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Prostacyclin: an Inflammatory Paradox

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Prostacyclin: an Inflammatory Paradox REVIEW ARTICLE published: 13 May 2011 doi: 10.3389/fphar.2011.00024 Prostacyclin: an inflammatory paradox Jeremiah Stitham, Charles Midgett, Kathleen A. Martin and John Hwa* Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, CT, USA Edited by: Prostacyclin (PGI2) is a member of the prostaglandin family of bioactive lipids. Its best- Angel Lanas, University of Zaragoza, characterized role is in the cardiovascular system, where it is released by vascular endothelial cells, Spain serving as a potent vasodilator and inhibitor of platelet aggregation. In recent years, prostacyclin Reviewed by: Emer Smyth, University of (PGI2) has also been shown to promote differentiation and inhibit proliferation in vascular smooth Pennsylvania, USA muscle cells. In addition to these well-described homeostatic roles within the cardiovascular Steven W. Kerrigan, Royal College of system, prostacyclin (PGI2) also plays an important role as an inflammatory mediator. In this Surgeons in Ireland, Ireland review, we focus on the contribution of prostacyclin (PGI2) as both a pathophysiological mediator *Correspondence: and therapeutic agent in three major inflammatory-mediated disease processes, namely John Hwa, Section of Cardiovascular Medicine, Department of Internal rheumatoid arthritis, where it promotes disease progression (“pro-inflammatory”), along Medicine, Yale School of Medicine, with pulmonary vascular disease and atherosclerosis, where it inhibits disease progression Cardiovascular Research Center, 300 (“anti-inflammatory”). The emerging role of prostacyclin (PGI2) in this context provides new George Street, Room 759H, New opportunities for understanding the complex molecular basis for inflammatory-related diseases, Haven, CT 06511, USA. e-mail: [email protected] and insights into the development of current and future anti-inflammatory treatments. Keywords: prostacyclin, IP receptor, inflammation, atherosclerosis, rheumatoid arthritis, pulmonary fibrosis PHARMACOLOGY OF PROSTACYCLIN AND ITS RECEPTOR to inhibit vascular smooth muscle cell (VSMC) proliferation and Prostacyclin (PGI2) is a member of the prostaglandin family of de-differentiation (Fetalvero et al., 2006, 2007). Within the lungs, bioactive lipids, and is a derivative of the 20-carbon, omega-6 fatty PGI2 reduces pulmonary blood pressure as well as bronchial hyper- acid, arachidonic acid (AA or 5,8,11,14-eicosatetraenoic acid). Both responsiveness (Idzko et al., 2007). Within the kidneys, PGI2 serves cyclooxygenase enzymes (COX-1 and COX-2) convert AA into the to regulate renal blood flow and glomerular filtration rate, as well as prostaglandin precursor PGH2, which is subsequently synthesized mediates the release of renin (Komhoff et al., 1998). In the nervous into prostacyclin (PGI2) via prostacyclin synthase (PGIS; Figure 1). system, PGI2 has been shown to elicit nociceptive pain response However, the majority of PGI2 produced in vivo, particularly within (Murata et al., 1997). the systemic and pulmonary vasculature (Moncada et al., 1977; Catella-Lawson et al., 1999; McAdam et al., 1999), and other regions PROSTACYCLIN AS AN INFLAMMATORY MEDIATOR like the synovium (Brodie et al., 1980; Crofford et al., 1994), appears As described, prostacyclin (PGI2) is best known for its regulatory to be derived from COX-2. PGI2 is unstable at physiological pH and, role within the cardiovascular system, where it promotes VSMC thus, has a very short half-life in vivo (<2 min), rapidly forming relaxation (vasodilatation) and inhibits platelet aggregation (anti- the inactive hydration product 6-keto-prostaglandin F1α (6-keto- thrombotic). However, it is also an important inflammatory media- PGF1α; Lewis and Dollery, 1983; Smyth and FitzGerald, 2002). The tor. The seminal work by Vane (1971) demonstrating the inhibition actions of PGI2 are mediated through a seven-transmembrane- of prostaglandin biosynthesis as the mechanism of action for aspirin spanning G-protein coupled receptor (GPCR), referred to as the (acetylsalicylic acid) and other aspirin-like drugs first highlighted IP receptor (International Union of Pharmacology nomenclature). the importance of the prostaglandin family of molecules, and set The IP receptor is a Class A rhodopsin-like GPCR that couples pre- the stage for the development of many pharmacologic agents, such dominately to the Gs subunit of the heterotrimeric G-protein and as traditional, non-selective non-steroidal anti-inflammatory drugs mediates intracellular signaling via adenylyl cyclase (AC) activation (tNSAIDs) and the newer selective COX-2 inhibitors. Further work and cyclic AMP (cAMP) production (Boie et al., 1994). Animal by Davies et al. (1984) pinpointed