Health

Eicosanoids: Health & Aging

Eicosanoids: Health & Aging

Eicosanoids are frequently referenced when we speak about how the human body ages. This is because eicosanoids are powerful hormones that have control over other hormones and are the key players in the inflammatory response process. Inflammation is shown to accelerate aging when it occurs chronically and some even say that “aging is just chronic low grade inflammation.” Keeping a balance between good and bad eicosanoids is needed for high level health. 

What is the inflammatory response? 

When tissue in the body is injured or infected, the immune systems initial response is to inflame the affected tissue. The purpose of inflammation is to remove the injuring factors and to restore the structure and function of the damaged tissue.

Acute Inflammation

Immediately after injury there will be a rapid influx of granulocytes, which are white blood cells capable of secreting various granules, such as neutrophils. Granulocytes appearance is followed by immature phagocytic cells called monocytes. The monocytes mature into macrophages, which are the white blood cells that eat particles such as bacteria and viruses.

The acute phase manifests with redness, heat, swelling, and pain in the inflamed tissue. Once the phagocytes remove the harmful substances through phagocytosis, inflammation resolves. During resolution, the granulocytes are removed. The macrophages and lymphocytes return to their original state and their levels decrease. Acute inflammation typically ends with resolution and tissue repair, as opposed to a chronic inflammatory response.

Chronic Inflammation

Occurs when there is repetitive stressors placed on the body such as in smoking, immune disorders, chronic excess exercise, or exposures to toxins in our environments and foods. Chronic inflammation to lead to severe changes of the tissues, remodeling, and possibly reduced function.

What are eicosanoids?

Eicosanoids are 20-carbon fatty acids synthesized from polyunsaturated fatty acids (PUFA) metabolites. They have many roles and act as mediators of inflammation, blood pressure, pain, allergies, immune responses, abortion, cell growth, blood flow, and endocrine function (hormones).

Like most things in the body, there are both good and bad eicosanoids. Good eicosanoids come from omega 3 fatty acids, while bad eicosanoids come from omega 6 fatty acids. Thus, we should aim to eat more omega 3 than omega 6.

Omega 3 is found naturally in fatty fish such as salmon, tuna, mackle, trout, but omega 3 is also being added to many food products such as fortified milk, eggs, juices, and grains. Omega 3 can also be found in the fat from nuts such as walnuts and flaxseed. Though be careful with nuts as they also contain omega 6.

Omega 6 is found in processed foods, fast food, nuts, tofu, oils such as safflower, corn, grapeseed, and soybean, cured meats, creamy foods, baked goods, etc.

When we have more bad eicosanoids than good, our body goes into a chronic state of inflammation, which leads to slew of diseased from Alzheimer’s, cardiovascular disease, high blood pressure, depression and even cancers. In addition, more bad eicosanoids leads to faster aging.

Types of eicosanoids

There are many types of eicosanoids, but some of the most referred to are prostaglandins, thromboxanes, and leukotrienes. Below is an overview of these 3 types.

Prostaglandins

The first eicosanoid discovered in 1936 by Ulf von Euler was the prostaglandin. This is not surprising as prostaglandins are found in almost all tissues and serve as autocrine and paracrine mediators.

The level of prostaglandins in healthy tissues is typically low. However, after acute inflammation, the level of prostaglandins increases. This is because prostaglandins play a major role in the development of the inflammatory response.

In an acute injury, prostaglandin production significantly increases prior to recruitment of leukocytes and immune cells to the injured or damaged site. Prostaglandins are made from arachidonic acid AA through the activity of prostaglandin G/H synthases. These enzymes are more commonly known as cyclooxygenases (COXs).

There are two COX enzymes, COX-1 and COX-2. COX-1 is expressed in all tissues and is the primary enzyme involved in the production of prostaglandins that are involved in maintaining homeostasis. COX-2 is involved in the production of prostaglandins involved in the inflammatory response and pathology. COX-2 is activated by inflammatory stimuli, hormones or growth factors. Both COX isoforms produce prostogladin H2 or PGH2. This is why when you have inflammation you take a COX-2 inhibitor such as advil or asprin.

