Ibuprofen belongs to the class of medications known as nonsteroidal anti-inflammatory drugs (NSAIDs). It is used to treat fever and mild-to-moderate pain caused by inflammation. It is believed to work by stopping the production of prostaglandins, which cause inflammation.
WHAT ARE PROSTAGLANDINS?
Unlike most hormones, the prostaglandins are not secreted from a gland to be carried in the bloodstream and work on specific areas around the body. Instead, they are made by a chemical reaction at the site where they are needed and can be made in nearly all the organs in the body. Prostaglandins are part of the body’s way of dealing with injury and illness.
The prostaglandins act as signals to control several different processes depending on the part of the body in which they are made. Prostaglandins are made at sites of tissue damage or infection, where they cause inflammation, pain and fever as part of the healing process. When a blood vessel is injured, a prostaglandin called thromboxane stimulates the formation of a blood clot to try to heal the damage; it also causes the muscle in the blood vessel wall to contract (causing the blood vessel to narrow) to try to prevent blood loss. Another prostaglandin called prostacyclin has the opposite effect to thromboxane, reducing blood clotting and removing any clots that are no longer needed; it also causes the muscle in the blood vessel wall to relax, so that the vessel dilates. The opposing effects that thromboxane and prostacyclin have on the width of blood vessels can control the amount of blood flow and regulate response to injury and inflammation.
Prostaglandins are also involved in regulating the contraction and relaxation of the muscles in the gut and the airways.
Prostaglandins are known to regulate the female reproductive system, and are involved in the control of ovulation, the menstrual cycle and the induction of labour. Indeed, manufactured forms of prostaglandins - prostaglandin E2 and F2 can be used to induce (kick-start) labour.
What happens if I have too much prostaglandins?
High levels of prostaglandins are produced in response to injury or infection and cause inflammation, which is associated with the symptoms of redness, swelling, pain and fever. This is an important part of the body’s normal healing process.
However, this natural response can sometimes lead to excess and chronic production of prostaglandins, which may contribute to several diseases by causing unwanted inflammation. This means that drugs, which specifically block cyclooxygenase-2, can be used to treat conditions such as arthritis, heavy menstrual bleeding and painful menstrual cramps and certain types of cancer, including colon and breast cancer. New discoveries are being made about cyclooxygenases which suggest that cyclooxygenase-2 is not just responsible for disease but has other functions.
Anti-inflammatory drugs, such as aspirin and ibuprofen, work by blocking the action of the cyclooxygenase enzymes and so reduce prostaglandin levels. This is how these drugs work to relieve the symptoms of inflammation. Aspirin also blocks the production of thromboxane and so can be used to prevent unwanted blood clotting in patients with heart disease.
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.
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.
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.
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.
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 . 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.
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 ...
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 . 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 . Redness and edema result from increased blood flow into the inflamed tissue through PGE2-mediated augmentation of arterial dilatation and increased microvascular permeability . Pain results from the action of PGE2 on peripheral sensory neurons and on central sites within the spinal cord and the brain
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
PGI2 is a potent vasodilator, and an inhibitor of platelet aggregation, leukocyte adhesion, and VSMC proliferation . PGI2 is also anti-mitogenic and inhibits DNA synthesis in VSMC . These actions of PGI2 are mediated through specific IP receptors . This receptor is expressed in kidney, liver, lung, platelets, heart, and aorta . 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. 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
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 . In the brain, PGD2 is involved in the regulation of sleep and other CNS activities, which includes pain perception . In peripheral tissues, PGD2 is produced mainly by mast cells, but also by other leukocytes, such as DCs and Th2 cells . 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
Prostaglandin F2α and inflammation
PGF2α 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
PGF2α, 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 . Recent studies have shown that PGF2α also plays a significant role in renal function , contraction of arteries , myocardial dysfunction , brain injury and pain
Administration of PGF2α leads to acute inflammation, and NSAIDs inhibit PGF2α biosynthesis both in vitro and in vivo
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 PGF2α metabolites, together with IL-6 and acute phase proteins in body fluids
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.
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081099/)
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