Prostaglandin E2 is an important modulator of airway physiology. During episodes of allergic inflammation such as in asthma, PGE2 may affect disease pathogenesis through 2 distinct pathways: by direct effects on airway tone and by modulating the intensity of the inflammatory response. These actions of PGE2 are mediated by 4 different receptors (EP1-4). In the previous funding period, we showed that activation of the EP1 and EP3 receptors by PGE2 leads to airway obstruction, while activation of the EP2 receptor protected against methacholine-induced bronchoconstriction. Moreover, EP1 and EP3 receptors are pro-inflammatory while the EP2 and EP4 receptors constrain inflammatory and immune responses. As a lipid mediator with a short half-life, regulation of PGE2 levels within specific pulmonary microenvironments could provide a mechanism to control these apparently disparate actions. PGE2 is synthesized from arachidonic acid by the sequential actions of phospholipases, cyclo-oxygenases, and PGE synthases. To date, 3 putative PGE synthases have been identified that generate PGE2 from endoperoxides. At least 1 enzyme responsible for in vivo metabolism of PGE2, 15-prostaglandin dehydrogenase (PGDH), has been identified. However, the roles of these various pathways for synthesis and metabolism of PGE2 in controlling its actions in the airways are not known. Our central hypothesis is that PGE2 primarily exerts a protective effect in allergic airway. We posit that the mechanism of this effect is: constraint of inflammation, protection against development of hyper reactive airways, and attenuation of airway remodeling. These protective effects are dependent on expression of the PGE2 EP2 and EP4 receptors. We will test this hypothesis using mouse models, some of which were developed in the previous funding period. Our preliminary studies suggest that the protective actions of PGE2 may diminish with age due to age-related increase in the pro-inflammatory PGE2 pathways. We hypothesize that the mechanism for this shift in the actions of PGE2 in older animals reflects a more prominent contribution of mast cells to promote airway inflammation. Defining the mechanisms used by PGE2 to control inflammation in the airways and developing strategies to enhance its anti-inflammatory effects should provide new approaches for attenuating the development of asthma.
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