A fundamental hypothesis in our Special Center of Research is that dysregulated cell-cell interactions initiate and/or amplify inflammatory injury to the alveolar capillary membrane in Acute Respiratory Distress. Syndrome (ARDS), a common and lethal cause of lung damage, and that endothelial cells are critically involved. Identification of signaling molecules and other factors dysregulated cell-cell interactions in ARDS is a central and long-term goal of this project. In the current application, we focus on signaling molecules for neutrophils synthesized by stimulated and injured human endothelial cells. Neutrophils (PMNs) initiate, amplify, and influence the maintenance and outcome of acute lung injury. Endothelial cells are the first structural cells that PMNs encounter in the inflamed and injured lung and, by virtue of their ability to synthesize signaling molecules on a variety of classes, are particular points of dysregulated information transfer to the leukocytes. The mechanisms that regulate the expression and biologic actions of endothelial signaling molecules of the same or different classes, the identities of some of these signaling factors, and the mechanisms by which they become dysregulated in inflammatory injury are largely unknown. This project addresses each of these issues in interrelated studies based on the above hypotheses and on observations and preliminary data generated in the current funding period. The first specific aim is to characterize the regulation of expression and actions of chemokines produced by human endothelial cells that signal neutrophil activation, focusing on ENA-78 and related family members. The second specific aim is to characterize new endothelial signaling factors that we have identified by screening cDNA libraries from stimulated endothelial cells and by subtractive hybridization. The third specific aim is to characterize expression and distribution of endothelial signaling molecules in lung tissue from patients with ARDS and in tissue from control and comparative subjects. The fundamental and correlative nature of these studies will yield new knowledge that may lead to novel strategies of prevention and therapy of ARDS.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
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University of Utah
Salt Lake City
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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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