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.
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.
|Banathy, Alex; Cheung-Flynn, Joyce; Goleniewska, Kasia et al. (2016) Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of Î²2-Adrenergic Receptor. Am J Respir Cell Mol Biol 55:225-33|
|Zhou, Weisong; Zhang, Jian; Goleniewska, Kasia et al. (2016) Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation. J Immunol 197:1577-86|
|Stier, Matthew T; Bloodworth, Melissa H; Toki, Shinji et al. (2016) Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. J Allergy Clin Immunol 138:814-824.e11|
|Zhou, Weisong; Toki, Shinji; Zhang, Jian et al. (2016) Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses. Am J Respir Crit Care Med 193:31-42|
|Toki, Shinji; Goleniewska, Kasia; Reiss, Sara et al. (2016) The histone deacetylase inhibitor trichostatin A suppresses murine innate allergic inflammation by blocking group 2 innate lymphoid cell (ILC2) activation. Thorax 71:633-45|
|Peebles Jr, R Stokes (2015) At the bedside: the emergence of group 2 innate lymphoid cells in human disease. J Leukoc Biol 97:469-75|
|Claar, Dru; Hartert, Tina V; Peebles Jr, Ray Stokes (2015) The role of prostaglandins in allergic lung inflammation and asthma. Expert Rev Respir Med 9:55-72|
|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; 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|
|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|
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