Prostaglandins and inflammation.
Journal: 2011/June - Arteriosclerosis, Thrombosis, and Vascular Biology
ISSN: 1524-4636
Abstract:
Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase isoenzymes, and their biosynthesis is blocked by nonsteroidal antiinflammatory drugs, including those selective for inhibition of cyclooxygenase-2. Despite the clinical efficacy of nonsteroidal antiinflammatory drugs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm.
Relations:
Content
Citations
(543)
References
(181)
Conditions
(1)
Chemicals
(5)
Organisms
(2)
Processes
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Arterioscler Thromb Vasc Biol 31(5): 986-1000

Prostaglandins and Inflammation

Biosynthesis of Prostaglandins

Prostaglandins and thromboxane A2 (TXA2), collectively termed prostanoids, are formed when arachidonic acid (AA), a 20-carbon unsaturated fatty acid, is released from the plasma membrane by phospholipases (PLAs) and metabolized by the sequential actions of prostaglandin G/H synthase, or cyclooxygenase (COX), and respective synthases.

There are four principal bioactive prostaglandins generated in vivo: prostaglandin (PG) E2 (PGE2), prostacyclin (PGI2), prostaglandin D2 (PGD2) and prostaglandin F (PGF).They are ubiquitously produced – usually each cell type generates one or two dominant products - and act as autacrine and paracrine lipid mediators to maintain local homeostasis in the body. During an inflammatory response, both the level and the profile of prostaglandin production changes dramatically. Prostaglandin production is generally very low in uninflamed tissues, but increases immediately in acute inflammation prior to the recruitment of leukocytes and the infiltration of immune cells.

Prostaglandin production (Figure 1) depends on the activity of prostaglandin G/H synthases, colloquially known as COXs, bifunctional enzymes that contain both cyclooxygenase and peroxidase activity and which exist as distinct isoforms referred to as COX-1 and COX-2 (2). COX-1, expressed constitutively in most cells, is the dominant source of prostanoids that subserve housekeeping functions, such as gastric epithelial cytoprotection and homeostasis (3). COX-2, induced by inflammatory stimuli, hormones and growth factors, is the more important source of prostanoid formation in inflammation and in proliferative diseases, such as cancer (3). However, both enzymes contribute to the generation of autoregulatory and homeostatic prostanoids, and both can contribute to prostanoid release during inflammation.

An external file that holds a picture, illustration, etc.
Object name is nihms271399f1.jpg

Biosynthetic pathway of prostanoids.

PGH2 is produced by both COX isoforms and it is the common substrate for a series of specific isomerase and synthase enzymes that produce PGE2, PGI2, PGD2, PGF and TXA2. COX-1 couples preferentially, but not exclusively, with thromboxane synthase (TXS), prostaglandin F synthase, and the cytosolic (c) prostaglandin E synthase (PGES) isozymes (4). COX-2 prefers prostaglandin I synthase (PGIS) and the microsomal (m) PGES isozymes, both of which are often coinduced along with COX-2 by cytokines and tumor promoters (4).

The profile of prostanoid production is determined by the differential expression of these enzymes within cells present at sites of inflammation. For example, mast cells predominantly generate PGD2 while macrophages produce PGE2 and TXA2 (5). In addition, alterations in the profile of prostanoid synthesis can occur upon cellular activation. While resting macrophages produce TXA2 in excess of PGE2, this ratio changes to favor PGE2 production after bacterial lipopolysaccharide (LPS) activation (5).

Prostaglandin receptors

Prostaglandins exert their effects by activating rhodopsin-like seven transmembrane spanning G protein-coupled receptors (GPCRs; Table). The prostanoid receptor subfamily is comprised of eight members: EP1 (E prostanoid receptor 1), EP2, EP3, and EP4 subtypes of the PGE receptor, PGD receptor (DP1), PGF receptor (FP), PGI receptor (IP), and TX receptor (TP) (6). Two additional isoforms of the human TP, (TPα, TPβ) and FP (FPA FPB) and eight EP3 variants are generated through alternative splicing, which differ only in their C-terminal tails (7). In addition, there is another GPCR termed chemoattractant receptor-homologous molecule expressed on T helper 2 (TH2) cells (CRTH2 or DP2) that responds to PGD2 but belongs to the family of chemokine receptors (8). CRTH2 is a member of the fMLP chemoattractant receptor superfamily (Figure 2).

An external file that holds a picture, illustration, etc.
Object name is nihms271399f2.jpg
Phylogenetic tree of lipid G protein–coupled receptors

Figure modified with permission from Shimizu (181).

Table

Signal transduction of Prostanoid Receptors

ClassSubtypeG-protein coupledSecond Messenger
TxA2TPα, TPβGq, G13, Gh, Gs(TPα), Gi(TPβ)An external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgIP3/DAG/Ca, RhoGEF
An external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgAn external file that holds a picture, illustration, etc.
Object name is nihms271399ig2.jpgcAMP
PGD2DPGsAn external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgcAMP
CRTH2GiAn external file that holds a picture, illustration, etc.
Object name is nihms271399ig2.jpgcAMP, An external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgCa2+
PGE2EP1GqAn external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgIP3/DAG/Ca2+
EP2GsAn external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgcAMP
EP3Gi, G12An external file that holds a picture, illustration, etc.
Object name is nihms271399ig2.jpgcAMP, An external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgCa, Rho
EP4GsAn external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgcAMP
PGI2IP-IPGsAn external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgcAMP
IP- TPαGsAn external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgcAMP
PGFFPA, FPBGqAn external file that holds a picture, illustration, etc.
Object name is nihms271399ig1.jpgIP3/DAG/Ca, Rho

Prostanoid receptors couple to a range of intracellular signaling pathways that mediate the effects of receptor activation on cell function. EP2, EP4, IP, and DP1 receptors activate adenylyl cyclase via Gs, increasing intracellular cyclic adenosine monophosphate (cAMP). EP1 and FP activate phosphatidylinositol metabolism via Gq, leading to the formation of inositol trisphosphate with mobilization of intracellular free calcium. In addition to signaling through Gq, the FP receptor couples to the small G-protein Rho via a Gq-independent mechanism (9). TP couples mainly to two types of G-proteins, the Gq (Gq, G11 G15, G16) and the G13 (G12, G13) families, resulting in the activation of phospholipase C and guanine nucleotide exchange factor of the small G protein Rho (RhoGEF), respectively. Additionally, TP can also be coupled via Gh to phospholipase C as well as via Gi and Gs to adenylate cyclase. Both TP isoforms are coupled to phospholipase C activation, but TPα stimulates adenylyl cyclase, whereas TPβ inhibits it. EP3 isoforms can couple via Gi or G12 to elevation of intracellular Ca, inhibition of cAMP generation, and activation of the small G protein Rho (10). The DP2/CRTH2 couples to a Gi-type G protein to inhibit cAMP synthesis and elevate intracellular Ca. However, the effects of prostanoids on these G protein–coupled signaling pathways may change as a function of ligand concentration or structure (6).

Some, but not all prostanoid receptors exhibit the capacity to dimerize which may alter ligand affinity and/or preference for downstream signaling pathways. Thus, while DP1/DP2 dimers appear not to form, under similar conditions, IP and TP receptors can associate to form homo- and heterodimers. TPα-TPβ heterodimers enhance the response to activation by free radical–catalyzed isoprostanes (11). Furthermore, dimerization of IP and TPα enables cAMP formation through TP receptor activation, a cellular outcome typically observed with IP activity (12). Moreover EP1 receptor activation has been shown to modulate β2- adrenoreceptor function in bronchial airways via formation of a heterodimeric complex (13).

Cyclooxygenases and Inflammation

The two cyclooxygenase isoforms, COX-1 and COX-2, are targets of nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs are competitive active site inhibitors of both COXs. Although both COXs exist as homodimers, only one partner is used at a time for substrate binding (14). COX-1/COX-2 heterodimers may also exist, but their role in biology remains to be established (15). NSAIDs bind to and inactivate the COX site at only one of the monomers of the COX dimer and this is sufficient to shut down prostanoid formation (14). The other monomer appears to play an allosteric function. The peroxidase capacity of both proteins is unaltered by NSAIDs.

The clinical efficacy of structurally distinct NSAIDs, all of which share this capacity for prostanoid inhibition, points to the importance of these mediators in the promotion of pain, fever and inflammation (16). The dramatic increase of COX-2 expression upon provocation of inflammatory cells, its expression in inflamed tissues and the assumption that inhibition of COX-1 derived prostanoids in platelets and gastric epithelium explains NSAID evoked gastrointestinal adverse effects and provided a rationale for development of NSAIDs designed to be selective for inhibition of COX-2 for treating arthritis and other chronic inflammatory diseases (17).

Although COX-2 appears to be the dominant source of prostaglandin formation in inflammation, there is some suggestion that both isoforms of the human enzyme may contribute to the acute inflammatory response. COX-1 is constitutively expressed in resident inflammatory cells and there is evidence for induction of COX-1 during LPS-mediated inflammatory response and cellular differentiation (18). Both COX isoforms are co-expressed in circulating inflammatory cells ex vivo and in both inflamed rheumatoid arthritis (RA) synovium and in atherosclerotic plaques obtained from patients (19, 20). Human data are compatible with COX-1-derived products driving the initial phase of an acute inflammation, with COX-2 upregulation occurring within several hours (4). However, controlled clinical trials to test the comparative efficacy of NSAIDs that inhibited both COXs versus COX-2 alone were never performed at scale. Such trials were designed to seek divergence in the incidence of gastrointestinal adverse effects rather than to assess comparative clinical efficacy.

Studies in both COX-1- and COX-2- knockout (KO) mice reveal impaired inflammatory responses, although the impacts of gene deletion diverge in time course and intensity. Mice deficient in COX-1, but not COX-2, exhibit a reduction in AA-induced ear edema although AA induces an equivalent inflammatory response in wild-type (WT) and COX-2-deficient mice (2123). By contrast, the level of edema induced by the tumor promoter tetradecanoyl phorbol acetate (TPA) was not significantly different between WT, COX-1-deficient and COX-2-deficient mice (2123). The ear inflammation studies indicate that COX-1, as well as COX-2, may contribute to inflammatory responses and the isoform responsible for the inflammation may depend on the type of inflammatory stimulus and/or the relative levels of each isoform in the target tissue.

Similarly, arthritis models exhibit a significant reliance on either the COX-1 or COX-2 isoforms for the development of clinical synovitis. This varies, depending on the experimental model used. Thus, in the K/BxN serum–transfer model of arthritis, COX-1 derived prostaglandins, in particular PGI2, make a striking contribution to the initiation and perpetuation of arthritis (24). In a collagen- induced arthritis (CIA) model, COX-2- deletion suppresses considerably synovial inflammation and joint destruction, whereas arthritis in COX- 1–deficient mice is indistinguishable from controls (25, 26).

COX-2 deletion also suppresses acute inflammation in the air pouch model. Here, the COX-2 inhibitor, NS-398, administered six hours after carageenan treatment, reduced PG production in wild-type mice to levels comparable to those seen in COX-2-KO mice, and was also effective during the early stages of inflammation (27). When compared to wild-type mice, the deficiency of COX-2 reduces the level of PGE2 production by approximately 75%, while the deficiency of COX-1 reduces the PGE2 level by 25% during this early stage. By day 7 following carrageenan treatment, higher numbers of inflammatory cells were present in the pouch fluid of COX-2-KO mice, and little resolution of inflammation was apparent compared to wild-type or COX-1-KO mice (27). These findings indicate that both COX isoforms contribute to PG production during inflammation and also that COX-2-derived PGs appear to be important in both the acute inflammatory process and in the resolution phase. A contribution of COX-2 to both phases of inflammation was also reported in other models. Gilroy et al. reported that COX-2 expression and PGE2 levels increased transiently early in the course of carrageenan-induced pleurisy in rats (28). Later in the response, COX-2 was induced again to even greater levels and generated anti-inflammatory prostaglandins, such as PGD2 and 15-deoxy-Δ-PGJ2 (15d-PGJ2) but only low levels of the proinflammatory PGE2. Further support for an anti-inflammatory role of COX-2 in this model was the finding that late administration of the COX-2–selective inhibitor, NS-398, exacerbates the inflammatory response. Furthermore, Wallace et al. observed that in the paw carrageenan model, the resultant inflammation resolves within 7 days in wild-type mice but is unaltered over this period in COX-2–deficient mice (29). An anti-inflammatory role of COX-2 derived prostanoids has also been reported in models of inflammatory colitis and allergic airway disease (30, 31). Thus, COX-2 appears to have a dual role in the inflammatory process, initially contributing to the onset of inflammation and later helping to resolve the process. While COX-2 does play a role in supporting resolution of this process in some models of inflammation, it is unclear which products of the enzyme might contribute in which settings to this effect. This is exemplified by the case of 15d-PGJ2. Long touted as an endogenous ligand to peroxisome proliferator-activated receptor gamma (PPARγ), it remains to be established that endogenous concentration sufficient to subserve this function are formed in any model of resolving inflammation. Erroneously elevated levels have been reported using a variety of immunoassays, but the concentrations of bound and free compound documented to be formed by quantitative mass spectrometry fall far short of the EC50 for PPARγ activation (32). It is one thing to show that putative pro-resolution products can be formed in vitro and that the synthetic compounds do exert pro- resolution actions when administered in vivo and another to document that the concentrations formed in vivo in the setting of inflammation are sufficient and necessary to mediate resolution.

