Lakhasly

On this page Chapters and Articles You might find these chapters and articles relevant to this topic.Hormones and growth factors A.S. Cole B.Sc., Ph.D., J.E. Eastoe D.Sc., Ph.D., F.D.S.R.C.S., D.I.C.A.R.C.S., in Biochemistry and Oral Biology (Second Edition) , 1988

Synthesis of prostaglandins The enzyme primarily responsible for the synthesis of prostaglandins is cyclooxygenose which converts arachidonic acid into endoperoxide intermediates (PGG and PGH) which are the immediate precursors not only of prostaglandins PGE and PGF but also of thromboxane and prostacyclin (Figure 24.10).Physiology G.F.M. Ball, in Encyclopedia of Food Sciences and Nutrition (Second Edition) , 2003

Prostaglandin Synthesis The prostaglandins (PG) are a group of hormone-like lipids formed in the body from derivatives of essential fatty acids, particularly arachidonic acid (20:4n-6).Decidua expresses both synthesizing and some metabolizing enzymes, but little overall change occurs in the capacity for prostaglandin synthesis with labor, and the levels of PGHS-2 and PGE isomerase are much lower in decidua compared with levels in amnion and chorion (451,453).In myometrial samples obtained from the lower segment, some workers reported that there was no significant change in the levels of PGHS-1 or PGHS-2 during labor at term or preterm (463,464), whereas others found that PGHS-2 mRNA expression increased with advancing gestation but did not change further with labor (461,462).The high PGDH activity in chorion trophoblasts forms a metabolic barrier preventing the passage of prostaglandins generated in the amnion or chorion from reaching the underlying decidua or myometrium.It should be noted that PGHS-2 is required for production of PGI2 (an inhibitory prostaglandin), as well as PGE2 and PGF2?, and PGI synthase expression was found to decrease in the myometrium with advancing gestation, although there was no change in the expression of PGES (90).Furthermore, if regional differences in prostaglandin synthase activity occur at the time of labor, measurements made on tissue obtained from the lower segment may not be representative of changes observed in the fundal region.Also, in vitro studies with isolated human myometrial cells indicate that stretch can upregulate expression of PGI synthase, resulting in increased PGI2 levels, but had no effect on PGE2 or PGF2?Prostaglandins have, potentially, very important applications in a wide range of clinical conditions, e.g. in the treatment of hypertension and thrombosis, as well as for contraception, the induction of abortions and the relief of asthma and peptic ulcers.It has been proposed that this deficiency might allow prostaglandins generated in amnion or chorion to pass unmetabolized to the underlying decidua and myometrium and provoke uterine contractility (456).Taken together, these studies would be consistent with a decrease in production of the inhibitory PGI2 and a decrease in metabolism of prostaglandins, resulting in increases in local levels of stimulatory prostaglandins, in the myometrium during labor.The functionally prevalent form of PGHS that increases with advancing gestation and with labor at term and preterm is PGHS-2 (457), although increased levels of PGHS-1 mRNA were also found in the chorion at these times.Parturition William Gibb, ... John R.G. Challis, in Knobil and Neill's Physiology of Reproduction (Third Edition) , 2006

Prostaglandin Synthesis.The cPLA2 enzyme with its specificity for arachidonic acid-containing phospholipids is the most extensively studied phospholipase in relation to parturition.The cPLA2 enzyme is expressed in the placenta, amnion, chorion, and myometrium, with the highest levels in the fetal membranes (437-439).At term, if the prostaglandins produced in the amnion and chorion are to access the myometrium, the synthetic activity of amnion/chorion would need to exceed the metabolic potential of chorionic trophoblasts.The synthesis of prostaglandins

The rate of PG production seems to be determined by the concentration of free essential fatty acids (page 123), chiefly arachidonic acid.PG synthesis is inhibited by anti-inflammatory agents such as aspirin, indomethacin and acetaminophen which inhibit cyclooxygenase.This effect occurs over the physiological range of vitamin C concentrations and is desirable because PGE1 is an inhibitor of platelet aggregation.PGE1 is also required for T lymphocyte formation, regulation of collagen and cholesterol metabolism, and regulation of responsiveness to insulin.sPLA2 levels are also elevated in maternal plasma and amniotic fluid in patients delivering preterm (445,446).In one study, sPLA2 and cPLA2 in the myometrium were unchanged with term or preterm labor (439), but others found that sPLA2 mRNA, although not cPLA2 mRNA, expression increased with gestational age and term labor in both the upper and lower segment of the myometrium (449).There is also a decrease in PGDH expression during labor in the region of the chorion overlying the cervix, and this may enable prostaglandins from the amnion and chorion to access the cervix (458).Studies on prostaglandin synthesis in myometrium during gestation are confusing, in part because of the difficulty in obtaining appropriate tissue for examination.In the baboon, the earliest change occurs with increased expression of PGHS-2 mRNA in the lower uterine segment and the cervix (467).

