Eicosanoids, products of arachidonic acid (AA) metabolism, are potent modulators of the inflammatory response. A significant role for these lipid mediators in the pathogenesis of asthma has been demonstrated, and drugs targeting one branch of this pathway, the leukotriene pathway, have recently been developed and added to our therapeutic armamentarium against asthma. A number of studies have suggested that prostanoids, cyclooxygenase (COX) metabolites of AA, have a significant impact on inflammation in asthmatic patients. The most extensively studied of these is prostaglandin E2 (PGE2). A number of lines of evidence suggests that PGE2 plays a significant anti-inflammatory role in asthma, and might produce many of the same beneficial effects observed after treatment with corticosteroids. Moreover, PGE2 has been shown to have not only immunomodulatory actions, but also to oppose antigen induced bronchoconstriction. While all other prostanoids are thought to act through a single cell surface receptor specific for that prostanoid, four receptors for PGE2 have been identified and cloned, and have been termed EP1-EP4. Each receptor subtype binds PGE2 with equal affinity, but these receptors can trigger unique signal transduction pathways, which in turn can evoke opposing physiologic actions. Most cells express a unique combination of EP receptor subtypes, and the physiologic response of that cell to PGE2 is determined by the subset of receptors expressed. The therapeutic potential of PGE2 has not yet been exploited in part due to this complex physiology. We hypothesize that PGE2 plays a key role in shaping the pathogenesis of allergic airway disease and that its role in asthma is complex due to the diverse and sometimes opposing actions of the different EP receptor isoforms. As increased intracellular cAMP levels cause relaxation of smooth muscle cells and inhibition of inflammatory responses, we posit that stimulation of the Gs-coupled EP2 and EP4 receptors will attenuate disease. Conversely, stimulation of the PLC-coupled EP1 receptor might cause bronchoconstriction and our preliminary studies have identified potent pro-inflammatory actions of the EP3 receptor. Therefore, we suggest that stimulation of EP1 and EP3 receptors might promote allergic airway disease. By defining the precise role of each EP receptor along with maneuvers designed to enhance or reduce PGE2 production in the lung, we will determine the potential of PGE2 and its receptors as therapeutic targets in asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068141-03
Application #
6638820
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Noel, Patricia
Project Start
2001-09-20
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
3
Fiscal Year
2003
Total Cost
$363,750
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kovarova, Martina; Koller, Beverly H (2014) PGE? promotes apoptosis induced by cytokine deprivation through EP3 receptor and induces Bim in mouse mast cells. PLoS One 9:e102948
Gruzdev, Artiom; Nguyen, MyTrang; Kovarova, Martina et al. (2012) PGE2 through the EP4 receptor controls smooth muscle gene expression patterns in the ductus arteriosus critical for remodeling at birth. Prostaglandins Other Lipid Mediat 97:109-19
Allen, Irving C; Lich, John D; Arthur, Janelle C et al. (2012) Characterization of NLRP12 during the development of allergic airway disease in mice. PLoS One 7:e30612
Cyphert, Jaime M; Allen, Irving C; Church, Rachel J et al. (2012) Allergic inflammation induces a persistent mechanistic switch in thromboxane-mediated airway constriction in the mouse. Am J Physiol Lung Cell Mol Physiol 302:L140-51
Kovarova, Martina; Koller, Beverly (2012) Differentiation of mast cells from embryonic stem cells. Curr Protoc Immunol Chapter 22:Unit 22F.10.1-16
Allen, Irving C; Jania, Corey M; Wilson, Justin E et al. (2012) Analysis of NLRP3 in the development of allergic airway disease in mice. J Immunol 188:2884-93
Church, Rachel J; Jania, Leigh A; Koller, Beverly H (2012) Prostaglandin E(2) produced by the lung augments the effector phase of allergic inflammation. J Immunol 188:4093-102
Cyphert, J M; Kovarova, M; Koller, B H (2011) Unique populations of lung mast cells are required for antigen-mediated bronchoconstriction. Clin Exp Allergy 41:260-9
Kovarova, Martina; Latour, Anne M; Chason, Kelly D et al. (2010) Human embryonic stem cells: a source of mast cells for the study of allergic and inflammatory diseases. Blood 115:3695-703
Arthur, Janelle C; Lich, John D; Ye, Zhengmao et al. (2010) Cutting edge: NLRP12 controls dendritic and myeloid cell migration to affect contact hypersensitivity. J Immunol 185:4515-9

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