What are prostaglandins

Prostaglandins are a family of lipid compounds that are derived enzymatically from arachidonic acid acting locally as autocrine or paracrine mediators with a wide range of effects throughout the body. The name prostaglandin derives from the prostate gland. When prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler, and independently by M.W. Goldblatt, it was believed to be part of the prostatic secretions ¹⁾. In fact, prostaglandins are produced by the seminal vesicles. It was later shown that many other tissues secrete prostaglandins for various functions. The first total syntheses of prostaglandin F2α and prostaglandin E2 were reported by E. J. Corey in 1969 ²⁾.

There are four principal bioactive prostaglandins (PG) generated in your body: prostaglandin E₂ (PGE₂), prostacyclin (PGI₂), prostaglandin D2 (PGD₂) and prostaglandin F_2α (PGF_2α). Prostaglandins 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.

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. For example, prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂) have significant vasodilatory properties, whereas platelet-released thromboxane A2 (TXA₂) is known as a vasoconstrictor that increases platelet aggregation. 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.

Prostaglandin synthesis

Prostaglandins are found in most tissues and organs. Prostaglandins are produced by almost all nucleated cells. Prostaglandins are autocrine and paracrine lipid mediators that act upon platelets, endothelium, uterine and mast cells. They are synthesized in the cell from the essential fatty acids. Arachidonic acid (AA) transformation is regulated by two cyclooxygenase (COX) isoenzymes, COX-1 and COX-2. Due to subsequent cyclooxygenation and peroxygenation, unstable prostaglandins PGG2 and PGH2 are formed. Next, these prostaglandins undergo further transformation in the presence of specific prostanoid synthases. The final transformation substrates are the prostaglandins PGE₂, PGF₂ and PGD₂; prostacyclin (PGI₂); and thromboxane A2 (TXA₂) ³⁾. The prostanoid synthesis profile is dependent on differences in enzymatic expression in cells under inflammation. Macrophages, for instance, release PGE2 and TXA2, whereas mast cells release prostaglandin PGD2 ⁴⁾.

Prostaglandins, prostacyclin (PGI₂) 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 also known as cyclooxygenase (COX), and respective synthases. Arachidonic acid metabolites are released from cells under the influence of many factors that act though specific membrane receptors. Growth factors (e.g, FGF, IFG and PDGF), hormones (vasopressin) and neurotransmitters (norepinephrine and acetylcholine) are among those factors ⁵⁾.

Prostaglandin production (Figure 1) depends on the activity of COXs (cyclooxygenases), bifunctional enzymes that contain both cyclooxygenase and peroxidase activity and which exist as distinct isoforms referred to as COX-1 (cyclooxygenase-1) and COX-2 (cyclooxygenase-2) ⁶⁾.

1. Cyclooxygenase-1 (COX-1), expressed constitutively in most cells, is the dominant source of prostanoids that subserve housekeeping functions, such as gastric epithelial cytoprotection and homeostasis ⁷⁾.
2. Cyclooxygenase-2 (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 ⁸⁾.

However, both enzymes COX-1 (cyclooxygenase-1) and COX-2 (cyclooxygenase-2) contribute to the generation of autoregulatory and homeostatic prostanoids, and both can contribute to prostanoid release during inflammation.

PGH₂ (prostaglandin H₂) is produced by both COX (cyclooxygenase) isoforms and it is the common substrate for a series of specific isomerase and synthase enzymes that produce PGE₂, PGI₂, PGD₂, PGF_2α and thromboxane A2 (TXA₂). COX-1 (cyclooxygenase-1) couples preferentially, but not exclusively, with thromboxane synthase (TXS), prostaglandin F synthase, and the cytosolic (c) prostaglandin E synthase (PGES) isozymes ⁹⁾. COX-2 (cyclooxygenase-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 ¹⁰⁾.

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 (prostaglandin D₂) while macrophages produce PGE₂ (prostaglandin E₂) and thromboxane A2 (TXA₂) ¹¹⁾. In addition, alterations in the profile of prostanoid synthesis can occur upon cellular activation. While resting macrophages produce TXA₂ in excess of PGE₂ (prostaglandin E₂), this ratio changes to favor PGE₂ (prostaglandin E₂) production after bacterial lipopolysaccharide (LPS) activation ¹²⁾.

