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| Prostaglandins, Enzymes and Cells |
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Prostaglandins (PG’s) are short-lived, hormone-like chemicals that regulate cellular activities on a moment-to-moment basis. PG’s are made due to the enzyme-controlled oxidation of highly unsaturated fatty acids.(see figures) The precision of enzyme-controlled
oxidation varies significantly from the random oxidation of fatty acids in air. PG’s fall into 3 series - PG1,
PG2, and PG3. Series 1 & 2 are produced from omega-6 (linoleic acid - LA), while
Series 3 is produced from omega-3 (alpha-linolenic acid - ALA) The following table lists the
physiological effects of Series 1 & 3 prostaglandins (the “Good”) and Series
2 prostaglandins (the “Bad”).
It is quite evident that asthmatics would likely benefit from an increase in Series 1 and Series 3 PG’s, and a decrease in Series 2 PG’s. Enzymes in Prostaglandin Production The enzymes which act as catalysts in
prostaglandin production include elongase (which elongates the carbon chain by adding
carbon atoms), and delta-6-desaturase and delta-5-desaturase (which both desaturate the
carbon chain by removing hydrogen atoms). The health of delta-6-desaturase enzymes are dependent upon sufficient amounts of B6, magnesium and zinc. Deficiencies in any of these nutrients (NB - all of these deficiencies are commonly found in asthmatics - link to B6, magnesium and zinc) can hinder the omega-3 and omega-6 pathways. Likewise, the delta-6-desaturase
enzymes are inhibited by stress, disease, increased insulin levels (as found in high
carbohydrate diets), trans fatty acids (like those found in margarine), saturated fats,
and alcohol. Delta-5-desaturase enzymes are responsible for the conversion of dihommo-gamma-linoleic acid (DGLA) into arachidonic acid (omega-6 pathway), and eicosatetraenoic acid into eicosapentaenoic acid (EPA;omega-3 pathway). Delta-5-desaturase enzymes require sufficient levels of vitamin C, niacin (B3), and zinc. They also are activated by increased insulin levels. It is suggested that deficiencies in any one of the following - vitamin C, niacin (B3), pyroxidine (B6), zinc, or magnesium - would result in a decrease in the enzyme conversion of essential fatty acids, and would therefore result in an increased state of inflammation in the body. Protective
Effect of EFA’s on Asthma Delta-5-desaturase prefers the omega-3 pathway with which to interact. By preferring this pathway, sufficient omega-3 in the diet helps provide for the proper upregulation of PGE1 and PGE3, while simultaneously downregulating PGE2. Sufficient omega-3
in the diet then is critical to proper prostaglandin metabolism, and therefore,
deficiencies in omega-3 fats would suggest that higher levels of inflammation in the body
would be present. There should be a healthy balance, between omega-3 and omega-6 fatty acids in the diet. If the above is true, there should be
evidence to show an anti-inflammatory effect on asthma when ratios of omega-3 to omega-6
are better balanced. The following studies support this hypothesis. The protective effect of EFA’s on asthma have been shown in a number of studies over the past few years. Masuev’s placebo-controlled study showed significant attenuation of late allergic response in atopic bronchial asthma (ABA). The effects were explained due to the
comparative replacement of arachidonic acid (AA), a pro-inflammatory prostaglandin
of the PGE2 series, by polyunsaturated fatty acids of the omega-3 class in the
membranes of cell effectors, leading to the inhibition of the production of
inflammatory lipid mediators.3
AA is produced as a result of LA metabolism (see figure). PGE2 prostaglandins are a primary influence in inflammatory conditions such as asthma. AA is controlled on a cellular level
by PGE1 and PGE3 (both anti-inflammatory prostaglandins). Both inhibit the release of AA
from cell membranes where it is stored. As long as AA is kept in cells, it can’t be
converted to inflammation creating PGE2’s. PGE3’s are made from
eicosapentaenoic acid (EPA;omega-3 pathway). EPA prevents AA from being released from
membranes thereby limiting inflammation. Other controlled studies support the hypothesis
that this inhibition is of benefit to asthma patients.