On this page
Chapters and Articles
You might find these chapters and articles relevant to this topic.

Hormones and growth factors
A.S. Cole B.Sc., Ph.D., J.E. Eastoe D.Sc., Ph.D., F.D.S.R.C.S., D.I.C.A.R.C.S., in
Biochemistry and Oral Biology (Second Edition)
, 1988

Synthesis of prostaglandins
The enzyme primarily responsible for the synthesis of prostaglandins is cyclooxygenose which converts arachidonic acid into endoperoxide intermediates (PGG and PGH) which are the immediate precursors not only of prostaglandins PGE and PGF but also of thromboxane and prostacyclin (Figure 24.10). Presumably the nature of the end product is determined by the enzyme system present in the tissue in question.

Sign in to download full-size image
Figure 24.10. The synthesis of prostaglandins

The rate of PG production seems to be determined by the concentration of free essential fatty acids (page 123), chiefly arachidonic acid. This, in turn, depends on the relese of the essential fatty acids from position 2 of cellular phospholipids. The enzyme responsible for this release is phospholipase A which is activated when the cell is injured. PG synthesis is inhibited by anti-inflammatory agents such as aspirin, indomethacin and acetaminophen which inhibit cyclooxygenase.

Prostaglandins have, potentially, very important applications in a wide range of clinical conditions, e.g. in the treatment of hypertension and thrombosis, as well as for contraception, the induction of abortions and the relief of asthma and peptic ulcers. However, much more work needs to be done before they can be put to routine use.

ASCORBIC ACID | Physiology
G.F.M. Ball, in
Encyclopedia of Food Sciences and Nutrition (Second Edition)
, 2003

Prostaglandin Synthesis
The prostaglandins (PG) are a group of hormone-like lipids formed in the body from derivatives of essential fatty acids, particularly arachidonic acid (20:4n-6). Prostaglandins have a vast range of effects and modulate cardiovascular, pulmonary, immune, and reproductive functions. Vitamin C stimulates the formation of PGE1 from dihomo-γ-linolenic acid in human platelets. This effect occurs over the physiological range of vitamin C concentrations and is desirable because PGE1 is an inhibitor of platelet aggregation. PGE1 is also required for T lymphocyte formation, regulation of collagen and cholesterol metabolism, and regulation of responsiveness to insulin. There are sufficient data to suggest that some of vitamin C's biological actions could be explained by a regulatory effect on prostaglandin synthesis.

Parturition
William Gibb, ... John R.G. Challis, in
Knobil and Neill's Physiology of Reproduction (Third Edition)
, 2006

Prostaglandin Synthesis.
The initial step in prostaglandin synthesis is the release of arachidonic acid from phospholipids by the action of phospholipases. During pregnancy, the roles of sPLA2-IIA and the arachidonic acid–specific cPLA2α have received considerable attention (431,436). However, studies on the expression of phospholipases during gestation and labor are often contradictory.

The cPLA2 enzyme with its specificity for arachidonic acid–containing phospholipids is the most extensively studied phospholipase in relation to parturition. The cPLA2 enzyme is expressed in the placenta, amnion, chorion, and myometrium, with the highest levels in the fetal membranes (437–439). In human amnion, cPLA2 is the principal enzyme involved in arachidonic acid release. cPLA2 activity in amnion increases with gestation but decreases during labor at term and preterm (440).

Secretory PLA2 is released from the placenta, human fetal membranes, and myometrium during gestation, but its role is undefined (434). In the placenta, type II sPLA2 predominates (437,441). Type II sPLA2 was found to increase in placenta with labor in one study, but not in another (442,443). It has been proposed that the change in sPLA2 activity that occurs in placenta with labor is due to post-translational modification caused by annexin-1, which inhibits the enzyme (443). In preterm labor tissues (amnion and choriodecidua), sPLA2 content is higher than in preterm tissues that were not in labor (444). sPLA2 levels are also elevated in maternal plasma and amniotic fluid in patients delivering preterm (445,446). It has been proposed that this increase is due to the action of bacterial endotoxin in infection-induced preterm labor (434,447,448). In one study, sPLA2 and cPLA2 in the myometrium were unchanged with term or preterm labor (439), but others found that sPLA2 mRNA, although not cPLA2 mRNA, expression increased with gestational age and term labor in both the upper and lower segment of the myometrium (449).