Prostaglandin Functions

Prostaglandin functions include: blood vessel constriction, platelet aggregation, pain sensitivity, labor induction, menstrual contractions, regulate intraocular pressure, regulate inflammation, regulate calcium movement, regulate hormones, control cell growth, modulate activity of thermoregulatory center of the hypothalamus, alter glomerular filtration rates, regulate gastric acid secretion, alter mucus production and bicarbonate secretion.

Clinical Uses of Prostaglandins: Induce labor, prevent and treat peptic ulcers, vasodilator, treat pulmonary hypertension (high blood pressure in lungs), treat glaucoma, and improve erectile dysfunction.

Prostacyclin (prostaglandin I2 or PGI2): Prostacyclins are lipid mediators that enhance immune activity. Prostacyclins are generated and released by vascular endothelial cells. They are metabolized quickly and thus have a very short half-life of 42 seconds.

Prostacyclins primarily function as strong vasodilators and inhibitors of platelet aggregation. They also inhibit vascular smooth muscle cell proliferation and differentiation. Therapeutically, they are used as pulmonary vasodilators to treat pulmonary hypertension and improve oxygen delivery and uptake in unhealthy individuals. They have also been shown to have anti-inflammatory and anti-metastatic properties.

Clinical Uses of PGI2: PGI2 can be used in treating lung cancer. Analogs of prostacyclin have been shown to activate the PPARδ receptor, resulting in hinderance of non-small cell lung cancer (NSCLC) cell lines. Overexpression has also been shown to increase expression of PPARγ resulting in growth inhibition of NSCLC cell lines.

Pulmonary arterial hypertension is a condition consisting of high blood pressure in the lungs due to the narrowing of blood vessels that connect to and within the lungs. Low levels of PGI2 are observed in pulmonary hypertension and thus many treatments aim to restore PGI2 to normal levels.

Synthetic PGI2, such as epoprostenol, improve the symptoms and blood flow in the lungs. While there are several options available, these treatments tend to be underused due to several obstacles associated with their use. Some obstacles include the need to up-titrate the therapy to identify the proper dose for a given patient, the need for some to be administered intravenously, subcutaneously or through inhalation.

Future Therapies of PGI2: Because of the obstacles, resulting in the underuse of these prostacyclin analogs in treating pulmonary arterial hypertension, several alternatives are being considered. Combination is considered one of the best solutions.

Combination treatment with selective phosphodiesterase ¾ inhibitor tolafentrine has had promising results in animal models of pulmonary arterial hypertension. The use of treprostinil with endothelin receptor antagonist bosentan has been shown to treat more severe forms of pulmonary arterial hypertension.

The greatest improvement to current treatments would be an oral therapy. While a PGI2 analog called beraprost showed promise, it was associated with severe side effects and only a modest improvement in condition. An oral form of treprostinil has also been developed, but like beraprost it also had relatively modest effects. This was in combination with phosphodiesterase inhibitors or endothelin receptor antagonists.

PGD2 and Inflammation: The role of PGD2 in inflammation is not clear, but there is evidence that it promotes inflammation. H-PGDS is a synthase of PGD2 and has been known to induce allergic inflammation. PGD2 also promotes T cell migration through one of its receptors CRTH2 and subsequently exacerbate asthma. However, other studies have found that PGD2 displays anti-inflammatory effects through DP by inhibiting migration and activation of neutrophils, basophils, dendritic cells and T cells.

PGD2 and Tumor Growth: A recent animal study found that mice deficient in H-PGDS, and thus low levels in PGD2, had tumors that grew at an accelerated rate. Tumors in the mutated mice also contained more infiltrating monocytes, macrophages and neutrophils and levels of inflammatory cytokines and chemokines, and accelerated angiogenesis and vascular leakage. These findings suggest that low levels of PGD2 promote tumor growth.