Figure 1. Prostaglandin synthesis

Footnotes: Prostaglandin synthesis pathway. The COX enzymes COX1 and COX2, which reduce arachidonic acid to prostaglandin H₂ (PGH₂), are the main targets of COX2-specific inhibitors and NSAIDs. PGH₂ becomes a substrate for thromboxane, prostacyclin and prostaglandin synthases, which are converted into thromboxane A₂ (TXA₂), PGI₂, PGE₂ and prostaglandin D₂ (PGD₂). Arachidonic lipoxygenesases and hydroperoxides (HPETEs) convert arachidonic acid into leukotrienes and other inflammation-mediating eicosanoids.

[Source ¹³⁾]

What does prostaglandin do

The structural differences between prostaglandins account for their different biological activities. A given prostaglandin may have different and even opposite effects in different tissues in some cases. The ability of the same prostaglandin to stimulate a reaction in one tissue and inhibit the same reaction in another tissue is determined by the type of receptor to which the prostaglandin binds. They act as autocrine or paracrine factors with their target cells present in the immediate vicinity of the site of their secretion. Prostaglandins differ from endocrine hormones in that they are not produced at a specific site but in many places throughout the human body.

Prostaglandins (PG) are powerful locally acting vasodilators and inhibit the aggregation of blood platelets. Through their role in vasodilation, prostaglandins are also involved in inflammation. They are synthesized in the walls of blood vessels and serve the physiological function of preventing needless clot formation, as well as regulating the contraction of smooth muscle tissue ¹⁴⁾. Conversely, thromboxanes (TXAs) (produced by platelet cells) are vasoconstrictors and facilitate platelet aggregation. Their name comes from their role in clot formation (thrombosis).

Specific prostaglandins are named with a letter (which indicates the type of ring structure) followed by a number (which indicates the number of double bonds in the hydrocarbon structure). For example, prostaglandin E1 is abbreviated PGE1 or PGE1, and prostaglandin I2 is abbreviated PGI2 or PGI2.

There are currently ten known prostaglandin receptors on various cell types. Prostaglandins ligate a sub-family of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP1-2, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2).

The diversity of receptors means that prostaglandins act on an array of cells and have a wide variety of effects such as:

• cause constriction or dilation in vascular smooth muscle cells
• cause aggregation or disaggregation of platelets
• sensitize spinal neurons to pain
• induce labor
• decrease intraocular pressure
• regulate inflammation
• regulate calcium movement
• regulate hormones
• control cell growth
• acts on thermoregulatory center of hypothalamus to produce fever
• acts on mesangial cells (specialised smooth muscle cells) in the glomerulus of the kidney to increase glomerular filtration rate
• acts on parietal cells in the stomach wall to inhibit acid secretion
• increase mucus production and bicarbonate secretion
• brain masculinization (in rats) ¹⁵⁾
• increases mating behaviors in goldfish ¹⁶⁾
• Prostaglandins are released during menstruation, due to the destruction of the endometrial cells, and the resultant release of their contents ¹⁷⁾. Release of prostaglandins and other inflammatory mediators in the uterus cause the uterus to contract. These substances are thought to be a major factor in primary dysmenorrhea ¹⁸⁾.
• Cyclooxygenases blocking by lornoxicam in acute stage of inflammation reduced the frequency of membrane formation by 43% in the dispase model of proliferative vitreoretinopathy and by 31% in the concanavalin one. Lornoxicam not only normalized the expression of cyclooxygenases in both models of proliferative vitreoretinopathy, but also neutralized the changes of the retina and the choroid thickness caused by the injection of pro-inflammatory agents. These facts underline the importance of prostaglandins in the development of proliferative vitreoretinopathy ¹⁹⁾.

Prostaglandins are potent but have a short half-life before being inactivated and excreted. Therefore, they send only paracrine (locally active) or autocrine (acting on the same cell from which it is synthesized) signals.

The following is a comparison of different types of prostaglandin, including prostaglandin I₂ (prostacyclin; PGI₂), prostacyclin D₂ (PGD₂), prostaglandin E₂ (PGE₂), and prostaglandin F_2α (PGF_2α).

Table 1. Prostaglandins functions

Type	Receptor	Receptor type	Function
PGI2	IP	Gs	vasodilation inhibit platelet aggregation bronchodilation
PGD2	PTGDR (DP1) and CRTH2 (DP2)	GPCR	produced by mast cells; recruits Th2 cells, eosinophils, and basophils In mammalian organs, large amounts of PGD2 are found only in the brain and in mast cells Critical to development of allergic diseases such as asthma
PGE2	EP1	Gq	bronchoconstriction GI tract smooth muscle contraction
	EP2	Gs	bronchodilation GI tract smooth muscle relaxation vasodilation
	EP3	Gi	↓ gastric acid secretion ↑ gastric mucus secretion uterus contraction (when pregnant) GI tract smooth muscle contraction lipolysis inhibition ↑ autonomic neurotransmitters ↑ platelet response to their agonists and ↑ atherothrombosis in vivo
	Unspecified		hyperalgesia pyrogenic
PGF2α	FP	Gq	uterus contraction bronchoconstriction