Once arachidonic acid is released from phospholipids, it is acted on by PGHS. The inducible form of PGHS, PGHS-2, appears to play an important role in human parturition, as it does in other species. In amnion, PGHS activity predominates and PGE2 is the major prostaglandin formed. The levels of PGHS-2 but not PGHS-1 mRNA and protein increase with advancing gestation and during preterm and term labor (450–452). In contrast, membrane-bound PGE isomerase (mPGES) levels do not change with term or preterm labor (453,454). The 3′ untranslated region of PGHS-2 mRNA contains sequences that confer instability in the message. Therefore, the observed increase in mRNA levels could be due to increased transcription or decreased degradation, or a combination of both. It was demonstrated that the level of PGHS-2 mRNA in term amnion is regulated at the transcriptional level (455). Labor did not increase PGHS-2 gene expression or mRNA stability, suggesting that upregulation of transcription occurred before labor, generating stable mRNA that continues to accumulate during labor.

In chorion, PGHS is expressed, but in contrast to the amnion there are very high levels of PGDH (456). The functionally prevalent form of PGHS that increases with advancing gestation and with labor at term and preterm is PGHS-2 (457), although increased levels of PGHS-1 mRNA were also found in the chorion at these times. The high PGDH activity in chorion trophoblasts forms a metabolic barrier preventing the passage of prostaglandins generated in the amnion or chorion from reaching the underlying decidua or myometrium.

Decidua expresses both synthesizing and some metabolizing enzymes, but little overall change occurs in the capacity for prostaglandin synthesis with labor, and the levels of PGHS-2 and PGE isomerase are much lower in decidua compared with levels in amnion and chorion (451,453). Decidual prostaglandin production may in fact result from constitutive expression of PGHS-1 rather than induction of PGHS-2.

At term, if the prostaglandins produced in the amnion and chorion are to access the myometrium, the synthetic activity of amnion/chorion would need to exceed the metabolic potential of chorionic trophoblasts. Certain patients who delivered preterm were found to have a relative deficiency of PGDH in chorion (456). It has been proposed that this deficiency might allow prostaglandins generated in amnion or chorion to pass unmetabolized to the underlying decidua and myometrium and provoke uterine contractility (456). There is also a decrease in PGDH expression during labor in the region of the chorion overlying the cervix, and this may enable prostaglandins from the amnion and chorion to access the cervix (458).

Studies on prostaglandin synthesis in myometrium during gestation are confusing, in part because of the difficulty in obtaining appropriate tissue for examination. It is likely that enzyme expression varies according to the region of the myometrium sampled, or with the proximity of the patient to labor. Increases, decreases, and no changes in PGHS-2 mRNA levels in myometrium at labor have been reported (459–462). Using in situ hybridization, PGHS-2 expression was found to decrease in labor both at term and preterm (459). In contrast, other investigators found that PGHS-2 mRNA increased with labor (460). In myometrial samples obtained from the lower segment, some workers reported that there was no significant change in the levels of PGHS-1 or PGHS-2 during labor at term or preterm (463,464), whereas others found that PGHS-2 mRNA expression increased with advancing gestation but did not change further with labor (461,462). In contrast, PGDH activity in the myometrium decreases during labor (463). It should be noted that PGHS-2 is required for production of PGI2 (an inhibitory prostaglandin), as well as PGE2 and PGF2α, and PGI synthase expression was found to decrease in the myometrium with advancing gestation, although there was no change in the expression of PGES (90). Taken together, these studies would be consistent with a decrease in production of the inhibitory PGI2 and a decrease in metabolism of prostaglandins, resulting in increases in local levels of stimulatory prostaglandins, in the myometrium during labor. Furthermore, if regional differences in prostaglandin synthase activity occur at the time of labor, measurements made on tissue obtained from the lower segment may not be representative of changes observed in the fundal region. Also, in vitro studies with isolated human myometrial cells indicate that stretch can upregulate expression of PGI synthase, resulting in increased PGI2 levels, but had no effect on PGE2 or PGF2α levels (465). This may therefore be an important way in which the quiescence of the myometrium is maintained during expansion of the uterus with advancing gestation. In placenta, PGHS synthase and PGDH are also expressed, but there are no changes in activity or expression with labor.

The baboon and rhesus monkey are important models for human parturition (466). Because myometrial activity can be monitored continuously in these animals, investigators can define more precisely the stages of labor than is possible in human pregnancy. In the baboon at late gestation and during labor, there is an increase in the PGHS enzyme, specifically the PGHS-2 isoform. The expression of other enzymes involved in prostaglandin synthesis does not change. Thus, the increase in the PGHS-2 isoform would appear to occur in all species studied to date. In the baboon, the earliest change occurs with increased expression of PGHS-2 mRNA in the lower uterine segment and the cervix (467). This increase occurs well before labor. It has been proposed that the increase in forebag prostaglandin concentrations as a result of this activation is responsible for preparing the cervix and lower birth canal at term (466). In the baboon, estrogen concentrations increase approximately 10 days before labor and may be responsible for the induction of the PGHS-2 before labor (468). Further studies have suggested that local paracrine factors may also be involved through stretch-induced mechanisms (466).