Mast cells are implicated in the pathogenesis of a broad spectrum of immunological disorders. These cells release inflammatory mediators in response to a number of stimuli, including IgE-Ag complexes. The degranulation of mast cells is modified by PGs. To begin to delineate the pathway(s) used by PGs to regulate mast cell function, we examined bone marrow-derived mast cells (BMMC) cultured from mice deficient in the EP1, EP2, EP3, and EP4 receptors for PGE2. Although BMMCs express all four of these PGE2 receptors, potentiation of Ag-stimulated degranulation and IL-6 cytokine production by PGE2 is dependent on the EP3 receptor. Consistent with the coupling of this receptor to Gαi, PGE2 activation of the EP3 receptor leads to both inhibition of adenylate cyclase and increased intracellular Ca2+. The magnitude of increase in intracellular Ca2+ induced by EP3 activation is similar to that observed after activation of cells with IgE and Ag. Although PGE alone is not sufficient to initiate BMMC degranulation, stimulation of cells with PGE along with PMA induces degranulation. These actions are mediated by the EP3 receptor through signals involving Ca2+ mobilization and/or decreased cAMP levels. Accordingly, these studies identify PGE2/EP3 as a proinflammatory signaling pathway that promotes mast cell activation.
Although cerebral vascular malformations are traditionally considered to be congenital lesions, they often become clinically evident in the 3rd to 4th decades of life, leading to the assumption of a long silent clinical period. Unlike vein of Galen malformations, antenatal diagnosis of cerebral arteriovenous malformations (AVMs) is highly uncommon. Postnatal development of an AVM is an emergent concept supported by more clinical observations. Genetic and biological studies demonstrate that an environmental trigger (“second hit”) in addition to genetic predisposition may be a key in understanding the pathophysiology of AVMs and other cerebral vascular lesions such as cavernous malformations (CMs). The authors describe a 6-year-old boy in whom a giant CM was diagnosed and a de novo AVM was detected 25 months after initial resection of the CM. This case seems to support the second-hit hypothesis.
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