In the case of atherosclerosis, deletion or inhibition of COX-2 has been shown variously to retard, accelerate or leave unaltered atherogenesis in mouse models (5). This may reflect an impact postnatally of disruption of the many roles of the enzyme in development in COX-2 KOs; differences in timing of interventions with COX-2 inhibitors and a failure in most cases to define biochemically the selectivity for inhibition of COX-2 of the drug regimen deployed. In contrast, COX-1 deletion markedly attenuated lesion development in the Apolipoprotein E (ApoE) KO mouse, as does inhibition of COX-1 and COX-2 together in low-density lipoprotein receptor (LDLR)- KO model (33, 34). Thus, products of COX-1 – like TxA2 – promote atherogenesis while there is more ambiguity around the role of COX-2. Nevertheless, deletion of the IP, the receptor for the major COX-2 product, PGI2, fosters the initiation and early development of atheroscelrosis in hyperlipidemic mice (35).

Prostaglandin E2 and inflammation

PGE2 is one of the most abundant PGs produced in the body, is most widely characterized in animal species, and exhibits versatile biological activities. Under physiological conditions, PGE2 is an important mediator of many biological functions, such as regulation of immune responses, blood pressure, gastrointestinal integrity, and fertility. Dysregulated PGE2 synthesis or degradation has been associated with a wide range of pathological conditions (36). In inflammation, PGE2 is of particular interest because it is involved in all processes leading to the classic signs of inflammation: redness, swelling and pain (37). Redness and edema result from increased blood flow into the inflamed tissue through PGE2-mediated augmentation of arterial dilatation and increased microvascular permeability (37). Pain results from the action of PGE2 on peripheral sensory neurons and on central sites within the spinal cord and the brain (37). PGE2 is synthesized from PGH2 by cPGES or mPGES-1 and mPGES-2 (38). cPGES is constitutively and abundantly expressed in the cytosol of various tissues and cells and it requires glutathione (GSH) as a cofactor (39). The role of cPGES and even its ability to form prostaglandin E2 is controversial. cPGES seems capable of converting COX-1-, but not COX-2-derived PGH2 to PGE2 in cells, particularly during the immediate PGE2-biosynthetic response elicited by Ca evoked stimuli. Localization of cPGES in the cytosol may allow coupling with proximal COX-1 in the endoplasmic reticulum (ER) in preference to distal COX-2 in the perinuclear envelope (39). Functional coupling of cPGES with COX-1 suggests that the functions of cPGES in vivo overlap significantly, if not entirely, with COX-1. CPGES-deficient mice were developed, but have not been particularly informative in addressing the importance of cPGES-derived PGE2, because deletion of this enzyme results in perinatal lethality (40).

mPGES-1 is a member of the MAPEG (membrane-associated proteins involved in eicosanoid and glutathione metabolism) superfamily and like cPGES, it requires GSH as cofactor (41). mPGES-1 is a perinuclear protein that is markedly induced by cytokines and growth factors and downregulated by anti-inflammatory glucocorticoids as in the case of COX-2 (42, 43). It is functionally coupled with COX-2 in marked preference to COX-1 (44). Constitutive expression of mPGES-1 in certain tissues and cell types was also reported.

The generation of mPGES-1-deficient mice has revealed the dominant role of this enzyme in PGE2 generation relevant to promotion of inflammation. In CIA, a disease model of human RA, mPGES-1 null mice exhibited a reduced incidence and severity of disease compared with wild-type controls (45). This difference was not associated with alterations in interleukin (IL)-6 production by peritoneal macrophages or significant differences in circulating IgG2a anticollagen antibodies. Likewise, in collagen-antibody-induced arthritis (CAIA), another model of RA that does not involve the activation of the immune system, mPGES-1 null mice had a similar incidence, but a lesser severity of arthritis than wild-type mice, as well as a 50% reduction in paw levels of PGE2 (46). In the same study, it was also observed that the migration of macrophages following peritoneal injection of thioglycollate was strikingly reduced in mPGES-1-null mice relative to wild-type mice (46).

The formation of inflammatory granulation tissue and attendant angiogenesis in the dorsum induced by subcutaneous implantation on the paw of a cotton thread was significantly reduced in mPGES-1 KO mice as compared with WT mice (46). In this model, mPGES-1 deficiency was also associated with reduced induction of vascular endothelial cell growth factor (VEGF) in the granulation tissue. These results indicate that mPGES-1-derived PGE2, in cooperation with VEGF, may play a critical role in the development of inflammatory granulation and angiogenesis, thus eventually contributing to tissue remodeling.

Together, these findings illustrate that deletion or inhibition of mPGES- 1 markedly reduces inflammatory response, in several mouse models. The pro-inflammatory effect of mPGES-1-derived PGE2 was also observed in atherosclerosis. Deletion of mPGES-1 retarded atherogenesis in fat-fed hyperlipidaemic mice, in both sexes (47). Interestingly, in addition to the expected depression of PGE2 production, deletion of mPGES-1 permits rediversion of the PGH2 substrate to other PG synthases, with, for example, augmented formation of PGI2 and PGD2 (47). This complicates the selection of mPGES-1 as a drug target. Thus, elevated PGI2 may contribute to the more benign cardiovascular profile of mPGES-1 deletion compared to COX-2 deletion or inhibition- less predisposition to hypertension and thrombogenesis. However, this same effect may attenuate relief of pain, in the case of augmented PGI2, or may mediate adverse effects on bronchial tone, allergic inflammatory disease or the sleep–wakefulness cycle, in case of elevated PGD2. This may account for the less impressive effectiveness of disrupting mPGES-1 vs COX-2 in some models of pain (48). Recently Geisslinger’s group has provided evidence that mPGES-1 derived PGE2 may contribute both to promotion and resolution of neuroinflammation in mice (49). Finally, the major substrate products of rediversion will be influenced by the dominant cell type in a particular setting. For example, augmented PGI2 may contribute to the restraint of atherogenesis in hyperlipidemic mice consequent to mPGES-1 deletion (47). However, it remains to be seen whether mPGES-1 inhibition in the setting of established atherosclerosis causes regression or possibly accelerates further progression of disease, due to endoperoxide rediversion to TxA2 in macrophage rich plaques.

mPGES-2 is synthesized as a Golgi membrane-associated protein, and the proteolytic removal of the N-terminal hydrophobic domain leads to the formation of a mature cytosolic enzyme. This enzyme is constitutively expressed in various cells and tissues and is functionally coupled with both COX-1 and COX-2 (37). mPGES-2-deficient mice showed no specific phenotype and no alteration in PGE2 levels in several tissues or in LPS-stimulated macrophages (50). Studies with PGES null mice have revealed that cross regulation between the different PGES isoforms may function, on occasion, as a compensatory mechanism. For example, mPGES-1-null mice exhibit a delayed increase in urinary PGE2 excretion in response to acute water loading, coincident with enhanced renal medullary expression of cPGES but not of mPGES-2 (51). Similar evidence suggestive of cross regulation was observed with the COXs. Thus, deletion of COX-2 in macrophages is associated with upregulated expression of COX-2 in vascular smooth muscle cells in atherosclerotic plaque (52).

After PGE2 is formed, it is actively transported through the membrane by the ATP-dependent multidrug resistance protein-4 (MRP4) or diffuses across the plasma-membrane to act at or nearby its site of secretion (53).

PGE2 then acts locally through binding of one or more of its four cognate receptors (Table), termed EP1–EP4 (45). Among the four EPs, EP3 and EP4 receptors are the most widely distributed with their mRNAs being expressed in almost all mouse tissues and have the highest affinity for binding PGE2. In contrast, the distribution of EP1 mRNA is restricted to several organs, such as the kidney, lung, and stomach, and EP2 is the least abundant of the EP receptors. Both EP1 and EP2 bind PGE2 with lower affinity (54). Each EP subtype shows a distinct cellular localization within tissues (54).

One of the lessons learned from the knock-out mouse studies is that PGE2 can exert both pro-inflammatory and anti-inflammatory responses, and these actions are often produced through regulation of receptor gene expression in relevant tissues. For example, hyperalgesia, a classic sign of inflammation, is mediated mainly by PGE2 through EP1 receptor signaling that acts on peripheral sensory neurons at the site of inflammation, as well as on central neuronal sites (55). Other studies have also implicated EP3 receptor in the inflammatory pain response mediated by low doses of PGE2 (56).

EP2 and EP4 redundantly mediate development of paw swelling associated with collagen-induced arthritis (57). Likewise, studies of carrageenin induced paw edema and carrageenin-induced pleurisy both revealed participation of EP2 and EP3 in inflammatory exudation (58). The EP4 receptor also appears to play a pro-inflammatory role in the pathogenesis of rheumatoid arthritis. PGE2 produced by rheumatoid synovium has been implicated in IL-6 production and joint destruction (59, 60). Mice deficient in the EP4 but not in the EP1, EP2, or EP3 receptors exhibit an attenuated response in the collagen antibody induced arthritis model, with significantly lower levels of the inflammatory cytokines IL-6 and IL-1 and a dramatic reduction in the clinical signs of disease (61). Anti-inflammatory actions of prostaglandins are seen typically in allergic or immune inflammation and are usually balanced by pro-inflammatory actions of other prostaglandins. Such contrasting biology is evident between the PGI2-IP and TxA2-TP pathways in cardiovascular disease and between the PGD2-DP and the PGE2-EP3 pathways in elicitation of allergic asthma (62, 63).

PGE2, binding to different EP receptors, can regulate the function of many cell types including macrophages, dendritic cells and T and B lymphocytes leading to both pro- and anti-inflammatory effects. As pro-inflammatory mediator, PGE2 contributes to the regulation of the cytokine expression profile of dendritic cells (DC)s and has been reported to bias T cell differentiation towards a T helper (Th) 1 or Th2 response (35). A recent study showed that PGE2-EP4 signaling in DCs and T cells facilitates Th1 and IL-23-dependent Th17 differentiation (64). Additionally, PGE2 is fundamental to induction of a migratory DC phenotype permitting their homing to draining lymph nodes (65, 66). Simultaneously, PGE2 stimulation early during maturation induces the expression of costimulatory molecules of the TNF superfamily on DCs resulting in an enhanced T cell activation (67). In contrast, PGE2 has also been demonstrated to suppress Th1 differentiation, B cell functions and allergic reactions (68). Moreover, PGE2 can exert anti-inflammatory actions on innate immune cells like neutrophils, monocytes and NK cells (68).

PGE2 can thus modulate various steps of inflammation in a context-dependent manner and coordinate the whole process in both pro-inflammatory and anti-inflammatory directions. This dual role of PGE2 and its receptors in modulating the inflammatory response has been observed in several disorders. In atherosclerosis, EP4 deficiency promotes macrophage apoptosis and suppresses early atherosclerosis in LDLR mice chimeric for EP4 in hematopoietic cells after 8 weeks on a Western diet (69). EP2 deficiency in hematopoietic cells revealed a trend for similar, but modest, effects on atherosclerosis (69). In the same study macrophage EP4 appeared to play a proinflammatory role in the early stages of atherosclerosis by regulating production of inflammatory cytokines such as IL-1β, IL-6 and monocyte chemotactic protein-1 (MCP-1) (69). In contrast, EP4 deletion in bone marrow-derived cells enhanced local inflammation (increased expression of chemotactic proteins, including MCP-1 and IL-10; and increased inflammatory cells, such as macrophages and T cells) and altered lesion composition (increased smooth muscle cells within plaque) but did not alter plaque size or morphology in established atherosclerosis (after 10 weeks of high-fat diet) (70).