PGD2 and Sleep-Wake Regulation: PGD2 is found in large concentrations in the brain. PGD2 concentrations in the rat brain exhibit circadian fluctuations, meaning that their concentrations were higher during the day when the rat was awake and lower at night when the rats went to sleep.

Injection of PGD2 into the third ventricle of the brain also induced slow-wave sleep and rapid eye movement in rats, similar to that seen during normal sleep. Not surprisingly, PGDS, the synthase of PGD2 is a key enzymatic regulator of sleep. PGDS was found in large concentrations in the membranes surrounding the brain: the arachnoid membrane and the choroid plexus. PGD2 induces sleep by binding to PGD2 receptors in the ventrorostral surface of the basal forebrain.

Prostaglandins and Male Pattern Baldness: PDGS may also play a role in male pattern baldness. PDGS and PGD2 are upregulated in bald scalps. Expression of PGD2 increases nearly 7-fold when hair is in the catagen phase—a phase that signals hair to stop growing. PGD2 also inhibits hair follicle regeneration after wounding. While PGD2 interacts with both GPR44 and PTGDR, only GPR44 is necessary to reduce hair growth.

Prostaglandins and Reproduction: In women, PGD2 synthase H-PGDS and PGD2 receptors are expressed in the placenta and L-PGDS is in amniotic fluid. H-PGDS induces PGD2, which blocks FSH signaling by increasing expression of Fshr and Lhcge receptors. This increase in expression causes activation of Cyp11a1 and Star genes and progesterone secretion.

In men, because L-PGDS is found in high concentrations in the testes and epididymis, it is proposed to play a role in the development and maturation of sperm. However, its role is still relatively unclear. L-PGDS as well as H-PGDS are expressed in Leydig cells (cells in the tissue adjacent to the seminiferous tubules) and mast cells, respectively.

PGE2 and Cancer: PGE2 receptors are prostaglandin E2 receptors 1-4 (EP1-4). As previously mentioned, EGFR is a protein that is transactivated by EP receptors and has been shown to contribute to progression of cancers. Despite inhibition of EGFR, many cancers become resistant to the treatment. One hypothesis is that PGE2 may contribute to EGFR promoted cancers through activation of EP receptors.

In some cancers, like breast cancer, EP1 activity has been shown to act as an anti-metastatic. It is unclear why it has different functions in different cancers. This may be due to the receptor having different functions in different tissues.

EP2 knockout mice have shed some light on the role of the receptor and its activation by PGE2 in cancer. Knockout mice have been found to develop less lung, skin and breast tumors following exposure to carcinogens.

EP2 is also highly expressed in several types of tumors such as colon, prostate, and breast cancer. EP2 is thought to contribute to cancer by promoting angiogenesis through activation of pro-angiogenic factor vascular endothelial growth factor (VEGF). EP2 also promotes the survival and motility of endothelial cells.

PGE2 also supports cancer progression by inhibiting the immune defense against tumors by increasing the concentration of cAMP in T helper cells, which in turn inhibits their activity by reducing interleukin (IL)-2 and interferon (IFN)γ.

The role of PGE2 signaling through EP4 in cancer is the most well-known. It contributes to several cancer promoting processes such as creation of a pro-tumorigenic immune response. Suppressing the function of natural killer cells and cytotoxic T lymphocytes.

EP4 has been shown to promote cell migration and metastasis through formation of the EP4/β-arrestin/c-Src signaling complex and increase cell growth and VEGF production. PGE2 has also been implicated in many other disease states including: inflammation, cardiovascular diseases, kidney disease, and pulmonary fibrosis.

Prostaglandin F2α (PGF2α): Prostagladin F2α or PGF2α is synthesized from a fatty-acid neurotransmitter called anandamide. It is associated with reproduction, glaucoma treatment, hair growth, and CNS function.

PGF2α and Reproduction: PGF2 is best known for its influence on the uterus. In response to high levels of oxytocin, PGF2 is secreted by the uterus which will lead to several effects.

