Menhaden fish oil, n-3 polyunsaturated fatty acids, and protection of newborn rats from oxygen toxicity

We have previously reported that newborn rats born to mothers fed a high n-6 polyunsaturated fatty acid (PUFA) (safflower oil) diet demonstrated increased n-6 PUFA in lung lipids and superior tolerance to high oxygen exposure. In the present study, we explored whether high n-3 PUFA might also protect against hyperoxic damage and by what mechanism. Adult female rats were fed either regular rat chow, a high n-3 (menhaden fish oil-based) diet, or a high n-6 (safflower oil-based) diet for 6 wk before and then throughout pregnancy and lactation. Newborn offspring of the high n-3 (fish oil) dams demonstrated increased n-3 PUFA (i.e. eicosapentaenoic and docosahexaenoic acid) and decreased n-6 PUFA (i.e. linoleic and arachidonic acid) in their lung lipids compared to the other two diet groups. The high n-6 (safflower oil) offspring had the opposite PUFA lung lipid pattern (with increases in total n-6 fatty acids and decreases in total n-3 fatty acids). The high n-3 offspring demonstrated markedly decreased lung levels of prostaglandin E2, F2 alpha and thromboxane B2, whereas the high n-6 offspring had higher eicosanoid levels than the regular diet offspring. Offspring of both high n-6 and high n-3 diet dams demonstrated essentially the same superior hyperoxic tolerance compared to regular diet offspring [7-d (greater than 95% O2) survival rates of 110/115 and 99/109, respectively, versus 70/91, p less than 0.01].(ABSTRACT TRUNCATED AT 250 WORDS)     

Intralipid increases lung polyunsaturated fatty acids and protects newborn rats from oxygen toxicity.

Intralipid, derived from soybean oil and containing a high percentage of n-6 family polyunsaturated fatty acids (PUFA) and also linolenic acid, an n-3 family PUFA, is commonly the first fat source provided to very low birth weight premature infants. Following up on our previous reports that newborn rats born to dams fed high-PUFA diets demonstrate superior tolerance to hyperoxia, we examined whether the high-PUFA fat source Intralipid might also protect against oxygen toxicity. Adult female rats were fed either regular Rat Chow or fat-free diet containing 20%-Intralipid as the fat source for 3 wk before and then throughout pregnancy and lactation. One- and 5-d-old offspring of Intralipid diet-fed dams demonstrated significant increases in lung lipid n-6 family PUFA plus elevated linolenic acid compared with regular diet-fed offspring. These characteristic fatty acid patterns, apparent in total lung lipids, were even more pronounced in the triglyceride fraction compared with the phospholipid fraction. Associated with these fatty acid changes were significantly improved hyperoxic survival rates (89 out of 95 = 94% survival after 7 d of greater than 95% O2 exposure) in Intralipid offspring (versus 89 out of 106 = 84%, p less than 0.05 in regular diet offspring) and evidence of superior clinical/pathologic status. No differences in pulmonary antioxidant enzyme or surfactant system development, response of antioxidant enzymes to hyperoxic exposure, or lung prostaglandin E2, 6-keto PGF1-alpha or leukotrienes C4-F4 were present. These findings continue to support the hypothesis that increasing lung PUFA content may provide increased O2 free radical scavenging capacity, thus protecting against hyperoxic lung damage.(ABSTRACT TRUNCATED AT 250 WORDS)     

Polyunsaturated fatty acids in infant nutrition

The availability of long-chain polyunsaturated fatty acids (LCP), such as arachidonic (C20:4n-6) and docosahexaenoic (C22:6n-3) acids, is important for early human growth and development. The capacity for endogenous synthesis of LCP from the precursor fatty acids lineoleic (C18:2n-6) and alpha-linolenic (C18:3n-3) acid is limited in preterm and probably also in term infants. In utero, LCPs seem to be transferred preferentially from the mother to the foetus by the placenta. After birth, breastfed infants receive preformed dietary LCP with human milk. In contrast, most current infant formulae are devoid of LCP. Premature infants fed such formulae develop rapid LCP depletion of plasma and tissue lipids, which is associated with reduced visual acuity during the first postnatal months. Therefore, LCP enrichment of formulae for premature infants is desirable. Recent observations indicate that term infants fed conventional formulae also exhibit lower plasma LCP values and may show functional disadvantages, but these data require further confirmation prior to drawing definite conclusions.     

