Allergic airway inflammation is a hallmark of asthma, a disease that affects approximately 5-10% of Americans. Prostaglandins are lipid mediators that have potent immunomodulatory effects which are produced in abundance by the cyclooxygenase enzymes during allergic airway inflammation. Using a mouse model of type I hypersensitivity to ovalbumin, inhibition of the cyclooxygenase (COX) pathway of arachidonic acid metabolism during the development of allergic airway disease results in a significant augmentation of the allergic inflammatory response in the lung. Thus, one or more COX products restrain the pulmonary allergen-induced inflammatory response. Published work from other groups and our own preliminary data suggest that prostaglandin I2 (PGI2) is an important negative regulator of allergic inflammation. In vivo studies reveal that the inability to signal through the PGI2 receptor, IP, results in augmentation of allergic inflammation when mice are sensitized and challenged with ovalbumin, suggesting that signaling through IP therefore inhibits allergic inflammation. Our in vitro preliminary data indicate that PGI2 analogs have profound anti-inflammatory effects on both dendritic cells and T lymphocytes. However, the effect of PGI2 signaling on dendritic cell and T cell function in vivo has not been fully investigated. In this proposal, we hypothesize that PGI2 and signaling through IP inhibits lung-specific allergic immune responses by regulating both dendritic cell and T cell functions. The proposed studies could have important therapeutic ramifications with the recent development of more stable PGI2 analogs for clinical use and of new delivery systems which allow effective targeting of these agents to the lung, thus perhaps providing the ability to use PGI2 analogs in allergic diseases such as asthma. Therefore, defining the role of PGI2 and its cellular receptor in allergic inflammation in vivo might result in novel targets for drug development in this important disease.

Public Health Relevance

Allergic airway inflammation is a hallmark of asthma, a disease that affects approximately 5- 10% of Americans. Prostaglandins are chemicals made by the body that can influence inflammation. PGI2 is a prostaglandin that may control asthma and we will study it in this project.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090664-05
Application #
8386950
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2008-12-10
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$361,677
Indirect Cost
$126,057
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Dulek, Daniel E; Newcomb, Dawn C; Toki, Shinji et al. (2014) STAT4 deficiency fails to induce lung Th2 or Th17 immunity following primary or secondary respiratory syncytial virus (RSV) challenge but enhances the lung RSV-specific CD8+ T cell immune response to secondary challenge. J Virol 88:9655-72
Zhou, Weisong; Goleniewska, Kasia; Zhang, Jian et al. (2014) Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling. J Allergy Clin Immunol 134:698-705.e5
Dulek, Daniel E; Newcomb, Dawn C; Goleniewska, Kasia et al. (2014) Allergic airway inflammation decreases lung bacterial burden following acute Klebsiella pneumoniae infection in a neutrophil- and CCL8-dependent manner. Infect Immun 82:3723-39
Sevin, Carla M; Newcomb, Dawn C; Toki, Shinji et al. (2013) Deficiency of gp91phox inhibits allergic airway inflammation. Am J Respir Cell Mol Biol 49:396-402
Newcomb, Dawn Catherine; Boswell, Madison G; Reiss, Sara et al. (2013) IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation. Thorax 68:717-23
Newcomb, Dawn C; Peebles Jr, R Stokes (2013) Th17-mediated inflammation in asthma. Curr Opin Immunol 25:755-60
Newcomb, Dawn C; Boswell, Madison G; Huckabee, Matthew M et al. (2012) IL-13 regulates Th17 secretion of IL-17A in an IL-10-dependent manner. J Immunol 188:1027-35
Peebles Jr, R Stokes (2011) The ever-expanding role of prostanoids in regulating immune responses. Am J Respir Crit Care Med 184:1-2
Dulek, Daniel E; Peebles, R Stokes (2011) Bacteria and asthma: more there than we thought. Expert Rev Respir Med 5:329-32
Dulek, Daniel E; Peebles Jr, R Stokes (2011) Viruses and asthma. Biochim Biophys Acta 1810:1080-90

Showing the most recent 10 out of 18 publications