Arachidonic acid - Wikipedia
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid (ω-6), PTGS2}) metabolize arachidonic acid to prostaglandin G2 and prostaglandin .. "Relationship of plasma polyunsaturated fatty acids to circulating. Arachidonic acid (AA) is a homeostatically important omega-6 long-chain, polyunsaturated Then under the influence of terminal synthases, prostaglandins. The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid.
Functions of Prostaglandins There are a variety of physiological effects including: Activation of the inflammatory response, production of pain, and fever.
When tissues are damaged, white blood cells flood to the site to try to minimize tissue destruction. Prostaglandins are produced as a result. Blood clots form when a blood vessel is damaged. A type of prostaglandin called thromboxane stimulates constriction and clotting of platelets.
Conversely, PGI2, is produced to have the opposite effect on the walls of blood vessels where clots should not be forming. Certain prostaglandins are involved with the induction of labor and other reproductive processes. PGE2 causes uterine contractions and has been used to induce labor.
Prostaglandins, arachidonic acid, and inflammation.
Prostaglandins are involved in several other organs such as the gastrointestinal tract inhibit acid synthesis and increase secretion of protective mucusincrease blood flow in kidneys, and leukotriens promote constriction of bronchi associated with asthma. Low-dose aspirin therapy for prevention of preeclampsia Early studies evaluating low-dose aspirin therapy for the prevention of preeclampsia reported dramatic decreases in the incidence of preeclampsia.
The initial report based on intent to treat of the NICHD Maternal—Fetal Medicine Unit Network trial of low-dose aspirin to prevent preeclampsia in nulliparous women found a modest reduction in the incidence of preeclampsia from 6. If only one-half of the patients in the treatment group are compliant in taking the test compound, the effectiveness of the compound is not being adequately evaluated.
Meta-analysis of low-dose aspirin trials demonstrates that aspirin is effective in preventing preeclampsia. Incidence of preeclampsia in relation to compliance of women on low-dose aspirin therapy. Pill compliance was significantly associated with a beneficial effect of aspirin for prevention of preeclampsia. Reanalysis of the data based on percentage of pill compliance of the aspirin group revealed a significant decrease in the incidence of preeclampsia from 5. Modified from Walsh SW.
Women in whom hypertension is destined to develop in pregnancy are more responsive to the vasoconstrictive effects of AII. The ratio of thromboxane to prostacyclin is positively correlated with maternal mean blood pressure: Low-dose aspirin therapy to lower the ratio of thromboxane to prostacyclin results in lower blood pressure.
In women with preeclampsia, low-dose aspirin therapy decreases systolic, diastolic, and mean blood pressures. Several comprehensive reviews have been published on this subject. These should be consulted for more detailed descriptions of the role of prostaglandins in labor. Evidence for prostaglandins in labor Three primary lines of evidence indicate the importance of prostaglandins to the process of labor: Inhibition of prostaglandin synthesis with cyclooxygenase inhibitors, such as indomethacin, flufenamic acid, or aspirin, inhibits uterine contractility, prolongs the length of gestation, and prolongs the duration of labor in monkeys and women.
Unlike the uterine responsiveness to oxytocin that is manifest at term, the human uterus contracts to prostaglandins at any stage of pregnancy and also during the nonfertile cycle. Prostaglandin production is increased at the time of labor but not before.
The amnion is a rich source of phosphatidylethanolamine and phosphatidylinositol, and these phospholipids appear to be the major source of arachidonate for human parturition. Phospholipase A2 acts on phosphatidylethanolamine to release arachidonate, and phospholipase C acts on phosphatidylinositol to release arachidonate-rich diacylglycerol, which then is further metabolized by diacylglycerol and monoacylglycerol lipases to yield arachidonic acid.
The specific activities of phospholipase A2 and phospholipase C are increased in amnion at term compared with during midgestation. In sheep, the fetus is the initiator of parturition.
In a beautiful set of classic ablation and endocrine experiments, Liggins and colleagues established the sequence of events initiated by the ovine fetus that results in parturition.
A summary diagram is presented in Fig. Briefly, the sequence of events is as follows: Fetal hypophysectomy or adrenalectomy results in a prolongation of gestation in sheep, whereas fetal ACTH or glucocorticoid infusion results in premature labor.
Schematic diagram of the pathway by which the fetal lamb influences endocrine events in the ewe. Also shown are experimental procedures that have been used to modify the activity of the pathway. The mechanism of initiation of parturition in the ewe. Recent Prog Horm Res ; In primates, the role of the fetus in parturition is less clear. Human anencephalic fetuses and monkey experimental anencephalic fetuses are born at an average gestational length that is not significantly different from healthy intact fetuses.
There is, however, a significant disruption in the timing of birth, with more fetuses born prematurely or postmaturely. Glucocorticoid administration to pregnant women or monkeys does not induce premature labor as it does in sheep. The fetus of primates does not play the key role in initiating labor as it does in sheep. However, the primate fetus does play an important role in influencing the timing of birth to ensure that it is not born too early or too late.
The mechanisms through which the primate fetus influences the timing of birth are not known, but they may involve nocturnal activity of the fetal adrenal glands.
In the monkey, fetal adrenal activity increases at night because of the release of negative feedback inhibition from transplacental passage of maternal cortisol. Dexamethasone administration not only suppresses fetal adrenal activity, but also abolishes the nocturnal increase in uterine activity, as does death of the fetus. Women, if allowed to deliver naturally, also have a nocturnal rhythm in uterine activity, with the onset of labor contractions being most frequent at night.