多不饱和脂肪酸与儿童注意力缺陷多动障碍

多不饱和脂肪酸对人体有着非常重要的生理功能,是人体生长发育不可缺少的物质,尤其是n-3多不饱和脂肪酸,对于婴幼儿神经系统正常的发育至关重要.随着现代医学的发展和人们对多不饱和脂肪酸认识和研究的不断深入,现已发现多种神经精神疾病和行为疾病与多不饱和脂肪酸的缺乏相关,其中包括儿童注意力缺陷多动障碍.临床发现本病的一些症状和体征与必需脂肪酸的缺乏症相似,而多不饱和脂肪酸在必需脂肪酸中发挥着重要的生物学意义,本文就儿童注意力缺陷多动障碍和多不饱和脂肪酸之间的关系进行综述.     

Polyunsaturated fatty acids influence neonatal monocyte survival

 The n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential dietary constituents. They are potent modulators of the human immune response, and research has endeavoured to optimise the ratio of n-3 to n-6 fatty acids in the lipid emulsion component of total parenteral nutrition to harness their beneficial effects in the clinical setting. PUFAs modulate apoptosis of certain tumour cells and cell lines. Monocytes, which are major effector cells of the innate immune system, play a central role in the initiation, development, and outcome of the immune response. They are crucial in the defence against invading pathogens and are involved in the lysis of infected or malignant cells, wound healing, repair, and remodelling of tissues. In the present study we investigated whether PUFAs might evoke apoptosis in newborn monocytes. Purified cord-blood monocytes collected from uncomplicated full-term pregnancies were incubated for 24 h in complete medium in the presence or absence of one of the n-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic (EPA) or the n-6 PUFA arachidonic acid (AA). Following incubation, cells were triple-labelled with annexin V, CD14, and propidium iodide prior to flow-cytometric analysis to determine the degree of cell death. All experiments were performed in triplicate and data expressed as mean ±1 S.D. (%). In the absence of fatty acids, 30 ± 4% of control cord monocytes underwent apoptosis or necrosis after 24 h incubation. At a concentration of 50 μM, none of the PUFAs had a significant effect on monocyte cell death, but at a dose of 100 μM, DHA resulted in 60 ± 4% cell death (P < 0.05) while the other PUFAs had no significant effect. In contrast, at higher concentrations (200 μM), all the PUFAs significantly increased monocyte cell death (AA: 70 ± 5%, DHA: 86 ± 2%, EPA: 70 ± 4%). PUFAs thus exert a potent influence on cord monocyte cell survival in vitro. Their effect is dose-dependent and DHA appears to be the most potent of the fatty acids tested. The influence of PUFAs on neonatal monocyte-cell survival suggests a novel mechanism whereby PUFAs may modulate the immune response.     

The effect of monosaturated and polyunsaturated fatty acids on oxygen toxicity in cultured cells.