Disintegration of the corpus luteum, a hormone releasing structure that forms in the ovaries temporarily after an ovum is released is one effect. PGF2α also reduces luteal blood flow and the number of luteal cells, influences activity of steroidogenic enzymes, reduces expression of steroidogenic regulatory proteins, increases prostaglandin G/H synthase, inhibits lipoprotein stimulated steroidogenesis, alters membrane fluidity and releases luteal oxytocin.

PGF2, known pharmaceutically as dinoprost, can be used to induce labor or for abortion. Small doses (around 1-4mg/day) stimulate the uterine muscles to contract to promote labor. However, a larger amount (40mg/day) can cause an abortion since the corpus luteum nourishes the fetus in the womb.

PGF2α and Glaucoma: Glaucoma is the progressive deterioration of the visual field caused by damage to the optic nerve. It is the primary cause of blindness. A major factor in the development of glaucoma is high intraocular pressure. Thus, treatments that reduce this pressure are highly sought after. Bimatoprost, an analog of prostamide F2α, has been shown to reduce intraocular pressure in animal studies. Latanoprost, another prostamide analog, is used to treat glaucoma.

PGF2 and Hair Growth: Prostamide F2α analogs have also been studied for their effects on hair growth. Treatment of glaucoma with these therapies resulted in increased eyelash growth for some patients. Bimatoprost is particularly effective compared to latanoprost and is now FDA approved for eyelash growth as Latisse by Allergan Inc.

PGF2 and the Central Nervous System: PGF2α is expressed throughout the brain and spinal cord, especially in the white matter. In the spinal cord, PGF2α exerts proalgesic effects and increases the activity of spinal nociceptive nerves.

PGF2 and Fat: PGF2α was shown to inhibit adipose cell differentiation and function. Use of prostamide analogs as glaucoma also revealed its effects on adipose tissue. Patients treated with bimatopost saw a reduction in the size and appearance of fat pads around the eyes during treatment. This effects is also seen with latanoprost and travoprost, another analog. PGF2α is thought to inhibit adipose tissue function through activation of the Gαq-calcium-calcineurin pathway.

Thromboxanes

The next type of eicosanoid we will talk about is thromboxane. There are two types of thromboxane: thromboxane A2 and thromboxane B2.

The main functions of thromboxane include blood clotting and blood vessel constriction. Thromboxane are synthesized by the Thromboxane-A synthase located primarily in platelets. Thromboxane synthase can also be found in the spleen, lung, kidney, gastric mucosa, decidual tissue, various vascular tissues, and the brain. The synthase converts prostaglandin H2 to thromboxane A2 (TXA2). TXA2 is then further metabolized into a more stable form called thromboxane B2 or TXB2

Leukotrienes

The third eicosanoid is the leukotriene. Leukotrienes are inflammatory lipid mediators and there are four different types; Cysteinyl leukotrienes (LTC4, LTD4, LTE4), Leukotriene B4, Leukotriene G4, and Leukotriene B5.

Leukotrienes are produced in inflammatory cells such as leukocytes (eosinophils, neutrophils, basophils), macrophages, and mast cells.

Cysteinyl leukotrienes (LTC4, LTD4, LTE4): Cysteinyl leukotrienes are peptide-conjugated lipids that primarily function in intestinal and bronchial smooth muscle contraction. They also are known as inflammatory mediators that induce several biological responses.

Leukotrienes and Allergic Rhinitis: CysLTs contribute to allergic rhinitis (AR) by influencing multiple mechanisms including; nasal blood vessel dilation, altering vascular permeability with edema formation, increasing mucus production and secretion, recruiting inflammatory cells into the affected tissue.

Inflammation in response to allergic rhinitis is initiated by mast cells, leukocytes, dendritic cells, monocytes and macrophages. Basophils and mast cells produce the most CysLTs (nearly 100-fold more than other CysLT producing cells). CystLT levels in nasal fluid, urine, the nose and the eyes is significantly higher in patients with AR and allergic responses than healthy individuals.

