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Prostacyclin: An Inflammatory Paradox

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Prostacyclin: An Inflammatory Paradox

Jeremiah Stitham et al. Front Pharmacol.

Abstract

Prostacyclin (PGI(2)) is a member of the prostaglandin family of bioactive lipids. Its best-characterized role is in the cardiovascular system, where it is released by vascular endothelial cells, serving as a potent vasodilator and inhibitor of platelet aggregation. In recent years, prostacyclin (PGI(2)) has also been shown to promote differentiation and inhibit proliferation in vascular smooth muscle cells. In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI(2)) also plays an important role as an inflammatory mediator. In this review, we focus on the contribution of prostacyclin (PGI(2)) as both a pathophysiological mediator and therapeutic agent in three major inflammatory-mediated disease processes, namely rheumatoid arthritis, where it promotes disease progression ("pro-inflammatory"), along with pulmonary vascular disease and atherosclerosis, where it inhibits disease progression ("anti-inflammatory"). The emerging role of prostacyclin (PGI(2)) in this context provides new opportunities for understanding the complex molecular basis for inflammatory-related diseases, and insights into the development of current and future anti-inflammatory treatments.

Keywords: IP receptor; atherosclerosis; inflammation; prostacyclin; pulmonary fibrosis; rheumatoid arthritis.

Figures

Figure 1
Figure 1
Prostanoid biosynthesis pathway. The enzyme phospholipase A2 (PLA2) hydrolyzes arachidonic acid (AA) from the phospholipids of the extracellular membrane. Arachidonic acid is modified by the cyclooxygenase (COX) enzymes (COX-1 and COX-2) to form the intermediate precursor prostaglandin G2 (PGG2) via the addition of two oxygen (O2) molecules. Prostaglandin H2 (PGH2) is subsequently formed by the actions of peroxidase enzyme, which releases a single oxygen (O2) molecule. As shown, all prostanoids are derived from the parent compound PGH2 and are formed via their respective synthase enzymes, namely prostaglandin I2 synthase (PGIS), prostaglandin E2 synthase (PGES-1), prostaglandin D2 synthase (PGDS), prostaglandin F synthase (PGES-2), and thromboxane A2 synthase (TBXAS-1).
Figure 2
Figure 2
Paradoxical actions of prostacyclin in three inflammatory diseases. Prostacyclin (PGI2) serves as a protective, anti-inflammatory mediator in the processes of atherosclerosis and pulmonary vascular diseases, such as pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). Conversely, in rheumatological conditions, such as rheumatoid arthritis (RA) and osteoarthritis (OA), PGI2 acts as a propagatory, pro-inflammatory molecule.

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