PGE2 also plays contrasting roles during neuroinflammation. LPS-induced PGE2 synthesis causes deleterious effects in neurons resulting in lesions or enhanced pain transmission (7173). However, PGE2 also has anti-inflammatory properties. It mediates bradykinin-induced neuroprotection and blocks LPS and ATP-induced cytokine synthesis in cultured microglia and in neuron-glia cocultures (74, 75). The anti-inflammatory and neuroprotective effects of PGE2 are mediated via microglial EP2- and EP4- receptors. Recently, it has been reported that PGE2 limits cytokine and prostaglandin synthesis mainly through EP2 activation in a model of LPS-induced neuroinflammation and that mPGES-1 is a critical enzyme in this negative feedback regulation (49).

Prostaglandin I2 and inflammation

PGI2 is one of the most important prostanoids that regulates cardiovascular homeostasis. Vascular cells, including endothelial cells, vascular smooth muscle cells (VSMCs) and endothelial progenitor cells (EPCs), are the major source of PGI2 (76).

It is generated by the sequential action of COX and PGIS, a member of the cytochrome P450 superfamily that specifically converts PGH2 to PGI2. PGIS co-localizes with COX in the ER, plasma membrane and nuclear membrane (77). PGIS is constitutively expressed in endothelial cells where it couples with COX-1 (78), although COX-2-dependent PGI2 production by endothelial cells has been reported to be modulated in vitro by thrombin, shear stress, oxidized LDL, hypoxia and inflammatory cytokines and it is synchronized by up-regulation of COX-2 (79, 80). In vivo studies in mice and humans showed that COX-2 was the dominant source of PGI2 (81).

Once generated, PGI2 is released to act upon neighboring VSMCs as well as circulating platelets. Indeed, PGI2 exerts its effects locally, is not stored, and is rapidly converted by non-enzymatic processes to an inactive hydrolysis product, 6-keto-PGF (82).

PGI2 is a potent vasodilator, and an inhibitor of platelet aggregation, leukocyte adhesion, and VSMC proliferation (75). PGI2 is also anti-mitogenic and inhibits DNA synthesis in VSMC (83). These actions of PGI2 are mediated through specific IP receptors (Table). This receptor is expressed in kidney, liver, lung, platelets, heart, and aorta (84). There is inconclusive evidence that some effects of PGI2 on the vasculature might be mediated by the PPAR δ pathway, in addition to the classical IP – cAMP signaling pathway (85). PGI2 can indeed activate PPAR δ, however, just like 15- dPGD2 and PPAR γ, it is unclear that it represents a biological target at concentrations of the ligand attained in vivo (86).

Although IP-deficient mice mature normally without suffering from spontaneous thrombosis, both the response to thrombogenic stimuli and VSMC proliferation in response to vascular injury are enhanced compared with control littermates (87). Mice lacking IP are also sensitive to dietary salt induced hypertension (88) and exhibit accelerated atherogenesis with enhanced platelet activation and increased adhesion of leukocytes on the vessel walls in both the LDL-receptor and ApoE KO models (35, 89).

In addition to its cardiovascular effects, PGI2 is an important mediator of the edema and pain that accompany acute inflammation. PGI2 is rapidly produced following tissue injury or inflammation and it is present at high concentrations in inflammatory milieus (90). PGI2 is the most abundant prostanoid in synovial fluid in human arthritic knee joints as well as in peritoneal cavity fluid from mice injected with irritants (91, 92). In IP receptor deficient mice, potentiation of bradykinin-induced microvascular permeability by PGI2 is abolished; in addition, these mice have substantially reduced carrageenan- induced paw edema (93). The level of paw edema observed in IP-deficient mice was equivalent to that of indomethacin treated controls and indomethacin treatment of IP-deficient animals did not induce a further decrease in swelling, indicating that PGI2 -IP receptor signaling is the major prostanoid pathway that mediates the acute inflammatory response in this model. It has also been suggested that bradykinin induces PGI2 formation leading to enhancement of microvascular permeability and edema (94). The IP receptor has been shown to mediate nociceptive pain during acute inflammation. IP receptor mRNA is present in dorsal root ganglion neurons including those that express substance P, a marker for nociceptive sensory neurons (95). IP receptor-deficient mice have an attenuated writhing response following intraperitoneal injection of either acetic acid or PGI2, indicating that the IP receptor plays a role in mediating peripheral nociceptive sensitization to inflammatory stimuli (93). The IP receptor is also expressed in the spinal cord and has been implicated in spinal pain transmission in response to peripheral inflammation (96). IP antagonists were shown to reduce pain responses in several models, including acetic acid-induced abdominal constriction, mechanical hyperalgesia produced by carrageenan and pain associated with models of osteoarthritis and inflammatory arthritis (97, 98). In contrast to the pro-inflammatory effects of IP receptor activation in nonallergic acute inflammation, some studies have suggested that IP receptor signaling suppresses Th2- mediated allergic inflammatory responses (99). IP receptor mRNA is up-regulated in CD4+ Th2 cells and inhibition of PGI2 formation by the COX-2 inhibitor, NS-398, during antigen-induced airway inflammation results in greater lung Th2-mediated lung inflammation (99). PGI2 has been suggested to exert this effect in part by enhancing Th2 cell production of the anti- inflammatory cytokine IL-10. This immunosuppressive role for the IP receptor in Th2-mediated inflammation is supported by the observation that in ovalbumin (OVA)-induced asthma, IP deletion results in increased antigen-induced leukocyte accumulation in bronchoalveolar lavage fluid and peribronchiolar and perivascular inflammatory infiltration (100). Thus, PGI2 may shift the balance within the immune system away from a Th2 dominant response and inhibit allergic inflammation.

Prostaglandin D2 and inflammation

PGD2 is a major eicosanoid that is synthesized in both the central nervous system (CNS) and peripheral tissues and appears to function in both an inflammatory and homeostatic capacity (101). In the brain, PGD2 is involved in the regulation of sleep and other CNS activities, which includes pain perception (102, 103). In peripheral tissues, PGD2 is produced mainly by mast cells, but also by other leukocytes, such as DCs and Th2 cells (104106). Two genetically distinct PGD2-synthesizing enzymes have been identified, including hematopoietic- and lipocalin type PGD synthases (H-PGDS and L-PGDS, respectively). H-PGDS is generally localized to the cytosolic of immune and inflammatory cells, whereas L-PGDS is more resigned to tissue-based expression (107).

PGD2 can be further metabolized to PGF, 9α,11β-PGF2 (the stereoisomer of PGF) and the J series of cyclopentanone PGs, including PGJ2, Δ-PGJ2, and 15d-PGJ2 (108). Synthesis of J series PGs involves PGD2 undergoing an initial dehydration reaction to produce PGJ2 and 15d-PGJ2, after which PGJ2 is converted to 15d-PGJ2 and Δ-PGJ2 via albumin-dependent and albumin-independent reactions, respectively (109).

PGD2 activity is principally mediated through DP or DP1 and CRTH2 or DP2, as described previously (Table). Also 15d-PGJ2, binds with low affinity the nuclear PPAR γ (110). PGD2 has long been associated with inflammatory and atopic conditions, although it might exert an array of immunologically relevant anti-inflammatory functions as well.

PGD2 is the predominant prostanoid produced by activated mast cells, which initiate IgE-mediated Type I acute allergic responses (104, 111). It is well established that the presence of an allergen triggers the production of PGD2 in sensitized individuals. In asthmatics, PGD2 which can be detected in the bronchoalveolar lavage fluid within minutes, reaches biologically active levels at least 150-fold higher than pre-allergen levels (112). PGD2 is produced also by other immune cells such as antigen-presenting dendritic cells and Th2 cells, suggesting a modulatory role for PGD2 in the development of antigen-specific immune system responses (104, 105). PGD2 challenge elicits several hallmarks of allergic asthma such as bronchoconstriction and airway eosinophil infiltration (113, 114), and mice that overexpress lipocalin-PGD synthase have elevated PGD2 levels and an increased allergic response in the OVA-induced model of airway hyperreactivity (115).

The pro-inflammatory effects of PGD2 appear to be mediated by both DP1 and DP2/CRTH2 receptors. Because both receptors bind PGD2 with similar high affinity, PGD2 produced by activated mast cells or T cells would be capable of activating multiple signaling pathways leading to different effects, depending on whether the DP1 or DP2/CRTH2 receptors or both are locally expressed.

The DP1 receptor is expressed on bronchial epithelium and has been proposed to mediate production of chemokines and cytokines that recruit inflammatory lymphocytes and eosinophils, leading to airway inflammation and hyperreactivity seen in asthma (116). Mice deficient in DP1 exhibit reduced airway hypersensitivity and Th2-mediated lung inflammation in the OVA-induced asthma model, suggesting that the DP1 plays a key role in mediating the effects of PGD2 released by mast cells during an asthmatic response (62). Furthermore, PGD2 may inhibit eosinophil apoptosis via the DP1 receptor (117).

DP1 antagonists exert anti-inflammatory properties in several experimental models including inhibition of antigen-induced conjunctival microvascular permeability in guinea pigs and OVA-induced airway hyperreactivity in mice (118, 119).

DP2/CRTH2 receptors contribute largely to pathogenic responses by mediating inflammatory cell trafficking and by modulating effector functions. PGD2 released from mast cells may mediate recruitment of Th2 lymphocytes and eosinophils directly via the DP2/CRTH2 receptor. In humans, the DP2/CRTH2 receptor is expressed on Th2 lymphocytes, eosinophils, and basophils (8, 120, 121), and an increase in DP2/CRTH2+ T-cells has been positively associated with certain forms of atopic dermatitis (122). The DP2/CRTH2 receptor has been demonstrated to mediate PGD2-stimulated chemotaxis of these cells in vitro and leukocyte mobilization in vivo (123).

In contrast to the pro-inflammatory role of PGD2 in allergic inflammation, PGD2 may act to inhibit inflammation in other contexts. The DP1 receptor is expressed on dendritic cells that play a key role in initiating an adaptive immune response to foreign antigens. PGD2 activation of the DP1 receptor inhibits dendritic cell migration from lung to lymph nodes following OVA challenge, leading to reduced proliferation and cytokine production by antigen specific T cells (124). DP1 activation also reduces eosinophilia in allergic inflammation in mice and mediates inhibition of antigen-presenting Langerhans cell function by PGD2 (125, 126). As mentioned, PGD2 and its degradation product, 15d-PGJ2 have been suggested as the COX-2 products involved in the resolution of inflammation (28, 127). Administration of a COX-2 inhibitor during the resolution phase exacerbated inflammation in a carageenan-induced pleurisy model (28). In a zymosan-induced peritonitis model, deletion of H-PGDS induced a more aggressive inflammatory response and compromised resolution, findings that were moderated by addition of a DP1 agonist or 15d-PGJ2 (123). While, these data appear to implicate PGD2 and 15d-PGJ2 in resolution, there is a large disparity between the nanomolar to picomolar amounts of 15d-PGJ2 detected by physicochemical methodology in in vivo settings and the amount needed to have a biologic effect in vitro on PPARγ or NFκB (micromolar amounts) (32, 128, 129). This discrepancy is supported by recent data reported in zymosan-induced peritonitis, where we observed evoked biosynthesis of PGD2 only during the proinflammatory phase, but not during resolution. Consistent with this observation, DP2/CRTH2 deletion reduced the severity of acute inflammation, but neither DP1 or DP2/CRTH2 deletion impacted resolution. Although 15d-PGJ2 is readily detected when synthetic PGD2 was infused into rodents (130), endogenous biosynthesis of 15d-PGJ2 was not detected during promotion or resolution of inflammation (Mehta J et al., 2010; unpublished data).

PGD2 may play a role in the evolution of atherosclerosis. In the context of inflamed intima, PGD2 in part derives from H-PGDS-producing inflammatory cells that are chemotactically compelled to permeate the vasculature (131, 132). Additionally, L-PGDS expression is induced by laminar sheer stress in vascular endothelial cells and is actively expressed in synthetic smooth muscle cells of atherosclerotic intima and coronary plaques of arteries with severe stenosis (133135). PGD2 has been shown to inhibit expression of pro-inflammatory genes, such as iNOS and plasminogen activator inhibitor (136, 137). Indeed, L-PGDS deficiency accelerates atherogenesis (138).

In summary, studies with COX-2 inhibitors suggest that products of this enzyme may play a role in resolution in several models of inflammation. However, it the identity of such products, whether formed directly by COX-2 or due to substrate diversion consequent to COX-2 inhibition, remains, in many cases, to be established.

