Project 1 """"""""Novel inflammatory responses of injured endothelium."""""""" Acute respiratory Distress Syndrome (ARDS) is a frequent syndrome with a mortality that remains high even 30 years after its initial description. A leading cause of ARDS is bacteremia and sepsis, accounting for a third of those diagnosed with ARDS, and about a third of those with sepsis syndrome will display the clinical features that lead to a diagnosis of ARDS. The outer leaflet of gram bacteria is comprised of lipopolysaccharide (LPS), and this is a potent pleotropic inflammatory mediator in vivo and in vitro. LPS injection recapitulates many of the manifestations of sepsis, and LPS inhalation approximates early features of ARDS. In contrast to models of LPS-endotoxemia, the results of therapeutic strategies based on blocking LPS have not been as encouraging in clinical trials of human sepsis and its consequences, including ARDS. While several valid reasons exist for the differences between LPS-induced endotoxemia versus clinical sepsis, one difference is that pathogenic bacteria elaborate more than a single agent that can activate cellular responses, dysregulate inflammatory cell-cell interactions, and open the doors to sepsis syndrome. A clinical observation that clearly supports this possibility is that ARDS is """"""""triggered"""""""" by gram+ bacteria that do not contain LPS, an event growing relevance as sepsis syndrome caused by gram+ bacteria may be increasing. Thus, there is more to sepsis than LPS. This proposal is predicated on our observation that two proteins with an N-terminal modification that is common among gram-, gram+, and even intracellular pathogens behave in some ways like LPS. This is clearly documented in our in vitro and in vivo preliminary studies. Success in elucidating the chemical structure of LPS has allowed LPS to become synonymous with the more general term endotoxin, and this has overshadowed older literature describing endotoxin proteins. We propose that a common lipid modification of bacterial proteins confers endotoxic properties to the nearly forgotten class of endotoxic proteins. The relative role of LPS and certain bacterial proteins as endotoxins is further confused by the contamination of LPS preparations with the more potent endotoxic proteins.
The Aims are designed to clarify the overlapping activities, and to determine if, and how, the triacylCys modification is pro-inflammatory.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL050153-07
Application #
6302255
Study Section
Project Start
1999-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
7
Fiscal Year
2000
Total Cost
$171,165
Indirect Cost
Name
University of Utah
Department
Type
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Yost, Christian C; Weyrich, Andrew S; Zimmerman, Guy A (2010) The platelet activating factor (PAF) signaling cascade in systemic inflammatory responses. Biochimie 92:692-7
Gomes, Rachel N; Bozza, Fernando A; Amancio, Rodrigo T et al. (2006) Exogenous platelet-activating factor acetylhydrolase reduces mortality in mice with systemic inflammatory response syndrome and sepsis. Shock 26:41-9
Matthay, Michael A; Zimmerman, Guy A (2005) Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33:319-27
Lindemann, Stephan W; Weyrich, Andrew S; Zimmerman, Guy A (2005) Signaling to translational control pathways: diversity in gene regulation in inflammatory and vascular cells. Trends Cardiovasc Med 15:9-17
Lindemann, Stephan W; Yost, Christian C; Denis, Melvin M et al. (2004) Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs. Proc Natl Acad Sci U S A 101:7076-81
Yost, Christian C; Denis, Melvin M; Lindemann, Stephan et al. (2004) Activated polymorphonuclear leukocytes rapidly synthesize retinoic acid receptor-alpha: a mechanism for translational control of transcriptional events. J Exp Med 200:671-80
Ishizaka, Akitoshi; Matsuda, Tomoyuki; Albertine, Kurt H et al. (2004) Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 286:L1088-94
Zimmerman, Guy A; McIntyre, Thomas M (2004) PAF, ceramide and pulmonary edema: alveolar flooding and a flood of questions. Trends Mol Med 10:245-8
Wu, Xiaoqing; Zimmerman, Guy A; Prescott, Stephen M et al. (2004) The p38 MAPK pathway mediates transcriptional activation of the plasma platelet-activating factor acetylhydrolase gene in macrophages stimulated with lipopolysaccharide. J Biol Chem 279:36158-65
Hoidal, John R; Brar, S S; Sturrock, Anne B et al. (2003) The role of endogenous NADPH oxidases in airway and pulmonary vascular smooth muscle function. Antioxid Redox Signal 5:751-8

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