CysLT1 has been found in many tissues involved in allergic rhinitis inflammation including nasal mucosal interstitial cells, blood vessels, and glandular epithelium.

CysLT2 receptors can be found in a larger range of tissues including the heart, brain, adrenal glands and vasculature. However, they may also contribute to inflammatory responses using mechanisms independent of CysLT1.

CysLT levels are also correlated with several allergic rhinitis symptoms including: sneezing, rhinorrhea (stuffy nose), nasal pruritus (itchy nose), ongestion, itchy throat and palate, eye irritation, rhinoconjunctivitis (inflammation of the eyes and nose).

The effects of CysLT following exposure to allergens is swift. Sneezing often begins within minutes of the exposure. Sneezing has been linked to the release of LTC4. Although it is unclear how CysLTs contribute to nasal pruritus, CysLT receptor anatgonists have been shown to improve itchiness.

LTD4 promotes rhinorrhea rapidly (within 5 min of exposure).Treatments that target CysLT receptors include: Zafirlukast, Montelukast, Pranlukast, and Zafirlukast. These drugs improve nasal congestion, sneezing, rhinorrhea and itchy nose throat and palate.

Montelukast improves both daytime (congestion, rhinorrhea, sneezing, nasal pruritus, tearing; and itchy, red, puffy eyes) and night-time (difficulty sleeping, arousal, congestion during awakening) symptoms of AR.

Pranlukast also improves daytime symptoms. Although it is not well-understood how CysLTs modulate inflammation. There appears to be a feedback loop between inflammatory mediators and CysLTs.

Leukotriene B4: LTB4 is a neutrophil chemoattractant and stimulates leukocyte adhesion to endothelial cells. It binds to two G protein-coupled receptors called leukotriene receptor (BLT)1 and BLT2. BLT1 induces inflammation, cytokine production, phagocytosis and regulates activities against microbes. LTB4 binds strongest with BLT1 and little is known about the effects of LTB4 induced BLT2 activity. However, signaling through both has been shown to increase NFκB activation. BLT1 activation by LTB4 increases expression of MyD88 expression.

Therapies that Target LTB4: There are two types of therapies that target LTB4: Antagonists of LTB4 receptors and inhibitors of the LTA4H enzyme.

Antagonists of LTB4 Receptors: Because the BLT2 receptor had not been discovered yet, many early antagonists targeted both the BLT1 and BLT2.

Etalocib is a small synthetic molecule by Lilly that binds to BLT1 on neutrophils. Etalocib has been studied for its potential therapeutic effects on cancer. In one phase 1 study, it was showed to stabilize cancer development in a few patients. However, when administered with gemcitabine, there was no significant effect on patient survival.

Amelubant is also a synthetic small molecule created by Boehringer Ingelheim. It can be converted into two active forms: BIIL 260 and BIIL 315. Several clinical trials have investigated this drug to investigate its effects on many different diseases including; adult chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), asthma, and cystic fibrosis (CF).

The studies found that the main active form in the blood is BIIL 315. While amelubant was found to reduce macrophage levels in patients with RA, no effects were observed in patients with COPD. However, another study found that BLT1 signaling is not a major contributing component to RA-related inflammation. The study involving children and adults with CF was ended prematurely due to major adverse side effects.

To Recap:

Eicosanoids are complex hormones that impact many aspects of our health. They come in good and bad forms and we should aim to eat more omega 3 than omega 6 to keep more good eicosanoids than bad. Too many bad eicosanoids lead to many diseases, even cancer, and causes accelerated gaining. In addition eicosanoids can be used to treat various diseases.

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Jessica Chrisman

Medical Provider

Health, like anything we do in life, is the accumulation of a bunch of small everyday decisions. When you make the choice to be healthy, you are committing to a lifestyle rather than a short cut. This doesn’t mean your life has to be overly restrictive and you can’t have cheat days, it just ...

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