The influence of oleic, linoleic (LIN), and eicosapentaenoic (EPA) acids incorporated into cellular lipids on susceptibility to O2-induced toxicity was evaluated in Chinese hamster fibroblasts (HA1) using a clonogenic cell survival assay. Fatty acid incorporation was achieved by incubating HA1 cells in 21% O2 for 72 h in the presence or absence of media supplemented with 25 microM oleic acid, 25 microM LIN, or 2, 4, and 25 microM EPA. This fatty acid incorporation period increased the percentage of composition in phospholipids 2-fold for oleic acid, 6-fold for LIN, and 6- to 20-fold for EPA. Vitamin E, total glutathione, superoxide dismutase activity, glutathione transferase activity, and catalase activity were unchanged, relative to control, in the 25-microM EPA-treated group, and only total glutathione was elevated in the LIN-treated group. After the incorporation period, the cells were placed in non-fatty acid supplemented media and exposed to 95% O2, and clonogenic survival responses were evaluated at time intervals up to 100 h. Sensitization to O2 toxicity in EPA-treated cells was apparent after 24 h of O2 exposure, whereas LIN-treated cells were significantly (p less than 0.05) sensitized to hyperoxia after 54 h of exposure, indicating that EPA was a more potent sensitizer for O2 injury. Furthermore, cells supplemented with 4 and 25 microM EPA were more sensitive to O2 toxicity than cells supplemented with 2 microM EPA. In contrast, cells treated with 25 microM oleic acid were significantly more resistant to O2 toxicity at 51, 72, and 98 h of O2 exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical manifestations of oxygen toxicity in the newborn lamb

The purpose of this project was to study the role of lipid peroxidation in oxygen-induced lung injury in the newborn lamb. It was our hypothesis that injury to the microvascular bed of the lung by oxygen would coincide with a burst of peroxidative activity and would be accompanied by an increased rate of excretion of ethane and pentane in expired gas. We measured vascular pressures, the rate of lung lymph flow and concentrations of ethane and pentane in exhaled gas in 10 newborn lambs that breathed greater than 95% oxygen continuously. Our marker for oxygen-induced lung injury was an increase in the permeability of the microvascular bed of the lung to protein (an increase in the rate of lung lymph flow accompanied by an increase in the protein concentration in lymph). Although all 10 lambs demonstrated an abrupt increase in microvascular permeability to protein within 48 to 96 h of exposure to greater than 95% oxygen, the rates of ethane and pentane excretion remained unchanged throughout the entire experimental period. Lung tissue concentrations of glutathione decreased by 40% in the oxygen-exposed lambs and the concentrations of glutathione disulfide increased 85% relative to air-breathing controls. Activities of glutathione reductase and superoxide dismutase were lower in the lungs of the oxygen-exposed lambs than in controls, whereas the activities of glutathione peroxidase and catalase were not changed. We conclude that, in the lamb, changes in the rates of excretion of ethane and pentane do not correlate with the timing of injury to the microvascular bed of the lung.     

Polyunsaturated fatty acids in plasma lipids of diabetic children during and after diabetic ketoacidosis

BACKGROUND AND AIM: Previously we reported significantly higher plasma values of the essential fatty acids but significantly lower values of their longer-chain metabolites in diabetic children than in healthy controls. Here, we report data on the acute effect of diabetic ketoacidosis (DKA) on the fatty acid composition of plasma lipids. METHODS: Diabetic children (n=9; age: 16.1 [3.3] y; duration of diabetes: 5.0 [5.3.] y; daily insulin dose: 0.87 [0.66] unit/kg body weight/d; glycated haemoglobin: 13.4 [2.8] %; median [IQR]) were investigated at admission for DKA (during DKA) and at the end of the treatment of DKA (after DKA). Fatty acid composition of plasma lipid classes was determined by high-resolution capillary gas-liquid chromatography. RESULTS: Blood glucose (27.0 [8.5] vs 6.5 [1.6] mmol/l), pH (7.28 [0.35] vs 7.36 [0.06]) and base excess (-8.9 [15.1] vs -2.2 [6.3] mmol/l) were grossly abnormal during but not after DKA. Values of linoleic acid were significantly lower after than during DKA (non-esterifed fatty acids (NEFA): 15.55 [1.47] vs 12.27 [5.74] % wt/wt; triacylglycerols (TG): 20.84 [9.23] vs 17.40 [5.78]; p<0.05). In contrast, values of gamma-linolenic acid (NEFA: 0.87 [0.54] vs 2.34 [1.85]; p<0.05) and arachidonic acid (TG: 1.37 [0.71] vs 1.74 [0.57]; p<0.05) were significantly lower during than after DKA. The product/substrate ratios for delta-6 desaturation were significantly lower during than after DKA. CONCLUSION: Successful treatment of diabetic ketoacidosis is associated with a significant increase of long-chain polyunsaturated fatty acid values in blood plasma in diabetic children. This observation suggests that disturbances of essential fatty acid metabolism in diabetic children are related not only to diet but to hypoinsulinaemia as well.     