Prostaglandin inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. Corticosteroids inhibit phospholipase A₂ production by boosting production of lipocortin, an inhibitor protein. The two cyclooxygenase isoforms, COX-1 (cyclooxygenase-1) and COX-2 (cyclooxygenase-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 ²⁰⁾. COX-1/COX-2 heterodimers may also exist, but their role in biology remains to be established ²¹⁾. Nonsteroidal anti-inflammatory drugs (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 ²²⁾. Relatively new drugs, known as COX-2 selective inhibitors or coxibs, are used as specific inhibitors of the COX-2 isoform of cyclooxygenase. The development of these drugs allowed the circumvention of the negative gastrointestinal side effects of NSAIDs while still effectively reducing inflammation.

Both NSAIDs and coxibs have been shown to increase the risk of myocardial infarction when taken on a chronic basis for at least 18 months. One emerging hypothesis that may explain these cardiovascular effects is that coxibs create an imbalance in circulating TxA2 (thromboxane A2) and PGI2 (prostacyclin) levels. An increase in the ratio of TxA2/PGI2 could lead to increased platelet aggregation and dysregulation of platelet homeostasis ²³⁾.

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 ²⁴⁾. 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 ²⁵⁾.

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 lipopolysaccharide (LPS)-mediated inflammatory response and cellular differentiation ²⁶⁾. 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 ²⁷⁾. 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 ²⁸⁾. 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 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 arachidonic acid (AA)-induced ear edema although arachidonic acid (AA) induces an equivalent inflammatory response in wild-type and COX-2-deficient mice ²⁹⁾. By contrast, the level of edema induced by the tumor promoter tetradecanoyl phorbol acetate was not significantly different between wild-type, COX-1-deficient and COX-2-deficient mice ³⁰⁾. 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 a autoantibody-driven 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 ³¹⁾. In a collagen- induced arthritis model, COX-2- deletion suppresses considerably synovial inflammation and joint destruction, whereas arthritis in COX- 1–deficient mice is indistinguishable from controls ³²⁾.

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-knockout mice, and was also effective during the early stages of inflammation ³³⁾. 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-knockout mice, and little resolution of inflammation was apparent compared to wild-type or COX-1-knockout mice ³⁴⁾. These findings indicate that both COX isoforms contribute to prostaglandin production during inflammation and also that COX-2-derived prostaglandins 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. ³⁵⁾ reported that COX-2 expression and PGE2 levels increased transiently early in the course of carrageenan-induced pleurisy in rats. Later in the response, COX-2 was induced again to even greater levels and generated anti-inflammatory prostaglandins, such as PGD2 and 15-deoxy-Δ12–14-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. ³⁶⁾ 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. An anti-inflammatory role of COX-2 derived prostanoids has also been reported in models of inflammatory colitis and allergic airway disease ³⁷⁾. 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 ³⁸⁾.

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 ³⁹⁾. This may reflect an impact postnatally of disruption of the many roles of the enzyme in development in COX-2 knockouts; 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) knockout mouse, as does inhibition of COX-1 and COX-2 together in low-density lipoprotein receptor-knockout model ⁴⁰⁾. Thus, products of COX-1 – like TxA2 – promote atherogenesis while there is more ambiguity around the role of COX-2. Nevertheless, deletion of the PGI receptor, the receptor for the major COX-2 product, PGI2, fosters the initiation and early development of atheroscelrosis in hyperlipidemic mice ⁴¹⁾.

What is prostaglandin used for?

Synthetic prostaglandins are used:

• To induce childbirth (parturition) or abortion (PGE₂ or PGF₂, with or without mifepristone, a progesterone antagonist)
  • Prostaglandins placed in your vagina next to your cervix will often ripen, or soften, the cervix, and contractions may even begin. Your baby’s heart rate will be monitored for a few hours. If labor does not begin, you may be allowed to leave the hospital and walk around.
• To prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart defects (PGE₁)
• To prevent and treat peptic ulcers (PGE)
• As a vasodilator in severe Raynaud’s phenomenon or ischemia of a limb
• In pulmonary hypertension
• In treatment of glaucoma (as in bimatoprost ophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity) (PGF2α)
• To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil).
• To treat egg binding in small birds