Prostacyclin, or PGI2, is an end product derived from the sequential metabolism of arachidonic acid via cyclooxygenase and PGI synthase (PGIS). The receptor for PGI2, IP, can be found on a variety of cell types and signaling through this receptor exhibits broad physiological effects. Historically, PGI2 has been understood to play a role in cardiovascular health, specifically having powerful vasodilatory effects via relaxation of smooth muscle and inhibiting of platelet aggregation. For these reasons, PGI2 has a long history of use for the treatment of pulmonary arterial hypertension (PAH). Only recently, its importance as an immunomodulatory agent has been investigated. PGI2 regulates both the innate and adaptive immune systems and its effects are, for the most part, thought to be anti-inflammatory or immunosuppressive in nature, which may have implications for its further clinical use. 1. Introduction Prostacyclin, or PGI2, was first reported by Needleman and Vane in 1976 and is an end product derived from the sequential metabolism of arachidonic acid via cyclooxygenase-2 (COX-2) and prostacyclin synthase (PGIS) [1]. COX-2 is expressed upon specific stimulation such as cytokines, growth factors, bacterial endotoxins, tumor promoters, and hormones by macrophages, neutrophils, and activated mesenchymal cells [2–4]. There is rare expression of COX-2 in unstimulated tissues [5–7], but it can be present at low basal levels in endothelium and the renal macula densa [2, 5]. COX-2 is typically associated with proinflammatory conditions such as atherosclerotic lesions, aortic aneurysms, or vascular damage where COX-2 derived products likely provide a protective effect [8–10]. COX-2 is inhibited by nonsteroidal anti-inflammatory (NSAIDS) and specific COX-2 inhibitors, which may have tissue specific effects. Several additional cells types have been shown to express COX-2 and PGIS and they include fibroblasts, follicular dendritic cells, endothelial cells, smooth muscle cells, and thymic nurse cells. Production of PGI2 is decreased by the inhibition of PGIS by tyrosine-nitrating agents such as peroxynitrite [11] and tetranitromethane [12]. Lastly, PGIS can be limited by substrate-dependent suicide inactivation if there is adequate conversion of PGH2, the substrate for PGIS, which causes accumulation of inactivated enzyme [13]. PGI2 is primarily produced in mammalian vasculature with elevated levels in pulmonary arterial segments when compared to systemic circulation [14]. As such, PGI2 has been understood to play a role in cardiovascular health specifically
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