Positive clinical changes were shown
by Gorelova, et al., in cellular and humoral
immunity status and eicosonoids synthesis in a group of patients receiving omega-3 biologically active supplements. 4
Villani, et al., reported bronchial
responsiveness to ultrasonically nebulized distilled water (UNDW) was significantly
improved by omega-3 supplementation (-11% vs -28%
before treatment). Maximum increase in airway resistance (RA) was +137% vs +265% before
treatment. 5
Another placebo controlled study by
Masuev, found supplementation with ALA decreased
frequency of severe attacks of asphyxia and allowed decrease in drug doses. A significant
decline of late allergic response was also shown, due to competitive replacement of
arachidonic acid in cell membranes of inflammation cell effectors by omega-3
PUFA inhibiting production of lipid mediators of inflammation. 6 C Maple and colleagues reported that white blood cell aggregation is significantly reduced with 3 month’s dietary supplementation with a combination of omega-3 and omega-6 fatty acids. They suggest that EFA’s may have other anti-inflammatory actions in addition to their role as modulators of mediator production. 7 KM Brown, et al., in a placebo-controlled study in 1998, showed the importance of sufficient levels of essential fatty acids and the associated benefits of adequate ratios of vitamin E to polyunsaturated fatty acids (PUFA) to protect cell membranes from oxidative damage. Their conclusion included the finding
that there was a significant correlation between susceptibility to peroxidation and the
PUFA content of red blood cells before supplementation with vitamin E, which suggested an
inadequate intake of vitamin E in relation to PUFA intake. 8
D Wu and colleagues at Tufts
University report that vitamin E supplementation in
old mice reversed the increased PGE2 production. Vitamin E completely reversed the
increased cyclo-ogygenase (COX) activity in macrophages.149 In another animal study, conducted by
AA Beharka, et al., it was reported that vitamin E decreased
PGE2 production, improved T cell proliferation and IL-2 production. 152 T Yano and associates demonstrated
that vitamin E induced decrease in PGE2 levels
probably contributes to the inhibition of ornithine decarboxylase induction and the
prevention of tumor development in the lungs of mice. 150 The effect on PGE2 levels of the balance between omega-3 to omega-6 fatty acids, was shown in a study by Wander et al., of Oregon State University, on dogs. They studied the effects of experimental diets containing (n-6) to (n-3) fatty acid ratios of 31:1, 5.4:1, and 1.4:1 to 20 healthy female geriatric Beagles. Compared with the 31:1 diet, consumption of the 5.4:1 and 1.4:1 diets significantly increased (n-3) fatty acids in plasma (2.17, 9.05 and 17.46 g/100 g fatty acids, respectively). After consumption of the 1.4:1 diet, stimulated mononucleur cells produced 52% less prostaglandin E2 (PGE2) than those from dogs fed the 31:1 diet. Plasma concentration of alpha-tocopherol was 20% lower in dogs fed the 1.4:1 diet compared to the 31:1 diet and lipid peroxidation was greater. These data suggest that although a ratio of dietary (n-6) to (n-3) fatty acids of 1.4:1 depresses the cell-mediated immune response and PGE2 production, it increases lipid peroxidation and lowers vitamin E concentration. This is in agreement with Brown et
al.’s 8 conclusion that suggests vitamin E
supplementation may be helpful in conjunction with omega-3 supplementation.