Studies in nonhuman primates demonstrate that the increase in fetal adrenal activity at night results in an increase in the circulating levels of dehydroepiandrosterone sulfate DHEAS and androstenedione, which then are converted to estrogens by the placenta. For example, estrogen stimulates the maternal secretion of oxytocin and increases the number of receptors for oxytocin in the myometrium.
Estrogen also stimulates the production of prostaglandins and the formation of gap junctions in the myometrium.#25 - The chemicals of inflammation - Arachidonic Acid,Prostaglandins,Leukotrienes,Lipoxins
Uterine muscle becomes more irritable under the influence of estrogen. The nocturnal rhythm in uterine contractility is under the influence of a nocturnal increase in the maternal circulating levels of oxytocin.
Several other stimulators of prostaglandin synthesis have been identified. Epidermal growth factor EGF stimulates PGE2 output by amniotic cells, increases the rate of synthesis of cyclooxygenase in amnion, and stimulates uterine contractility in estrogen-primed rats. Neutrophils are also a source of prostaglandins at the time of labor. Labor is associated with extensive infiltration of neutrophils into the decidua and myometrium.
Interleukin-8, a potent neutrophil chemokine, and COX-2, the inducible form of cyclooxygenase, were two key inflammatory genes with increased expression early in the labor process. Inhibitors of prostaglandin synthesis An alternative hypothesis to parturition being initiated by stimulators of prostaglandin synthesis is that pregnancy is maintained until the time for delivery by inhibitors of prostaglandin synthesis.
At the time of delivery, the inhibitors are removed or overwhelmed by the appearance of prostaglandin stimulators. Inhibitors of prostaglandin synthesis have been identified in human amniotic fluid.
This corresponds to a simultaneous increase in the activity of stimulators of prostaglandin synthesis in the amniotic fluid. The inhibitory actions appear to be exerted either at the cyclooxygenase enzyme or at the phospholipase A2 enzyme. The chemical identities of the inhibitors are not known, but at least one appears to be similar to lipomodulin lipocortin, macrocortinthe inhibitory protein active against phospholipase A2 that is stimulated by the glucocorticoids.
The pregnancy factors responsible for regulating the prostaglandin synthesis inhibitors are not known. Steroids In many nonprimate species e. Overt changes such as these in maternal peripheral blood do not occur in human or nonhuman primate pregnancy, so the concept that progesterone withdrawal precedes labor has been questioned for primates.
Progesterone withdrawal may, however, occur locally within the intrauterine tissues. Estrogens also are formed in these tissues, and they inhibit this enzyme system. At the time of labor, there is a decrease in the formation of progesterone from pregnenolone within the decidua and chorion. At the same time, there is an increase in the activity of the estrone sulfatase enzyme in decidua and chorion.
Another possibility for progesterone withdrawal involves an alteration in progesterone receptors in the myometrium. Progesterone maintains uterine quiescence by binding to the progesterone receptor PR -B isoform. Presence of the PR-A isoform antagonizes the relaxing action of progesterone.
The arachidonic acid cascade. The prostaglandins, thromboxanes and leukotrienes.
Evidence suggests that the change in progesterone receptors is mediated by prostaglandins. Arachidonic acid also can be metabolized by the lipoxygenase enzymes in the human amnion, chorion, decidua, and placenta to form HETEs and leukotrienes.
Furthermore, serial measurements of amniotic fluid 5-HETE demonstrated that its concentrations were altered in association with uterine contractions and labor. InRomero and others reported that HETE, HETE, and LTB4 all were present in human amniotic fluid at term and that all were significantly higher in amniotic fluid collected from women in labor compared with women not in labor at term.
Labor contractions were nocturnal. On days 1 and 0, the mother demonstrated labor types of behavior characteristic of rhesus monkeys i. A male fetus, g, was delivered late in the evening on day 0. Hatch marks on X-axis indicate midnight or The concentrations of LTC4 in amniotic fluid of monkeys also increase significantly with the onset of labor Fig.
Amniotic fluid levels of 5-HETE and LTC4, however, increased progressively until the onset of labor and rupture of the amniotic fluid sac.
This demonstrates that labor can occur in the absence of prostaglandins with the presence of HETEs and leukotrienes. There are so few data available for the lipoxygenase compounds in association with pregnancy and labor that one can only speculate as to their physiologic functions.
The HETEs are best known for their chemokinetic and chemotaxic actions on leukocytes. LTC4 is best known for its potent smooth-muscle stimulating activity. Liggins has likened cervical ripening at the time of labor to an inflammatory reaction. Considerable evidence now exists that the entire parturitional process is an inflammatory reaction. The arachidonic acid metabolites are important compounds in pregnancy.
They affect maternal blood pressure and blood flow to the uterus, placenta and umbilical—fetal circulation. In preeclampsia, there is an imbalance of increased thromboxane and decreased prostacyclin production that helps explain many of the clinical symptoms of this disorder, such as hypertension, platelet aggregation, and reduced uteroplacental blood flow.
Low doses of aspirin selectively inhibit thromboxane without affecting prostacyclin, and all clinical trials with low-dose aspirin for the prevention of preeclampsia show a decreased incidence. The arachidonic acid metabolites also are important compounds for parturition. Prostaglandins stimulate uterine contractility, and there is considerable evidence about their role in the process of labor.
However, while COX-1 and COX-2 are both located in the blood vesselsstomach and the kidneysprostaglandin levels are increased by COX-2 in scenarios of inflammation and growth. Several prostaglandin E synthases have been identified. To date, microsomal prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE2. Other terminal prostaglandin synthases[ edit ] Terminal prostaglandin synthases have been identified that are responsible for the formation of other prostaglandins.
A thromboxane synthase TxAS has also been identified. Functions[ edit ] 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.