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.
Project Narrative 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.
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