151 Vitamin E has been shown to reduce the augmentation in eicosanoid production usually observed when alveolar macrophages (AM) are exposed to mine dust. Demers and Kuhn report that the AM responds to stimuli such as coal mine dust by releasing inflammatory mediators such as cytokines, growth factors, reactive oxygen species, and eicosanoids. Eicosanoids are synthesized by AM through the action of cyclo-oxygenase and lipoxygenase enzymes and serve to modulate the proinflammatory function of this cell as part of the lung’s host defense mechanism. Reactive oxygen species (ROS) can be generated by AM as a by-product in the biosynthetic pathway of the prostaglandins. AM produces primarily PGE2, thromboxane A2, and leukotriene B4 as part of the cellular response to an inflammatory stimulus. The results of this study suggest
that vitamin E may effectively reduce the inflammatory and
fibrotic response produced by the inhalation of mineral dust through an antioxidant
mechanism.154 Romach and colleagues report that vitamin E is thought to enhance immunity by increasing interlukin-1 (IL-1) production and by downregulating PGE2 synthesis. In an effort to understand the mechanism(s) whereby the form of vitamin E succinate (VES) ameliorates retrovirus-induced immune dysfunctions, they pretreated peritoneal exudate cells (PEC) with VES prior to exposure to virus. Pretreatment of PEC with VES maintained PGE2 levels at normal control levels as compared to controls which showed a 256% increase in PGE2 levels. On the basis of these studies, the
researchers concluded that downregulation of retrovirus-induced PGE2 production
and/or upregulation of IL-1 production by VES are
potential mechanisms for VES amelioration of
retrovirus-induced immune suppression. 155 PGE2 production in macrophages was also shown to be inhibited by vitamin E in a study by W Sakamoto, et al.. They reported that PGE2 production in the macrophages from vitamin E-treated rats was significantly suppressed. The release of arachidonic acid from pre-labeled macrophages and the conversion of arachidonic acid to PGE2 by the homogenate of the cells were remarkably reduced. The researchers concluded that the
results strongly suggested the inhibition of PGE2 production by vitamin
E results from the inhibition of the activities of both phospholipase A2 and
cycloogygenase. 156 Oral omega-3 (n-3) fatty acid supplementation was shown to suppress cytokine production and lymphocyte proliferation in a study by Meydani and associates. Two groups of women (23-33y and 51-68y) supplemented their diet with 2.4 g of (n-3) fatty acid/d for 3 months. The (n-3) fatty acid supplementation reduced total interleukin-1 (IL-1) beta synthesis by 48% in young women but by 90% in older women; tumor necrosis factor was reduced by 58% in young and 70% in older women. Interleukin-6 was reduced in young women by 30% but by 60% in older women. The (n-3) fatty acid supplementation reduced IL-2 production in both groups, however, this reduction was significant only in older women. Thus, long-term (n-3) fatty acid supplementation reduced cytokine production and T cell mitogenesis in older women. The reduction was more dramatic in older women that in young women. Although (n-3) fatty acid-induced
reduction in cytokine production may have beneficial anti-inflammatory effects, the
researchers noted its suppression in older women may not be desirable. 157 This suppression however, may be offset by supplementation by vitamin E, as shown in a previous study by Meydani and colleagues. In that study they reported that in a vitamin E (800 mg dl-alpha-tocopheryl acetate) supplemented group of older, healthy women, IL-2 production and mitogenic response were increased, while PGE2 synthesis and plasma lipid peroxides were reduced. The researchers concluded that
short-term vitamin E supplementation improves immune responsiveness in healthy elderly
individuals; this effect appears to be mediated by a decrease in PGE2 and/or other
lipid-peroxidation products. 158 Once again, understanding of the synergy of nutrients is shown to be critical in the interpretation of study results. This is underlined by the findings of another study researching the effects of low fat diets on alpha-tocopherol (vitamin E) levels, LDL oxidation and eicosanoid biosynthesis (prostaglandin PGE2). O Adam and associates reported that PGE2 levels increased by 344% concomitantly with significantly increased catalyzed oxidation of lipid peroxides (as measured in LDL samples). Both of these increases were linked to reductions in vitamin E and vitamin A in blood plasma. The researchers concluded that fat restricted diets can lead to an unwanted stimulation of lipid peroxidation and eicosanoid formation, which may be relevant in states of disease.173 Their conclusions also suggest vitamin E and vitamin A supplementation for those on low-fat diets, or for those who wish to reduce PGE2 production (e.g. asthmatics). Permeability of Cells and EFAs WG Jiang and associates investigated tight junctions (TJ), the topical most structure of epithelial and endothelial cells which play a key role in the control of permeability and prevention of tumour cell invasion of endothelium. Treatment of the endothelial cells with gamma linolenic acid (GLA), increased the transendothelial resistance (TER) and reduced the paracellular permeability to large molecules. The effects were seen without any changes in the viability of the endothelial cells. GLA also upregulated occludin, a molecule which plays a major role in TJ’s. Eicosapentaenoic acid (EPA) also exhibited an up-regulatory effect of occludin. Arachidonic acid (AA) and linolenic