Prostaglandin F and inflammation

PGF is synthesized from PGH2 via PGF synthase, and it acts via the FP, which couples with Gq protein to elevate the intracellular free calcium concentration (Table). Two differentially spliced variants of the sheep FP receptor ortholog have been reported: FPA and FPB, which differ from each other in the length of their C-terminal tails (139). The FP receptor is the least selective of the prostanoid receptors in binding the principal endogenous prostaglandins; both PGD2 and PGE2 ligate the FP with EC50s in the nanomolar range (140). PGF ring compounds can be formed as minor products from other prostaglandins. For example, enzymatic reduction of 9-keto group of PGE compounds by 9-ketoreductases results in either 9a-hydroxyl, yielding PGFα compounds or more rarely, a 9b-hydroxyl, yields PGFβ compounds (141). PGF ring metabolites may also be formed from PGD ring compounds by 11-keto reductases (142). 15-Keto-dihydro-PGF, a major stable metabolite of PGF that reflects in vivo PGF biosynthesis, is found in larger quantities first in the peripheral plasma and later on in the urine both in basal physiological conditions and in certain physiological and pathophysiological situations like acute and chronic inflammation (143).

PGF, derived mainly from COX-1 in the female reproductive system, plays an important role in ovulation, luteolysis, contraction of uterine smooth muscle and initiation of parturition (144, 145). Recent studies have shown that PGF also plays a significant role in renal function (146), contraction of arteries (147), myocardial dysfunction (148, 149), brain injury (150) and pain (151). Analogs of PGF have previously been developed for estrus-synchronization and abortion in domestic animals (152, 153) and to influence human reproductive function (154). FP agonists are being widely used worldwide to reduce intraocular pressure in the treatment of glaucoma (155).

Administration of PGF leads to acute inflammation, and NSAIDs inhibit PGF biosynthesis both in vitro and in vivo (144). In models of acute inflammation evoked biosynthesis of PGF may coincide with free radical catalyzed generation of F ring isoprostanes, indices of lipid peroxidation (156, 157). The tachycardia induced in wild-type mice by injection of LPS is greatly attenuated in FP-deficient or TP-deficient mice and is completely absent in mice lacking both of these receptors (148). A recent study reported that deletion of FP selectively attenuates pulmonary fibrosis without a change in alveolar inflammation after microbial invasion (158). Elevated biosynthesis of PGF has been reported in patients suffering from rheumatoid arthritis, psoriatic arthritis, reactive arthritis, and osteoarthritis (159).

Cardiovascular risk factors such as diabetes, obesity, smoking, and thickening of intima-media ratio in the carotid artery have been variably associated with elevations in PGF metabolites, together with IL-6 and acute phase proteins in body fluids (160, 161). Deletion of the FP reduces blood pressure and retards the attendant atherogenesis in hyperlipidemic mice despite the absence of detectable FP in large blood vessels and their atherosclerotic plaques (162). PGF is the most abundant prostanoid formed by human umbilical cord endothelial cells in response to laminar shear stress that upregulates expression of COX-2 (163).

The emerging role of PGF in acute and chronic inflammation opens opportunities for the design of new anti-inflammatory drugs.

Thromboxane and inflammation

TXA2, an unstable AA metabolite with a half-life of about 30 seconds, is synthesized from PGH2 via TXS and it is non-enzymatically degraded into biologically inactive TXB2. TXA2 is predominantly derived from platelet COX-1, but can also be produced by other cell types, including by macrophage COX-2(164, 165).

TXA2 activity is principally mediated through the TP, which couples with Gq, G12/13 and multiple small G proteins which in turn regulate several effectors, including phospholipase C, RhoGEF and adenylyl cyclase (166, Table). TPα and TPβ, two spliced isoforms of TP in humans, communicate with different G proteins and undergo heterodimerization, resulting in changes in intracellular traffic and receptor protein conformations. Only the TPα protein is expressed in mice.

TP activation mediates several physiological and pathophysiological responses, including platelet adhesion and aggregation, smooth muscle contraction and proliferation, and activation of endothelial inflammatory responses (167). TP function is regulated by several factors, such as oligomerization, desensitization and internalization, glycosylation, and cross-talk with receptor tyrosine kinases (167).

Although TXA2 is the preferential physiological ligand of the TP receptor, PGH2 particularly, also can activate this receptor (168). Additionally, isoprostanes (nonenzymatic free radical-catalyzed peroxidative products of polyunsaturated fatty acids) and hydroxyeicosatetraenoic acids (HETEs, generated by lipoxygenases and cytochrome P450 monooxygenases or formed by nonenzymatic lipid peroxidation) are also potent agonists at TP receptors (169, 170).

Epoxyeicosatrienoic acid (cytochrome P450 metabolites of AA) dihydro derivatives, in contrast, are selective endogenous antagonists of TP (171). However, whether PGH2, isoprostanes or HETEs significantly contribute to the responses attributed to TP activation in vivo is still to be investigated. For example, TP activation by isoprostanes may play an important role in clinical settings of oxidative stress, such during reperfusion after organ transplant.

TP deficient mice are normotensive but have blunted vascular responses to TP agonists and show a tendency to bleeding (172).

The deletion of TP decreases vascular proliferation and platelet activation in response to vascular injury, delays atherogenesis and prevents angiotensin II- and L-NAME-induced hypertension and the associated cardiac hypertrophy (87, 89, 173, 174).

In septic shock models, TP deletion or TP antagonism protected against various LPS-induced responses, such as the increase in inducible nitric oxide synthase expression, acute renal failure, and inflammatory tachycardia (175, 176), suggesting a potential role of TXA2 as pro-inflammatory mediator.

The phenotype of TXS deficient mice is much less pronounced, perhaps because TXA2 is only one of the endogenous ligands of TP and more likely because the deletion of this enzyme may redirect the PGH2 toward other countervailing synthases (177).

Prostanoids in Translation

This review has described a stunning complexity of evidence about the role of prostanoids in inflammation. Different products have conflicting effects on both the promotion and resolution of inflammation. The same product formed by different enzymes – COX-1 or COX-2 – may either promote or resolve inflammation. Products of the same enzyme may promote or resolve inflammation in different models. Different cell types that predominate at varying stages of disease evolution generate prostanoids that have contrasting effects on inflammation. Individual prostanoids overlap considerably in their biological effects with other mediators.

These observations prompt several questions.

Given this complex array of biological effects mediated by prostanoids, how does their general inhibition, high up in the cascade, result in drugs that are reasonably well tolerated and reasonably effective? Aspirin and the myriad NSAIDs, including acetaminophen and those developed to inhibit selectively COX-2, are amongst the most commonly consumed drugs on the planet. Hard evidence with which to address this question is in short supply, but let’s speculate. Aspirin at doses less than 100 mg per day or greater than 1 gm per day have equivalent effects on platelet COX-1 derived TxA2. They both suppress it completely. However, increasing daily doses of aspirin increasingly inhibit PGI2 coincidentally with this effect. We don’t have direct randomized comparisons across doses, but indirect comparisons suggest that the cardioprotective efficacy of aspirin may be progressively attenuated as the dose is increased. Similarly, locally formed, COX-1 derived PGE2 and PGI2 are protective of gastroduodenal epithelial integrity and platelet COX-1 derived TxA2 contributes to hemostatic competence. Disruption of these pathways by NSAIDs that inhibit COX-1 is thought to account for NSAID induced ulcers. However, NSAIDs selective for inhibition of COX-2 only halve the comparative incidence of serious gastrointestinal events. This may in part reflect their impact on gastroduodenal epithelial COX-2 dependent prostanoids that accelerate ulcer healing. In these examples, inhibitors high up in the pathway confer benefit, but it is a net benefit and of course the margin of that benefit may vary substantially between individuals. We poorly understand inter-individual differences in anti-inflammatory efficacy amongst the reversibly acting NSAIDs.

Prostanoids tend to be relatively weak agonists in systems where their blockade has resulted in clinical efficacy. For example, TxA2 is a relatively weak platelet agonist compared to thrombin and there is a considerable amount of redundancy in the system.

Why does blockade of just one of the many pathways of platelet activation result in an effect so great that its impact can be detected by as crude and instrument as a randomized clinical trial? Similarly why does blockade of sulfidopeptide leukotrienes alone amongst many bronchoconstrictors result in clinical efficacy in asthma or why do other mediators, such as NO, not substitute for the cardioprotective effects of PGI2, suppressed by NSAIDs selective for inhibition of COX-2? Perhaps drug efficacy is because eicosanoids often tend to function as amplifying signals for other, more potent agonists. Activate platelets with thrombin, ADP or collagen and release of TxA2 amplifies and sustains the aggregation response. Perhaps this is why aspirin is so effective in the secondary prevention of myocardial infarction or stroke. As for why other mediators do not step in to substitute for suppressed prostanoids, this may speak to their singular importance in circumstances of phenotypic perturbations, as discussed next.

Given the myriad biological effects of these compounds, how are drugs that shut down their synthesis even tolerated? NSAIDs may indeed result in life threatening gastrointestinal or cardiovascular adverse events, but only in a small minority (maybe 1–2%) of patients exposed. This may reflect the fact that prostanoid formation is a homeostatic response system. Under physiological conditions, trivial amounts of these compounds are formed and their biological importance is, in many cases marginal. However, when a system is stressed they may become pivotal. Examples include their essential role in the maintenance of renal blood flow under renoprival conditions, their antihypertensive effects in patients infused with vasopressors or their antithrombotic effects in patients at increased risk of thrombogenesis. For example, deletion of the IP does not result in spontaneous thrombosis but rather accentuates the response to thrombogeneic stimuli. Similarly, although pre-existing cardiovascular disease was often used to dilute the legal liability of the sponsor in cases where patients suffered myocardial infarctions (MIs) while taking coxibs, the relative risk of MIs on celecoxib relates to the underlying burden of cardiovascular disease, an expected consequence of suppression of COX-2 derived PGI2 (164).

Given the contrasting effects of prostanoids, should we move down the pathway to get a more targeted and safer response? Presently, we have almost no data that address this question. In the case of downstream PG synthase versus COX-2 inhibition, the experience with mPGES-1 deletion highlights the complexity of the comparison. Here, substrate rediversion to PGIS, may attenuate the cardiovascular risk of COX-2 inhibition, but dilute analgesic efficacy. Another example is the comparison between low dose aspirin for cardioprotection and TP antagonism. The latter strategy avoids PGI2 suppression, but this is very modest, on average ~15%, with low dose aspirin. One would need an enormous clinical trial to detect that theoretical benefit. Alternatively, the antagonist, unlike aspirin, might block TP activation by unconventional ligands, such as isoprostanes and HETEs. However, while these compounds can activate the TP, their relevance in vivo, even in settings of tissue reperfusion where they are formed in excess, remains speculative. One might of course model this comparison and use COX-1 knock down mice which mimic the asymmetric impact on platelet COX-1 of low dose aspirin, to address the question. Finally, as the overlap in the biological consequences of activating several prostanoid receptors – the IP, EP2, EP4, DP1 or the FP, TP, EP1 groups for example, hint at the possibility that efficacy might be diluted as one moves downstream to target just one prostanoid in the pathway. Our poor understanding of such potential functional redundancy at the receptor level, never mind insight into the implications of receptor dimerization leave these as open questions for drug development.

Surely, this complexity suggests that experiments in animals are going to be of virtually no value when it comes to predicting drug effects in vivo? Certainly the limitations of standard experimental paradigms apply in this pathway as in others. We study mouse models of atherosclerosis that fail to undergo spontaneous plaque fissure and thrombotic occlusion of vital arteries to reach conclusions about prevention or provocation of MI. We extrapolate from drug action on murine tolerance of a hotplate to patients undergoing molar extraction in an effort to divine therapies for elderly ladies with osteoarthritis of the knees. These and many such examples inspire caution in the field of translational therapeutics. However, consistency of evidence from different model systems across multiple species can, especially when integrated with independent lines of evidence, predict with some confidence the outcome in randomized clinical trials of drug action in this pathway. Such was the case in the prediction and mechanistic elucidation of the cardiovascular hazard from NSAIDs (178).

Finally, is it likely that this pathway will yield more therapeutic opportunities? Besides drugs already approved for various indications - aspirin and the myriad NSAIDs, analogues of PGE2, PGF and PGI2, TP and leukotriene antagonists, currently inhibitors of mPGES-1, 5 – lipoxygenase and its activating factor (FLAP) and antagonists of DP1, DP2 and EP4 are all undergoing clinical evaluation. Many other targets in the eicosanoid pathway are undergoing preclinical evaluation, just as others, such as the multiple secretory phospholipases and the soluble epoxide hydrolase, emerge. This coincides with new information about old targets.