particular prostaglandins, princi- studies have also shown that PGI2 may also signal through alternate pally prostaglandin E2 (PGE2) and prostacyclin (PGI2), in the medi- Gq- and Gi-related pathways (Lawler et al., 2001), as well as nuclear ation of vascular permeability associated with the hyperemia and receptor-mediated pathways, such as the peroxisome proliferator edema seen with acute inflammation. Murata et al. (1997) demon- activated receptor gamma (PPARδ) pathway (Lim and Dey, 2002). strated the involvement of prostacyclin (PGI2)-mediated inflamma- Stitham et al. (2003) have elucidated the putative binding pocket tory swelling in vivo, using prostacyclin receptor deficient (IP−/−) for the human IP receptor, which has been reported to also accom- mice. In these critical experiments, it was shown that mice lacking modate type E prostanoids (i.e., PGE1 and PGE2) in addition to the prostacyclin receptor had a reduced inflammatory response, its native ligand PGI2 and its analogs (Boie et al., 1994; Nakagawa as measured by percent change in vascular permeability using a et al., 1994). The physiological effects of PGI2 are vast with much carrageenan-induced paw-edema model (Murata et al., 1997). Limb remaining to be uncovered. Within the vasculature, PGI2 serves edema was decreased by approximately 50% in IP-deficient mice, as a potent vasodilator and is the major inhibitory prostanoid in similar to levels seen in mice pre-treated with the non-steroidal platelet aggregation (Smyth et al., 2009), and has also been shown anti-inflammatory agent indomethacin. Moreover, a significant www.frontiersin.org May 2011 | Volume 2 | Article 24 | 1 Stitham et al. Prostacyclin and inflammation FIGURE 1 | Prostanoid biosynthesis pathway. The enzyme phospholipase enzyme, which releases a single oxygen (O2) molecule. As shown, all A2 (PLA2) hydrolyzes arachidonic acid (AA) from the phospholipids of the prostanoids are derived from the parent compound PGH2 and are formed extracellular membrane. Arachidonic acid is modified by the cyclooxygenase via their respective synthase enzymes, namely prostaglandin I2 synthase (COX) enzymes (COX-1 and COX-2) to form the intermediate precursor (PGIS), prostaglandin E2 synthase (PGES-1), prostaglandin D2 synthase prostaglandin G2 (PGG2) via the addition of two oxygen (O2) molecules. (PGDS), prostaglandin F2α synthase (PGES-2), and thromboxane A2 Prostaglandin H2 (PGH2) is subsequently formed by the actions of peroxidase synthase (TBXAS-1). reduction in lung exudate volume, using a carrageenan-induced or the prostacyclin receptor (IP−/−), in order to determine the rela- pleurisy model, was also observed (although data not shown) for tive importance of PGE2 and PGI2, respectively. Findings revealed IP-deficient mice as well (Murata et al., 1997). In contrast, a study by that mice deficient in prostaglandin E synthase-1 mPGES-1 (and Takahashi et al. (2002) demonstrated the IP-deficient mice showed therefore unable to produce PGE2), developed arthritis in normal higher skin and airway immune responses (relating to increased fashion, whereas mice lacking the receptor for PGI2 demonstrated capillary permeability in these tissues) in antigen-sensitized inflam- a significant decrease (31% versus wild-type) in clinical arthritis. mation, suggesting a protective role for PGI2 in allergic inflamma- Furthermore, using COX-1 and COX-2 knockout animals, it was tion. These studies (among others) have highlighted prostacyclin shown that mice the lacking COX-1 isoform were resistant to the as a major endogenous mediator of inflammation – both pro- development of arthritic disease, while those lacking the COX-2 inflammatory and anti-inflammatory, depending upon the tissue isoform remained vulnerable (Wang et al., 2008). and pathological model being studied (Figure 2). These results convey two important points: (1) a substantial proportion of the prostanoid contribution to joint inflamma- ROLE OF PROSTACYCLIN IN ARTHRITIS tion (at least in the K/BxN serum-transfer arthritis model) can be While the majority of focus has centered around the role of prostag- accounted for by PGI2 and its interaction with the IP receptor, and landin E2 (PGE2) in rheumatoid arthritis (RA), some studies have (2) selective COX-1 inhibition through genetic knockout prevented shown that the predominate prostaglandin detected within the syn- the development of disease, suggesting that COX-1-derived PGI2 ovial fluid of patients with RA is in fact prostacyclin (PGI2; Brodie is the major inflammatory mediator within this arthritis model et al., 1980). Moreover, using both collagen-induced arthritis and (Wang et al., 2008). More importantly, such studies lend weight to collagen-antibody-induced arthritis models, Honda et al. (2006) the involvement of prostacyclin in
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