acid (omega-6) however downregulated the
expression, adding to previous research indicating the destructive role AA plays in
inflammatory conditions and, the role that excess omega-6 in western diet plays with
regards to the imbalance of omega-3/omega-6 ratios in cells. 9 The importance of strength, maintenance and repair of cells was underlined in a report by M Skold. He noted that the pulmonary epithelium forms a continuous lining to the airways and to the environment. In addition to its mechanical and transport functions, the epithelium may also contribute to host defense via interactions with other inflammatory cells and with its surrounding matrix. Moreover, the bronchial epithelium
manifests ability to undergo repair after injury. However, this repair process may be
impaired, resulting in fibrotic scarring and compromised physiological function. Thus in
all likelihood repair processes play a crucial part in such airway diseases as asthma and
chronic obstructive airway disease. 10 In 1998, L Hodge and colleagues
reported plasma concentrations of phospholipid omega-3 fatty acids can be significantly
increased through the supplementation of omega-3
through the use of fish oil plus canola oil. 11 Oily fish could be a help in preventing asthma, according to the results of a new study carried out in Australia. The study of 468 children by the Sydney Royal Prince Alfred Institute of Respiratory Medicine has found that children who eat fresh oily fish, including salmon, tuna and mackerel at least once a week may avoid asthma. It was found that two out of four children prone to asthma did not suffer attacks if they included oily fish in their diet. Professor Anne Woolcock, director of
the institute, says it may be that omega-3 fatty acids,
found in cold water fish, can decrease the amount of inflammation in airways caused by
allergens. However, eating tinned oil fish such as tuna or salmon or fish fingers made
no difference to asthma risk and researchers believe this is due to processing. 12 In a double blind study, JP Arm and
associates reported that the magnitude of the allergen-induced late asthmatic response was
significantly attenuated from 2 to 7 h after allergen challenge following dietary
supplementation with Max-EPA (3.2 g eicosapentanoic acid and 2.2
g docosahexaenoic acid/day, but not with placebo. 13
PT Bozza, et al. noted that lipid bodies are characteristically abundant in cells associated with inflammation, including eosinophils. There is now evidence that the formation of lipid bodies is not attributable to adverse mechanisms, but is centrally mediated by specific signal transduction pathways. Arachidonic acid (AA) and other cis fatty acids are potent stimulators of lipid body induction. Increases in lipid body numbers correlated with enhanced production of both lipoxygenase and cyclooxygenase-derived eicosanoids. The researchers hypothesised that
lipid bodies are distinct inducible sites for generating eicosanoids as paracrine
mediators with varied activities in inflammation. The inhibition of lipid body
induction by reduction of AA represents a potential novel and specific target for
anti-inflammatory therapy. 14 Easton and Fraser reported on their
investigation of the permeability-increasing effect of arachidonic acid (AA) on pial
venular capillaries in vivo. They found that AA increased the permeability, but that
the increases could be prevented by co-application of a mixture of the antioxidants
superoxide dismutase and catalase. It was concluded that the permeability response
to arachidonic acid depends on the formation of free radicals and subsequent lipid
peroxidation. 14A A link between AA production and
increases in eosinophil levels in inflammatory diseases has been made by WS Powell and
associates. In 1995, they reported that human neutrophils and monocytes contain specific
microsomal dehydrogenase which converts 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE)
to 5-oxo-6,8,11,14,-eicosatetraenoic acid (5-oxo-ETE). The figure below indicates the
metabolism. 15
Later in 1995, Powell and associates (having shown that human neutrophils convert arachidonic acid to its 5-oxo metabolite, 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE)), conducted another study. 5-oxo-ETE, which is synthesized by oxidation of 5-hydroxy- 6,8,11,14-eicosatetraenoic acid (5-HETE) by a highly specific microsomal dehydrogenase, is a potent stimulator of human neutrophils and eosinophils. The researchers found that neutrophils readily convert 5,8,11,14,17-eicosapentaenoic acid (EPA) into its 5-oxo metabolite, 5-oxo-6,8,11,14,17-eicosapentaenoic acid (5-oxo-EPE). They also found that 5-oxo-EPE was only one-tenth as active as 5-oxo-ETE in stimulating the migration of both human neutrophils and human eosinophils. These results support the contention