Why do we need to inhibit both COXs, not just COX-1 to see gastrointestinal injury in model systems (29)? Why is a form of aspirin confined to platelet inhibition in the presystemic circulation associated with a reduction in the incidence of colon cancer (179, 180)? Much remains to be discovered about the biology of the eicosanoids and from this is likely to come new therapeutic opportunity.

Concluding remarks

Prostanoids can promote or restrain acute inflammation. Products of COX-2 in particular may also contribute to resolution of inflammation in certain settings. Presently, we have little information on which products of COX-2 might subserve this role or indeed if the dominant factors reflect rediversion of the arachidonic acid substrate to other metabolic pathways consequent to deletion or inhibition of COX-2. As with cyclopentanone prostanoids, many arachidonate derivatives, including transcellular products, when synthesized and administered as exogenous compounds, can promote resolution in models of inflammation. However, rigorous physico-chemical evidence for the formation of the endogenous species in relevant quantities to subserve this role in vivo is limited. Elucidation of whether and how prostanoids might restrain inflammation and how substrate modification, such as with fish oils, might exploit this understanding is currently a focus of much research from which novel therapeutic strategies are likely to emerge.

Acknowledgments

The work that formed the basis for opinions expressed in this review was supported by National Institutes of Health grants HL062250, {"type":"entrez-nucleotide","attrs":{"text":"HL083799","term_id":"1051654207","term_text":"HL083799"}}HL083799 and {"type":"entrez-nucleotide","attrs":{"text":"HL054500","term_id":"1051591996","term_text":"HL054500"}}HL054500 (G.A.F). Dr FitzGerald is the McNeil Professor of Translational Medicine and Therapeutics. He has consulted in the past year for Astra Zeneca, Daiichi Sankyo, Logical Therapeutics, Lilly, and Nicox on NSAIDs and related compounds. The other authors report no conflicts.

Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pa
Address for correspondence: Garret. A. FitzGerald, 153 Johnson Pavilion, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ude.nnepu@terrag, Tel: 215 898 1184. Fax: 215 573 9135

Abstract

Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase (COX) isoenzymes and their biosynthesis is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs), including those selective for inhibition of COX-2. Despite the clinical efficacy of NSAIDs, prostaglandins may function in both the promotion and resolution of inflammation.

This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm.

Abstract

Inflammation is the immune system’s response to infection and injury and has been implicated in the pathogeneses of arthritis, cancer and stroke, as well as in neurodegenerative and cardiovascular disease. Inflammation is an intrinsically beneficial event that leads to removal of offending factors and restoration of tissue structure and physiological function. The acute phase of inflammation is characterized by the rapid influx of blood granulocytes, typically neutrophils, followed swiftly by monocytes that mature into inflammatory macrophages that subsequently proliferate and thereby affect the functions of resident tissue macrophages. This process causes the cardinal signs of acute inflammation: rubor (redness), calor (heat), tumor (swelling) and dolor (pain). Once the initiating noxious stimulus is removed via phagocytosis, the inflammatory reaction can decrease and resolve. During the resolution of inflammation, granulocytes are eliminated and macrophages and lymphocytes return to normal pre-inflammatory numbers and phenotypes. The usual outcome of the acute inflammatory program is successful resolution and repair of tissue damage, rather than persistence and dysfunction of the inflammatory response, which can lead to scarring and loss of organ function. It may be anticipated, therefore, that failure of acute inflammation to resolve may predispose to auto-immunity, chronic dysplastic inflammation and excessive tissue damage (1).

Prostaglandins play a key role in the generation of the inflammatory response. Their biosynthesis is significantly increased in inflamed tissue and they contribute to the development of the cardinal signs of acute inflammation. While the pro-inflammatory properties of individual prostaglandins during the acute inflammatory response are well established, their role in the resolution of inflammation is more controversial.

In this review, we will discuss the biosynthesis of and response to prostaglandins and the pharmacology of their blockade in orchestrating the inflammatory response, with particular regard to cardiovascular disease.

