko et al. (2009) p53 Attenuates lipopolysaccharide-induced NF-kappaB activation and acute lung injury. J Immunol 182:5063-71
Zmijewski, Jaroslaw W; Lorne, Emmanuel; Banerjee, Sami et al. (2009) Participation of mitochondrial respiratory complex III in neutrophil activation and lung injury. Am J Physiol Lung Cell Mol Physiol 296:L624-34
Liu, Gang; Friggeri, Arnaud; Yang, Yanping et al. (2009) miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proc Natl Acad Sci U S A 106:15819-24

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