that EPA can alleviate certain inflammatory diseases by reducing the contribution of
arachidonate-derived eicosanoids. 15,16 This also suggests a link between
eosinophil migration and omega-3 EFA deficiency. These
two studies add further data on the important role in asthma, of the down regulation of
arachidonic acid by correct ratios of omega-3/omega-6 fatty acids, and specifically by
increasing omega-3 fatty acids. In 1998, T Koshino and associates showed that leukotrienes were increased in the serum of asthmatic patients. Leukotrienes are a family of
arachidonic acid (AA) metabolites with potent biological activities such as
bronchoconstriction and leukocyte chemotaxis. This suggests that down regulation of AA would reduce leukotriene production. 17 Black and Sharpe, of the Dept of Medicine, University of Auckland, Auckland Hospital, New Zealand reviewed (72 references) the possible connection between the decreased consumption of saturated fat, the significant rise of polyunsaturated fat in the diet and the increased number of cases of asthma, eczema and allergic rhinitis in developed countries. The results of the study indicate that the changes in the types of fats consumed in the diet is largely due to a reduction in the consumption of animal fat and and an increase in the use of margarine and vegetable oils which contain omega-6 polyunsaturated fatty acids (PUFAs) including linoleic acid. Additionally, a reduced consumption of oily fish containing omega-3 PUFAs, including eicosapentaenoic acid, (EPA) has occurred. In some countries, there are social class and regional differences between the prevalence of allergic disease which are associated with differences in the consumption of PUFAs. Linoleic acid, a precursor to arachidonic acid, can be converted to prostaglandin E2 (PGE2), whereas EPA inhibits PGE2 formation. PGE2 acts upon T-lymphocytes, reducing the formation of interferon-gamma (IFN-gamma) but not affecting the formation of interleukin-4 (IL-4). This may lead to allergic sensitization, as IL-4 promotes immunoglobulin E (IgE) synthesis, whereas IFN-gamma has the opposite effect. The researchers concluded that changes in diet may explain the increased prevalence of asthma, eczema and allergic rhinitis and, the effects of diet may be mediated through an increased synthesis of prostaglandin E2, which in turn may promote the formation of immunoglobulin E. 18
Variation in fluidity is another example of the differences between dietary fats. Traditional western diets are high in saturated and trans fatty acids, and, as a result, cell membranes are much less fluid. The importance of this is highlighted
when it is understood that the ability of the cell membrane to perform it’s vital
function - to act as a selective barrier that regulates the passage of certain
materials in and out of the cell - is dependent upon the cell’s relative fluidity.
When the structure or function of the cell membrane is disturbed, homeostasis is interrupted. Homeostasis is the maintenance of
static, or constant, conditions in the internal environment of the cell and, on a larger
scale, the human body as a whole. In other words, with a disturbance in cellular membrane
structure or function, virtually all cellular processes are disrupted. This weakening of cell membranes increases permeability, “so that substances in the environment can permeate the mucosal lining of the airways, skin and gastrointestinal tract easily and indiscriminately. Once the cell membrane is strengthened, the system is able to screen out unwanted substances, and attacks (asthma) are averted.” 19 The interaction of toxic compounds with either the protein or the lipid component of cell membranes may sustantially alter membrane function. The xenobiotics which can
significantly alter membrane function include: effects of heavy metals on passive ion
permeability, impairment of osmoregulation and calcium transport by organochlorine
pesticides, inhibition of the transport of neurotransmitter metabolites by phenoxyacetic
acid herbicides in choroid plexus, and reduction in intestinal nutrient transport by heavy
metals. 20
Reductions of toxins in the body
improves cell functioning. One of the nutrients that can help with toxin reduction is alpha lipoic acid. Surveys of the general population of western diets suggest 90% of the population are deficient in omega-3 EFA’s. Although modern diets are relatively rich in omega-6 or linoleic acid (LA) , they are deficient in omega-3 or alpha-linolenic acid (ALA). Ratios of LA:ALA found naturally occurring in the human body (brain1:1, fat tissure 5:1, other tissues about 4:1) suggest that supplementation should complement existing dietary intake. Enzymes convert omega-6 fatty acids
only about one quarter as quickly as they convert omega-3 fatty acids. Due to the
increased levels of omega-6 in the diet, to get equal conversion, the ratio should favor
omega-3 in the order of 2 to 2.5 omega-3:1 omega-6. 159 To balance ratios, it is estimated
that the addition of 1-2 teaspoons of high quality, organic flax oil, per day, or the use
of a high quality blend of EFAs help to establish
levels towards the optimum range. |
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