References

  • 1. Nathan CPoints of control in inflammation. Nature. 2002;420:846–885.[PubMed][Google Scholar]
  • 2. Smith WL, DeWitt DL, Garavito RMCyclooxygenases: Structural, cellular, and molecular biology. Annu Rev Biochem. 2000;69:145–182.[PubMed][Google Scholar]
  • 3. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, Lipsky PECyclooxygenase in biology and disease. FASEB J. 1998;12:1063–1073.[PubMed][Google Scholar]
  • 4. Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GAProstanoids in health and disease. J Lipid Res. 2009;50:S423–428.[Google Scholar]
  • 5. Tilley SL, Coffman TM, Koller BHMixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest. 2001;108:15–23.[Google Scholar]
  • 6. Narumiya S, FitzGerald GAGenetic and pharmacological analysis of prostanoid receptor function. J Clin Invest. 2001;108:25–30.[Google Scholar]
  • 7. Breyer RM, Bagdassarian CK, Myers SA, Breyer MDProstanoid receptors: Subtypes and signaling. Annu Rev Pharmacol Toxicol. 2001;41:661–690.[PubMed][Google Scholar]
  • 8. Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori Y, Ichimasa M, Sugamura K, Nakamura M, Takano S, Nagata KProstaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med. 2001;193:255–261.[Google Scholar]
  • 9. Pierce KL, Fujino H, Srinivasan D, Regan JWActivation of FP prostanoid receptor isoforms leads to Rho-mediated changes in cell morphology and in the cell cytoskeleton. J Biol Chem. 1999;274:35944–35949.[PubMed][Google Scholar]
  • 10. Hatae N, Sugimoto Y, Ichikawa AProstaglandin receptors: advances in the study of EP3 receptor signaling. J Biochem. 2002;131:781–784.[PubMed][Google Scholar]
  • 11. Wilson SJ, McGinley K, Huang AJ, Smyth EMHeterodimerization of the alpha and beta isoforms of the human thromboxane receptor enhances isoprostane signaling. Biochem Biophys Res Commun. 2007;352:397–403.[Google Scholar]
  • 12. Wilson SJ, Roche AM, Kostetskaia E, Smyth EMDimerization of the human receptors for prostacyclin and thromboxane facilitates thromboxane receptor-mediated cAMP generation. J Biol Chem. 2004;279:53036–53047.[PubMed][Google Scholar]
  • 13. McGraw DW, Mihlbachler KA, Schwarb MR, Rahman FF, Small KM, Almoosa KF, Liggett SBAirway smooth muscle prostaglandin-EP1 receptors directly modulate beta2-adrenergic receptors within a unique heterodimeric complex. J Clin Invest. 2006;116:1400–1409.[Google Scholar]
  • 14. Yuan C, Sidhu RS, Kuklev DV, Kado Y, Wada M, Song I, Smith WLCyclooxygenase Allosterism, Fatty Acid-mediated Cross-talk between Monomers of Cyclooxygenase Homodimers. J Biol Chem. 2009;284:10046–10055.[Google Scholar]
  • 15. Yu Y, Fan J, Chen XS, Wang D, Klein-Szanto AJ, Campbell RL, FitzGerald GA, Funk CDGenetic model of selective COX2 inhibition reveals novel heterodimer signaling. Nat Med. 2006;12:699–704.[PubMed][Google Scholar]
  • 16. Vane JRInhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232–235.[PubMed][Google Scholar]
  • 17. Mardini IA, FitzGerald GASelective inhibitors of cyclooxygenase-2: a growing class of anti-inflammatory drugs. Mol Interv. 2001;1:30–38.[PubMed][Google Scholar]
  • 18. McAdam BF, Mardini IA, Habib A, Burke A, Lawson JA, Kapoor S, FitzGerald GAEffect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation. J Clin Invest. 2000;105:1473–1482.[Google Scholar]
  • 19. Crofford LJ, Wilder RL, Ristimaki AP, Sano H, Remmers EF, Epps HR, Hla T. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues. Effects of interleukin- 1 beta, phorbol ester, and corticosteroids. J Clin Invest. 1994;93:1095–1101.
  • 20. Schonbeck U, Sukhova GK, Graber P, Coulter S, Libby PAugmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol. 1999;155:1281–1291.[Google Scholar]
  • 21. Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Mahler JF, Lee CA, Goulding EH, Kluckman KD, Kim HS, Smithies OProstaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell. 1995;83:483–492.[PubMed][Google Scholar]
  • 22. Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, Mahler JF, Kluckman KD, Ledford A, Lee CA, Smithies OProstaglandin synthase-2 gene disruption causes severe renal pathology in the mouse. Cell. 1995;83:473–482.[PubMed][Google Scholar]
  • 23. Dinchuk JE, Car BD, Focht RJ, Johnston JJ, Jaffee BD, Covington MB, Contel NR, Eng VM, Collins RJ, Czerniak PM, Gorry SA, Trzaskos JMRenal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature. 1995;378:406–409.[PubMed][Google Scholar]
  • 24. Chen M, Boilard E, Nigrovic PA, Clark P, Xu D, Fitzgerald GA, Audoly LP, Lee DMPredominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody-driven K/BxN serum-transfer arthritis. Arthritis Rheum. 2008;58:1354–1365.[PubMed][Google Scholar]
  • 25. Myers LK, Kang AH, Postlethwaite AE, Rosloniec EF, Morham SG, Shlopov BV, Goorha S, Ballou LRThe genetic ablation of cyclooxygenase 2 prevents the development of autoimmune arthritis. Arthritis Rheum. 2000;43:2687–2693.[PubMed][Google Scholar]
  • 26. Ochi T, Ohkubo Y, Mutoh SRole of cyclooxygenase-2, but not cyclooxygenase-1, on type II collagen-induced arthritis in DBA/1J mice. Biochem Pharmacol. 2003;66:1055–1060.[PubMed][Google Scholar]
  • 27. Langenbach R, Loftin C, Lee C, Tiano HCyclooxygenase knockout mice-Models for elucidating isoform-specific functions. Biochem Pharmacol. 1999;58:1237–1246.[PubMed][Google Scholar]
  • 28. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DAInducible cyclooxygenase may have anti-inflammatory properties. Nat Med. 1999:698–701.[PubMed][Google Scholar]
  • 29. Wallace JL, Mcknight W, Reuter BK, Vergnolle NNSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology. 2000;119:706–714.[PubMed][Google Scholar]
  • 30. Morteau O, Morham SG, Sellon R, Dieleman LA, Langenbach R, Smithies O, Sartor RBImpaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2. J Clin Invest. 2000;105:469–478.[Google Scholar]
  • 31. Gavett SH, Madison SL, Chulada PC, Scarborough PE, Qu W, Boyle JE, Tiano HF, Lee CA, Langenbach R, Roggli VL, Zeldin DCAllergic lung responses are increased in prostaglandin H synthase-deficient mice. J Clin Invest. 1999;104:721–732.[Google Scholar]
  • 32. Bell-Parikh LC, Ide T, Lawson JA, McNamara P, Reilly M, FitzGerald GABiosynthesis of 15-deoxy-delta12,14-PGJ2 and the ligation of PPAR gamma. J Clin Invest. 2003;112:945–955.[Google Scholar]
  • 33. McClelland S, Gawaz M, Kennerknecht E, Konrad CS, Sauer S, Schuerzinger K, Massberg S, Fitzgerald DJ, Belton OContribution of cyclooxygenase-1 to thromboxane formation, platelet-vessel wall interactions and atherosclerosis in the ApoE null mouse. Atherosclerosis. 2009;202:84–91.[PubMed][Google Scholar]
  • 34. Pratico D, Tillmann C, Zhang ZB, Li H, FitzGerald GAAcceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice. Proc Natl Acad Sci USA. 2001;98:3358–3363.[Google Scholar]
  • 35. Egan KM, Lawson JA, Fries S, Koller B, Rader DJ, Smyth EM, et al COX-2-derived prostacyclin confers atheroprotection on female mice. Science. 2004;306:1954–1957.[PubMed][Google Scholar]
  • 36. Legler DF, Bruckne M, Uetz-von Allmen E, Krause PProstaglandin E2 at new glance: Novel insights in functional diversity offer therapeutic chances. Int J Biochem Cell Biol. 2010;42:198–201.[PubMed][Google Scholar]
  • 37. Funk CDProstaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294:1871–1875.[PubMed][Google Scholar]
  • 38. Samuelsson B, Morgenstern R, Jakobsson PJMembrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev. 2007;59:207–24.[PubMed][Google Scholar]
  • 39. Tanioka T, Nakatani Y, Semmyo N, Murakami M, Kudo IMolecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Chem. 2000;275:32775–32782.[PubMed][Google Scholar]
  • 40. Nakatani Y, Hokonohara Y, Kakuta S, Sudo K, Iwakura Y, Kudo IKnockout mice lacking cPGES/p23, a constitutively expressed PGE2 synthetic enzyme, are perinatally lethal. Biochem Biophys Res Commun. 2007;362:387–392.[PubMed][Google Scholar]
  • 41. Jakobsson PJ, Thorén S, Morgenstern S, Samuelsson BIdentification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci U S A. 1999;96:7220–7225.[Google Scholar]
  • 42. Mancini JA, Blood K, Guay J, Gordon R, Claveau D, Chan CC, Riendeau DCloning, expression, and up-regulation of inducible rat prostaglandin E synthase during lipopolysaccharide-induced pyresis and adjuvant-induced arthritis. J Biol Chem. 2001;276:4469–4475.[PubMed][Google Scholar]
  • 43. Thorén S, Jakobsson PJ. Coordinate up- and down-regulation of glutathione dependent prostaglandin E synthase and cyclooxygenase-2 in A549 cells. Inhibition by NS-398 and leukotriene C4. Eur J Biochem. 2000;267:6428–6434.[PubMed]
  • 44. Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, Ikeda T, Fueki M, Ueno A, Oh S, Kudo IRegulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem. 2000;275:32783–32792.[PubMed][Google Scholar]
  • 45. Trebino CE, Stock JL, Gibbons CP, Naiman BM, Wachtmann TS, Umland JP, Pandher K, Lapointe JM, Saha S, Roach ML, Carter D, Thomas NA, Durtschi BA, McNeish JD, Hambor JE, Jakobsson PJ, Carty TJ, Perez JR, Audoly LPImpaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci U S A. 2003;100:9044–9049.[Google Scholar]
  • 46. Kamei D, Yamakawa K, Takegoshi Y, Mikami-Nakanishi M, Nakatani Y, Oh-Ishi S, Yasui H, Azuma Y, Hirasawa N, Ohuchi K, Kawaguchi H, Ishikawa Y, Ishii T, Uematsu S, Akira S, Murakami M, Kudo IReduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin E synthase-1. J Biol Chem. 2004;279:33684–33695.[PubMed][Google Scholar]
  • 47. Wang M, Zukas AM, Hui Y, Ricciotti E, Pure E, FitzGerald GADeletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis. Proc Natl Acad Sci U S A. 2006;103:14507–14512.[Google Scholar]
  • 48. Brenneis C, Coste O, Schmidt R, Angioni C, Popp L, Nusing RM, Becker W, Scholich K, Geisslinger GConsequences of altered eicosanoid patterns for nociceptive processing in mPGES-1-deficient mice. J Cell Mol Med. 2008;12:639–648.[Google Scholar]
  • 49. Brenneis C, Coste O, Altenrath K, Angioni C, Schmidt H, Schuh CD, Zhang DD, Henke M, Weigert A, Bruene B, Rubin B, Nusing R, Scholich K, Geisslinger GAnti-inflammatory role of microsomal prostaglandin E synthase-1 in a model of neuroinflammation. J Biol Chem. 2010 Nov 12; [Epub ahead of print] [Google Scholar]
  • 50. Jania LA, Chandrasekharan S, Backlund MG, Foley NA, Snouwaert J, Wang IM, Clark P, Audoly LP, Koller BHMicrosomal prostaglandin E synthase-2 is not essential for in vivo prostaglandin E2 biosynthesis. Prostaglandins Other Lipid Mediat. 2009;88:73–81.[Google Scholar]
  • 51. Soodvilai S, Jia Z, Wang MH, Dang Z, Yang TmPGES-1 deletion impairs diuretic response to acute water loading. Am J Physiol. 2009;296:1129–1135.[Google Scholar]
  • 52. Hui Y, Ricciotti E, Crichton I, Yu Z, Wang D, Stubbe J, Wang M, Puré E, FitzGerald GATargeted deletions of cyclooxygenase-2 and atherogenesis in mice. Circulation. 2010;121:2654–2660.[Google Scholar]
  • 53. Park JY, Pillinger MH, Abramson SBProstaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin Immunol. 2006;119:229–240.[PubMed][Google Scholar]
  • 54. Sugimoto Y, Narumiya SProstaglandin E receptors. J Biol Chem. 2007;282:11613–7.[PubMed][Google Scholar]
  • 55. Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, Tominaga MSensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain. 2005;1:3.[Google Scholar]
  • 56. Minami T, Nakano H, Kobayashi T, Sugimoto Y, Ushikubi F, Ichikawa A, Narumiya S, Ito SCharacterization of EP receptor subtypes responsible for prostaglandin E2-induced pain responses by use of EP1 and EP3 receptor knockout mice. Br J Pharmacol. 2001;133:438–444.[Google Scholar]
  • 57. Honda T, Segi-Nishida E, Miyachi Y, Narumiya SProstacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis. J Exp Med. 2006;203:325–335.[Google Scholar]
  • 58. Yuhki K, Ueno A, Naraba H, Kojima F, Ushikubi F, Narumiya S, Oh-ishi SProstaglandin receptors EP2, EP3, and IP mediate exudate formation in carrageenin-induced mouse pleurisy. J Pharmacol Exp Ther. 2004;311:1218–1224.[PubMed][Google Scholar]
  • 59. Portanova JP, Zhang Y, Anderson GD, Hauser SD, Masferrer JL, Seibert K, Gregory SA, Isakson PCSelective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo. J Exp Med. 1996;184:883–891.[Google Scholar]
  • 60. Dayer JM, Krane SM, Russell RG, Robinson DRProduction of collagenase and prostaglandins by isolated adherent rheumatoid synovial cells. Proc Natl Acad Sci USA. 1976;73:945–949.[Google Scholar]
  • 61. McCoy JM, Wicks JR, Audoly LPThe role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis. J Clin Invest. 2002;110:651–658.[Google Scholar]
  • 62. Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya SProstaglandin D2 as a mediator of allergic asthma. Science. 2000;287:2013–2017.[PubMed][Google Scholar]
  • 63. Kunikata T, Yamane H, Segi E, Matsuoka T, Sugimoto Y, Tanaka S, Tanaka H, Nagai H, Ichikawa A, Narumiya SSuppression of allergic inflammation by the prostaglandin E receptor subtype EP3. Nat Immunol. 2005;6:524–531.[PubMed][Google Scholar]
  • 64. Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, Kuroiwa K, et al Prostaglandin E(2)-EP4 signaling promotes immune inflammation through T(H)1 cell differentiation and T(H)17 cell expansion. Nat Med. 2009;15:633–640.[PubMed][Google Scholar]
  • 65. Kabashima K, Sakata D, Nagamachi M, Miyachi Y, Inaba K, Narumiya SProstaglandin E2-EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells. Nat Med. 2003;9:744–749.[PubMed][Google Scholar]
  • 66. Legler DF, Krause P, Scandella E, Singer E, Groettrup MProstaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors. J Immunol. 2006;176:966–973.[PubMed][Google Scholar]
  • 67. Krause P, Bruckner M, Uermosi C, Singer E, Groettrup M, Legler DFProstaglandin E2 enhances T cell proliferation by inducing the co-stimulatory molecules OX40L, CD70 and 4-1BBL on dendritic cells. Blood. 2009;113:2451–2460.[PubMed][Google Scholar]
  • 68. Harris SG, Padilla J, Koumas L, Ray D, Phipps RPProstaglandins as modulators of immunity. Trends Immunol. 2002;23:144–150.[PubMed][Google Scholar]
  • 69. Babaev VR, Chew JD, Ding L, Davis S, Breyer MD, Breyer RM, Oates JA, Fazio S, Linton MFMacrophages EP4 deficiency increases apoptosis and suppresses early atherosclerosis. Cell Metab. 2008;8:492–501.[Google Scholar]
  • 70. Tang EH, Shimizu K, Christen T, Rocha VZ, Shvartz E, Tesmenitsky Y, Sukhova G, Shi GP, Libby PLack of EP4 receptors on bone marrow-derived cells enhances inflammation in atherosclerotic lesions. Cardiovasc Res. 2011;81:234–243.[Google Scholar]
  • 71. Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian TActivation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A. 2003;100:8514–8519.[Google Scholar]
  • 72. Montine TJ, Milatovic D, Gupta C, Valyi-Nagy T, Morrow JD, Breyer RMNeuronal oxidative damage from activated innate immunity is EP2 receptor-dependent. J Neurochem. 2002;83(2):463–470.[PubMed][Google Scholar]
  • 73. Reinold H, Ahmadi S, Depner UB, Layh B, Heindl C, Hamza M, Pahl A, Brune K, Narumiya S, Muller U, Zeilhofer HUSpinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. J Clin Invest. 2005;115:673–679.[Google Scholar]
  • 74. Caggiano AO, Kraig RPProstaglandin E2 and 4-aminopyridine prevent the lipopolysaccharide-induced outwardy rectifying potassium current and interleukin-1 beta production. J Neurochem. 1999;72:565–575.[Google Scholar]
  • 75. Noda M, Kariura Y, Pannasch U, Nishikawa K, Wang L, Seike T, Ifuku M, Kosai Y, Wang B, Nolte C, Aoki S, Kettenmann H, Wada KNeuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia. J Neurochem. 2007;101:397–410.[PubMed][Google Scholar]
  • 76. Kawabe J, Ushikubi F, Hasebe NProstacyclin in Vascular Diseases. Circ J. 2010;74:836–843.[PubMed][Google Scholar]
  • 77. Smith WL, DeWitt DL, Allen MLBimodal distribution of the prostaglandin I2 synthase antigen in smooth muscle cells. J Biol Chem. 1983;258:5922–5926.[PubMed][Google Scholar]
  • 78. Liou JY, Shyue SK, Tsai MJ, Chung CL, Wu KKColocalization of prostacyclin synthase with prostaglandin H synthase-1 (PGHS-1) but not phorbol ester-induced PGHS-2 in cultured endothelial cells. J Biol Chem. 2000;275:15314–15320.[PubMed][Google Scholar]
  • 79. Miyata A, Hara S, Yokoyama C, Inoue H, Ullrich V, Tanabe TMolecular cloning and expression of human prostacyclin synthase. Biochem Biophys Res Commun. 1994;200:1728–1734.[PubMed][Google Scholar]
  • 80. Caughey GE, Cleland LG, Gamble JR, James MJ. Up-regulation of endothelial cyclooxygenase-2 and prostanoid synthesis by platelets. Role of thromboxane A2. J Biol Chem. 2001;276:37839–37845.[PubMed]
  • 81. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GASystemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999;96:272–277.[Google Scholar]
  • 82. Wu KK, Liou JYCellular and molecular biology of prostacyclin synthase. Biochem Biophys Res Commun. 2005;338:45–52.[PubMed][Google Scholar]
  • 83. Libby P, Warner SJ, Friedman GBInterleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Invest. 1988;81:487–498.[Google Scholar]
  • 84. Smyth EM, FitzGerald GAHuman prostacyclin receptor. Vitam Horm. 2002;65:149–165.[PubMed][Google Scholar]
  • 85. Lim H, Dey SKA novel pathway of prostacyclin signaling-hanging out with nuclear receptors. Endocrinology. 2002;143:3207–3210.[PubMed][Google Scholar]
  • 86. Huang JC, Wun WS, Goldsby JS, Egan K, FitzGerald GA, Wu KKProstacyclin receptor signaling and early embryo development in the mouse. Hum Reprod. 2007;22(11):2851–6.[PubMed][Google Scholar]
  • 87. Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, Lawson JA, FitzGerald GARole of prostacyclin in the cardiovascular response to thromboxane A2. Science. 2002;296:539–541.[PubMed][Google Scholar]
  • 88. Francois H, Athirakul K, Howell D, Dash R, Mao L, Kim HS, Rockman HA, Fitzgerald GA, Koller BH, Coffman TMProstacyclin protects against elevated blood pressure and cardiac fibrosis. Cell Metab. 2005;2:201–7.[PubMed][Google Scholar]
  • 89. Kobayashi T, Tahara Y, Matsumoto M, Iguchi M, Sano H, Murayama T, Arai H, Oida H, Yurugi-Kobayashi T, Yamashita JK, Katagiri H, Majima M, Yokode M, Kita T, Narumiya SRoles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice. J Clin Invest. 2004;114:784–794.[Google Scholar]
  • 90. Bombardieri S, Cattani P, Ciabattoni G, Di Munno O, Pasero G, Patrono C, Pinca E, Pugliese FThe synovial prostaglandin system in chronic inflammatory arthritis: differential effects of steroidal and nonsteroidal anti-inflammatory drugs. Br J Pharmacol. 1981;73:893–901.[Google Scholar]
  • 91. Higgs GA, Moncada S, Salmon JA, Seager KThe source of thromboxane and prostaglandins in experimental inflammation. Br J Pharmacol. 1983;79:863–8.[Google Scholar]
  • 92. Berkenkopf JW, Weichman BMProduction of prostacyclin in mice following intraperitoneal injection of acetic acid, phenylbenzoquinone and zymosan: its role in the writhing response. Prostaglandins. 1988;36:693–709.[PubMed][Google Scholar]
  • 93. Murata T, Ushikubi F, Matsuoka T, Hirata M, Yamasaki A, Sugimoto Y, Ichikawa A, Aze Y, Tanaka T, Yoshida N, Ueno A, Oh-ishi S, Narumiya SAltered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature. 1997;388:678–682.[PubMed][Google Scholar]
  • 94. Ueno A, Naraba H, Ikeda Y, Ushikubi F, Murata T, Narumiya S, Oh-ishi SIntrinsic prostacyclin contributes to exudation induced by bradykinin or carrageenin: A study on the paw edema induced in IP-receptor-deficient mice. Life Sci. 2000;66:155–160.[PubMed][Google Scholar]
  • 95. Oida H, Namba T, Sugimoto Y, Ushikubi F, Ohishi H, Ichikawa A, Narumiya SIn situ hybridization studies of prostacyclin receptor mRNA expression in various mouse organs. Br J Pharmacol. 1995;116:2828–2837.[Google Scholar]
  • 96. Doi Y, Minami T, Nishizawa M, Mabuchi T, Mori H, Ito SCentral nociceptive role of prostacyclin (IP) receptor induced by peripheral inflammation. NeuroReport. 2002;13:93–96.[PubMed][Google Scholar]
  • 97. Bley KR, Bhattacharya A, Daniels DV, Gever J, Jahangir A, O’Yang C, Smith S, Srinivasan D, Ford AP, Jett MFRO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists. Br J Pharmacol. 2006;147:335–345.[Google Scholar]
  • 98. Pulichino AM, Rowland S, Wu T, Clark P, Xu D, Mathieu MC, Riendeau D, Audoly LPProstacyclin antagonism reduces pain and inflammation in rodent models of hyperalgesia and chronic arthritis. J Pharmacol Exp Ther. 2006;319:1043–1050.[PubMed][Google Scholar]
  • 99. Jaffar Z, Wan KS, Roberts KA key role for prostaglandin I2 in limiting lung mucosal Th2, but not Th1, responses to inhaled allergen. J Immunol. 2002;169:5997–6004.[PubMed][Google Scholar]
  • 100. Takahashi Y, Tokuoka S, Masuda T, Hirano Y, Nagao M, Tanaka H, Inagaki N, Narumiya S, Nagai HAugmentation of allergic inflammation in prostanoid IP receptor deficient mice. Br J Pharmacol. 2002;137:315–322.[Google Scholar]
  • 101. Jowsey IR, Thomson AM, Flanagan JU, Murdock PR, Moore GB, Meyers DJ, et al Mammalian class Sigma glutathione S transferases: catalytic properties and tissue-specific expression of human and rat GSH-dependent prostaglandin D2 synthases. Biochem J. 2001;359:507–516.[Google Scholar]
  • 102. Urade Y, Hayaishi OProstaglandin D2 and sleep regulation. Biochim Biophys Acta. 1999;1436:606–615.[PubMed][Google Scholar]
  • 103. Eguchi N, Minami T, Shirafuji N, Kanaoka Y, Tanaka T, Nagata A, Yoshida N, Urade Y, Ito S, Hayaishi OLack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-deficient mice. Proc Natl Acad Sci USA. 1999;96:726–730.[Google Scholar]
  • 104. Lewis RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ., II Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE. J Immunol. 1982;129:1627–1631.[PubMed]
  • 105. Urade Y, Ujihara M, Horiguchi Y, Ikai K, Hayaishi O. The major source of endogenous prostaglandin D2 production is likely antigenpresenting cells. Localization of glutathione-requiring prostaglandin D synthetase in histiocytes, dendritic, and Kupffer cells in various rat tissues. J Immunol. 1989;143:2982–2989.[PubMed]
  • 106. Tanaka K, Ogawa K, Sugamura K, Nakamura M, Takano S, Nagata KDifferential production of prostaglandin D2 by human helper T cell subsets. J Immunol. 2000;164:2277–2280.[PubMed][Google Scholar]
  • 107. Herlong JL, Scott TRPositioning prostanoids of the D and J series in the immunopathogenic scheme. Immunol Lett. 2006;102:121–131.[PubMed][Google Scholar]
  • 108. Fitzpatrick FA, Wynalda MAAlbumin-catalyzed metabolism of prostaglandin D2. J Biol Chem. 1983;258:11713–11718.[PubMed][Google Scholar]
  • 109. Shibata T, Kondo M, Osawa T, Shibata N, Kobayashi M, Uchida K15-Deoxy-delta 12,14-prostaglandin J2: a prostaglandin D2 metabolite generated during inflammatory processes. J Biol Chem. 2002;277:10459–10466.[PubMed][Google Scholar]
  • 110. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM15-deoxy-Δ12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ Cell. 1995;83:803–812.[PubMed][Google Scholar]
  • 111. Roberts LJ, II, Sweetman BJ, Lewis RA, Austen KF, Oates JAIncreased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med. 1980;303:1400–1404.[PubMed][Google Scholar]
  • 112. Murray JJ, Tonnel AB, Brash AR, Roberts LJ, 2nd, Gosset P, Workman R, Capron A, Oates JARelease of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med. 1986;315:800–804.[PubMed][Google Scholar]
  • 113. Hardy CC, Robinson C, Tattersfield AE, Holgate STThe bronchoconstrictor effect of inhaled prostaglandin D2 in normal and asthmatic men. N Engl J Med. 1984;311:209–213.[PubMed][Google Scholar]
  • 114. Emery DL, Djokic TD, Graf PD, Nadel JAProstaglandin D2 causes accumulation of eosinophils in the lumen of the dog trachea. J Appl Physiol. 1989;67:959–962.[PubMed][Google Scholar]
  • 115. Fujitani Y, Kanaoka Y, Aritake K, Uodome N, Okazaki-Hatake K, Urade YPronounced eosinophilic lung inflammation and Th2 cytokine release in human lipocalin-type prostaglandin D synthase transgenic mice. J Immunol. 2002;168:443–449.[PubMed][Google Scholar]
  • 116. Kabashima K, Narumiya SThe DP receptor, allergic inflammation and asthma. Prostaglandins Leukot Essent Fatty Acids. 2003;69:187–194.[PubMed][Google Scholar]
  • 117. Gervais FG, Cruz RP, Chateauneuf A, Gale S, Sawyer N, Nantel F, Metters KM, O’Neill GPSelective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP. J Allergy Clin Immunol. 2001;108:982–988.[PubMed][Google Scholar]
  • 118. Tsuri T, Honma T, Hiramatsu Y, Okada T, Hashizume H, Mitsumori S, Inagaki M, Arimura A, Yasui K, Asanuma F, Kishino J, Ohtani MBicyclo[2.2.1]heptane and 6,6- dimethylbicyclo[3.1.1]heptane derivatives: Orally active, potent, and selective prostaglandin D2 receptor antagonists. J Med Chem. 1997;40:3504–3507.[PubMed][Google Scholar]
  • 119. Arimura A, Yasui K, Kishino J, Asanuma F, Hasegawa H, Kakudo S, Ohtani M, Arita HPrevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. J Pharmacol Exp Ther. 2001;298:411–419.[PubMed][Google Scholar]
  • 120. Nagata K, Hirai H, Tanaka K, Ogawa K, Aso T, Sugamura K, Nakamura M, Takano SCRTH2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cell-derived factor(s) FEBS Lett. 1999;459:195–199.[PubMed][Google Scholar]
  • 121. Nagata K, Tanaka K, Ogawa K, Kemmotsu K, Imai T, Yoshie O, Abe H, Tada K, Nakamura M, Sugamura K, Takano SSelective expression of a novel surface molecule by human Th2 cells in vivo. J Immunol. 1999;162:1278–1286.[PubMed][Google Scholar]
  • 122. Iwasaki M, Nagata K, Takano S, Takahashi K, Ishii N, Ikezawa ZAssociation of a new-type prostaglandin D2 receptor CRTH2 with circulating T helper 2 cells in patients with atopic dermatitis. J Invest Dermatol. 2002;119:609–616.[PubMed][Google Scholar]
  • 123. Shichijo M, Sugimoto H, Nagao K, Inbe H, Encinas JA, Takeshita K, Bacon KB, Gantner FChemoattractant receptorhomologous molecule expressed on Th2 cells activation in vivo increases blood leukocyte counts and its blockade abrogates 13,14- dihydro-15-keto-prostaglandin D2-induced eosinophilia in rats. J Pharmacol Exp Ther. 2003;307:518–525.[PubMed][Google Scholar]
  • 124. Hammad H, de Heer HJ, Soullie T, Hoogsteden HC, Trottein F, Lambrecht BNProstaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1. J Immunol. 2003;171:3936–3940.[PubMed][Google Scholar]
  • 125. Spik I, Brenuchon C, Angeli V, Staumont D, Fleury S, Capron M, Trottein F, Dombrowicz DActivation of the prostaglandin D2 receptor DP2/CRTH2 increases allergic inflammation in mouse. J Immunol. 2005;174:3703–708.[PubMed][Google Scholar]
  • 126. Angeli V, Faveeuw C, Roye O, Fontaine J, Teissier E, Capron A, Wolowczuk I, Capron M, Trottein FRole of the parasite derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection. J Exp Med. 2001;193:1135–1147.[Google Scholar]
  • 127. Rajakariar R, Hilliard M, Lawrence T, Trivedi S, Colville-Nash P, Bellingan G, Fitzgerald D, Yaqoob MM, Gilroy DWHematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2. Proc Natl Acad Sci U S A. 2007;104:20979–20984.[Google Scholar]
  • 128. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CKThe peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82.[PubMed][Google Scholar]
  • 129. Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, Sengchanthalangsy LL, Ghosh G, Glass CK15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci U S A. 2000;97:4844–4949.[Google Scholar]
  • 130. Song WL, Wang M, Ricciotti E, Fries S, Yu Y, Grosser T, Reilly M, Lawson JA, FitzGerald GATetranor PGDM, an abundant urinary metabolite reflects biosynthesis of prostaglandin D2 in mice and humans. J Biol Chem. 2008;283(2):1179–1188.[PubMed][Google Scholar]
  • 131. Tsukada T, Rosenfeld M, Ross R, Gown AMImmunocytochemical analysis of cellular components in lesions of atherosclerosis of the Watanabe and fat-fed rabbit using monoclonal antibodies. Arteriosclerosis. 1986;6:601–613.[PubMed][Google Scholar]
  • 132. Kaartinen M, Penttila A, Kovanen PTMast cells of two types differing in neutral protease composition in the human aortic intima: demonstration of tryptase- and tryptase/chymase-containing mast cells in normal intimas, fatty streaks, and the shoulder region of atheromas. Arterioscler Thromb Vasc Biol. 1994;14:966–972.[PubMed][Google Scholar]
  • 133. Taba Y, Sasaguri T, Miyagi M, Abumiya T, Miwa Y, Ikeda T, Mitsumata MFluid shear stress induces lipocalin-type prostaglandin D2 synthase expression in vascular endothelial cells. Circ Res. 2000;86:967–973.[PubMed][Google Scholar]
  • 134. Eguchi Y, Eguchi N, Oda H, Seiki K, Kijima Y, Matsu-ura Y, Urade Y, Hayaishi OExpression of lipocalin-type prostaglandin D synthase (beta-trace) in human heart and its accumulation in the coronary circulation of angina patients. Proc Natl Acad Sci USA. 1997;94:14689–14694.[Google Scholar]
  • 135. Hirawa N, Uehara Y, Yamakado M, Toya Y, Gomi T, Ikeda T, Eguchi Y, Takagi M, Oda H, Seiki K, Urade Y, Umemura SLipocalin-type prostaglandin dsynthase in essential hypertension. Hypertension. 2002;39:449–454.[PubMed][Google Scholar]
  • 136. Nagoshi H, Uehara Y, Kanai F, Maeda S, Ogura T, Goto A, Toyo-oka T, Esumi H, Shimizu T, Omata MProstaglandin D2 inhibits inducible nitric oxide synthase expression in rat vascular smooth muscle cells. Circ Res. 1998;82:204–209.[PubMed][Google Scholar]
  • 137. Negoro H, Soo Shin W, Hakamada-Taguchi R, Eguchi N, Urade Y, Goto A, Toyo-Oka T, Fujita T, Omata M, Uehara YEndogenous prostaglandin D2 synthesis reduces an increase in plasminogen activator inhibitor-1 following interleukin stimulation in bovine endothelial cells. J Hypertens. 2002;20:1347–1354.[PubMed][Google Scholar]
  • 138. Tanaka R, Miwa Y, Mou K, Tomikawa M, Eguchi N, Urade Y, Takahashi-Yanaga F, Morimoto S, Wake N, Sasaguri TKnockout of the l-pgds gene aggravates obesity and atherosclerosis in mice. Biochem Biophys Res Commun. 2009;378:851–856.[PubMed][Google Scholar]
  • 139. Pierce KL, Bailey TJ, Hoyer PB, Gil DW, Woodward DF, Regan JWCloning of a carboxyl-terminal isoform of the prostanoid FP receptor. J Biol Chem. 1997;272:883–887.[PubMed][Google Scholar]
  • 140. Abramovitz M, Adam M, Boie Y, Carriere M, Denis D, Godbout C, Lamontagne S, Rochette C, Sawyer N, Tremblay NM, Belley M, Gallant M, Dufresne C, Gareau Y, Ruel R, Juteau H, Labelle M, Ouimet N, Metters KMThe utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Biochim Biophys Acta. 2000;1483:285–293.[PubMed][Google Scholar]
  • 141. Samuelsson B, Granstrom E, Green K, Hamberg M, Hammarstrom SProstaglandins. Annu Rev Biochem. 1975;44:669–695.[PubMed][Google Scholar]
  • 142. Liston TE, Roberts LJ., II Transformation of prostaglandin D2 to 9 alpha, 11 beta-(15S)-trihydroxyprosta- (5Z,13E)-dien-1-oic acid (9 alpha, 11 beta-prostaglandin F2): A unique biologically active prostaglandin produced enzymatically in vivo in humans. Proc Natl Acad Sci USA. 1985;82:6030–6034.
  • 143. Basu SNovel cyclooxygenase-catalyzed bioactive prostaglandin F2alpha from physiology to new principles in inflammation. Med Res Rev. 2007;27:435–468.[PubMed][Google Scholar]
  • 144. Sugimoto Y, Yamasaki A, Segi E, Tsuboi K, Aze Y, Nishimura T, Oida H, Yoshida N, Tanaka T, Katsuyama M, Hasumoto K, Murata T, Hirata M, Ushikubi F, Negishi M, Ichikawa A, Narumiya SFailure of parturition in mice lacking the prostaglandin F receptor. Science. 1997;277:681–683.[PubMed][Google Scholar]
  • 145. Saito O, Guan Y, Qi Z, Davis LS, Kömhoff M, Sugimoto Y, Narumiya S, Breyer RM, Breyer MDExpression of the prostaglandin F receptor (FP) gene along the mouse genitourinary tract. Am J Physiol-Renal. 2003;284:1164–1170.[PubMed][Google Scholar]
  • 146. Breyer MD, Breyer RMG protein-coupled prostanoid receptors and the kidney. Annu Rev Physiol. 2001;63:579–605.[PubMed][Google Scholar]
  • 147. Nakahata K, Kinoshita H, Tokinaga Y, Ishida Y, Kimoto Y, Dojo M, Mizumoto K, Ogawa K, Hatano YVasodilation mediated by inward rectifier K? channels in cerebral microvessels of hypertensive and normotensive rats. Anesth Analg. 2006;102:571–576.[PubMed][Google Scholar]
  • 148. Takayama K, Yuhki K, Ono K, Fujino T, Hara A, Yamada T, Kuriyama S, Karibe H, Okada Y, Takahata O, Taniguchi T, Iijima T, Iwasaki H, Narumiya S, Ushikubi FThromboxane A2 and prostaglandin F2a mediate inflammatory tachycardia. Nat Med. 2005;11:562–566.[PubMed][Google Scholar]
  • 149. Jovanovic N, Pavlovic M, Mircevski V, Du Q, Jovanovic AAn unexpected negative inotropic effect of prostaglandin F2a in the rat heart. Prostaglandins Other Lipid Mediat. 2006;80:110–119.[PubMed][Google Scholar]
  • 150. Saleem S, Ahmad AS, Maruyama T, Narumiya S, Doré SPGF(2alpha) FP receptor contributes to brain damage following transient focal brain ischemia. Neurotox Res. 2009;15(1):62–70.[Google Scholar]
  • 151. Kunori S, Matsumura S, Mabuchi T, Tatsumi S, Sugimoto Y, Minami T, Ito SInvolvement of prostaglandin F 2 alpha receptor in ATP-induced mechanical allodynia. Neuroscience. 2009;163:362–71.[PubMed][Google Scholar]
  • 152. Seguin BUse of prostaglandin in cows with unobserved oestrus. Acta Vet Scand. 1981;77:343–352.[PubMed][Google Scholar]
  • 153. Schultz RH, Copeland DDInduction of abortion using prostaglandins. Acta Vet Scand. 1981;77:353–361.[PubMed][Google Scholar]
  • 154. Karim SMProstaglandins in fertility control. Lancet. 1970;1:1115.[PubMed][Google Scholar]
  • 155. Alexander CL, Miller SJ, Abel SRProstaglandin analog treatment of glaucoma and ocular hypertension. Ann Pharmacother. 2002;36:504–511.[PubMed][Google Scholar]
  • 156. Basu S, Eriksson MOxidative injury and survival during endotoxemia. FEBS Lett. 1998;438:159–160.[PubMed][Google Scholar]
  • 157. Basu SOxidative injury induced cyclooxygenase activation in experimental hepatotoxicity. Biochem Biophys Res Commun. 1999;254:764–767.[PubMed][Google Scholar]
  • 158. Oga T, Matsuoka T, Yao C, Nonomura K, Kitaoka S, Sakata D, Kita Y, Tanizawa K, Taguchi Y, Chin K, Mishima M, Shimizu T, Narumiya SProstaglandin F(2alpha) receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta. Nat Med. 2009;15:1426–1430.[PubMed][Google Scholar]
  • 159. Basu S, Whiteman M, Mattey DL, Halliwell BRaised levels of F(2)-isoprostanes and prostaglandin F(2alpha) in different rheumatic diseases. Ann Rheum Dis. 2001;60:627–631.[Google Scholar]
  • 160. Helmersson J, Larsson A, Vessby B, Basu SActive smoking and a history of smoking are associated with enhanced prostaglandin F(2alpha), interleukin-6 and F2-isoprostane formation in elderly men. Atherosclerosis. 2005;181:201–207.[PubMed][Google Scholar]
  • 161. Helmersson J, Vessby B, Larsson A, Basu SAssociation of type 2 diabetes with cyclooxygenase-mediated inflammation and oxidative stress in an elderly population. Circulation. 2004;109:1729–1734.[PubMed][Google Scholar]
  • 162. Yu Y, Lucitt MB, Stubbe J, Cheng Y, Friis UG, Hansen PB, Jensen BL, Smyth EM, FitzGerald GAProstaglandin F2alpha elevates blood pressure and promotes atherosclerosis. Proc Natl Acad Sci U S A. 2009;106:7985–7990.[Google Scholar]
  • 163. Di Francesco L, Totani L, Dovizio M, Piccoli A, Di Francesco A, Salvatore T, Pandolfi A, Evangelista V, Dercho RA, Seta F, Patrignani PInduction of prostacyclin by steady laminar shear stress suppresses tumor necrosis factor-alpha biosynthesis via heme oxygenase-1 in human endothelial cells. Circ Res. 2009;104:506–513.[PubMed][Google Scholar]
  • 164. Funk CD, FitzGerald GACOX-2 inhibitors and cardiovascular risk. J Cardiovasc Pharmacol. 2007;50:470–479.[PubMed][Google Scholar]
  • 165. Félétou M, Verbeuren TJ, Vanhoutte PMEndothelium-dependent contractions in SHR: a tale of prostanoid TP and IP receptors. Br J Pharmacol. 2009;156:563–574.[Google Scholar]
  • 166. Félétou M, Vanhoutte PM, Verbeuren TJ. J Cardiovasc Pharmacol. 2010;55:317–32.[PubMed]
  • 167. The thromboxane/endoperoxide receptor (TP): the common villainNakahata N.Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology. Pharmacol Ther. 2008;118:18–35.[PubMed][Google Scholar]
  • 168. Gluais P, Lonchampt M, Morrow JD, Vanhoutte PM, Félétou MAcetylcholine-induced endothelium-dependent contractions in the SHR aorta: the Janus face of prostacyclin. Br J Pharmacol. 2005;146:834–845.[Google Scholar]
  • 169. Audoly LP, Rocca B, Fabre JE, Koller BH, Thomas D, Loeb AL, Coffman TM, FitzGerald GACardiovascular responses to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo. Circulation. 2000;101:2833–2840.[PubMed][Google Scholar]
  • 170. Montuschi P, Barnes PJ, Roberts LJ., II Isoprostanes: Markers and mediators of oxidative stress. FASEB J. 2004;18:1791–1800.[PubMed]
  • 171. Behm DJ, Ogbonna A, Wu C, Burns-Kurtis CL, Douglas SAEpoxyeicosatrienoic acids function as selective, endogenous antagonists of native thromboxane receptors: identification of a novel mechanism of vasodilation. J Pharmacol Exp Ther. 2009;328:231–239.[PubMed][Google Scholar]
  • 172. Thomas DW, Mannon RB, Mannon PJ, Latour A, Oliver JA, Hoffman M, Smithies O, Koller BH, Coffman TMCoagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2. J Clin Invest. 1998;102:1994–2001.[Google Scholar]
  • 173. Francois H, Athirakul K, Mao L, Rockman H, Coffman TMRole for thromboxane receptors in angiotensin-II-induced hypertension. Hypertension. 2004;43:364–369.[PubMed][Google Scholar]
  • 174. Francois H, Makhanova N, Ruiz P, Ellison J, Mao L, Rockman HA, Coffman TMA role for the thromboxanereceptor in L-NAME hypertension. Am J Physiol Renal Physiol. 2008;295:1096–1102.[Google Scholar]
  • 175. Yamada T, Fujino T, Yuhki K, Hara A, Karibe H, Takahata O, Okada Y, Xiao CY, Takayama K, Kuriyama S, Taniguchi T, Shiokoshi T, Ohsaki Y, Kikuchi K, Narumiya S, Ushikubi FThromboxane A2 regulates vascular tone via its inhibitory effect on the expression of inducible nitric oxide synthase. Circulation. 2003;108:2381–2386.[PubMed][Google Scholar]
  • 176. Boffa JJ, Just A, Coffman TM, Arendshorst WJThromboxane receptor mediates renal vasoconstriction and contributes to acute renal failure in endotoxemic mice. J Am Soc Nephrol. 2004;15:2358–2365.[PubMed][Google Scholar]
  • 177. Yu IS, Lin SR, Huang CC, Tseng HY, Huang PH, Shi GY, Wu HL, Tang CL, Chu PH, Wang LH, Wu KK, Lin SWTXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate induced death. Blood. 2004;104:135–142.[PubMed][Google Scholar]
  • 178. Grosser T, Yu Y, FitzGerald GAEmotion recollected in tranquility; lessons from the COX-2 saga. Ann Rev Med. 2010;61:17–33.[PubMed][Google Scholar]
  • 179. FitzGerald GA, Lupinetti M, Charman SA, Charman WNPresystemic acetylation of platelets by aspirin: reduction in rate of drug delivery to improve biochemical selectivity for thromboxane A2. J Pharmacol Exp Ther. 1991;259:1043–1049.[PubMed][Google Scholar]
  • 180. Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade TWLong-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376:1741–1750.[PubMed][Google Scholar]
  • 181. Shimizu TLipid Mediators in Health and Disease: Enzymes and Receptors as Therapeutic Targets for the Regulation of Immunity and Inflammation. Annu Rev Pharmacol Toxicol. 2009;49:123–50.[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.