Polyunsaturated fatty acids in school children in relation to allergy and serum IgE levels

Altered composition of polyunsaturated fatty acids (PUFA) has been observed in allergic individuals and it has been proposed that this is due to an impairment of δ-6-desaturase activity. We have studied the composition of PUFA in serum phospholipids in twenty-two 12-15 year old children with asthma and/or allergic dermatitis and 23 non-atopic controls of similar age. The relative levels of docosahexaenoic acid (DHA, C22:6n-3) and total n-3 long-chain polyunsaturated fatty acids (LCP) were lower (1.46%± 0.54 vs. 1.90%± 0.58, P = 0.01 for DHA and 2.34%± 0.67 vs. 2.80%± 0.77, P <0.05 for total n-3 LCP) and the ratio of total n-6 to n-3 LCP was higher (P < 0.01) in the allergic children than in the controls. In addition to these differences, the relative levels of docosapentaenoic acid (DPA, C22:5n-3) and the ratio of arachidonic acid (AA, C20:4n-6) to dihomo-γ-linolenic acid (DHGLA, C20:3n-6) were also lower in the 12 allergic children with positive skin prick test, as compared with the SIT negative children (both P < 0.05). In non-allergic children, the levels of total n-3 correlated with n-6 LCP (r = 0.76, p < 0.001). Furthermore, the n-3 LCP, i.e. EPA, DPA and DHA, correlated significantly with each other (r = 0.52-0.78, all p < 0.01) and correlated with n-6 LCP, i.e. C20:2, DHGLA and AA respectively (r = 0.56-0.83, all P < 0.01). Most of these correlations were absent in allergic children.
Higher levels of C20:2n-6 and lower levels of eicosapentaenoic acid (EPA, C20:5n-3) were recorded in 11 allergic children with serum IgE above the median level (56 kU/1), as compared to 11 with lower IgE levels (both P < 0.05). Furthermore, the levels of C20:2n-6 correlated with the IgE levels in the children (r = 0.65, P = 0.001).
The findings could not confirm an impaired δ-6-desaturase activity in allergic school children and suggest that a disturbance of LCP metabolism is associated with allergic diseases.     

Variable effects of short chain fatty acids and lactic acid in inducing intestinal mucosal injury in newborn rats

BACKGROUND: Short chain fatty acids and lactic acid are colonic bacterial fermentation products. METHODS: To evaluate the effects of these organic acids on the intestinal mucosa, a total of 72 newborn Sprague-Dawley rats (10 days old) were studied. A 3.5F catheter was inserted per rectum 4.0 cm deep into the proximal colon for organic acid administration at a volume of 0.1 ml/10 g body weight. The pH of organic acid solutions and normal saline was adjusted to 4.0. Group 1 (n = 10) received normal saline as a control. Group 2 (n = 11) received 150 mM acetic acid. Group 3 (n = 11) received 300 mM acetic acid. Group 4 (n = 10) received 150 mM butyric acid. Group 5 (n = 11) received 300 mM butyric acid. Group 6 (n = 7) received 150 mM lactic acid, and group 7 (n = 12) received 300 mM lactic acid. Animals were killed 24 hours after colonic installation of test solutions. RESULTS: Both 300 mM acetic acid and 300 mM butyric acid were associated with impaired weight gain, increased colon wet weight, and increased histologic injury scores in the colon and distal ileum (P < 0.05, analysis of variance). Both 150 mM acetic acid and butyric acid at 150 mmol/L induced minimal injury in the colon and distal ileum. Neither 150 mM nor 300 mM lactic acid induced any identifiable gross or microscopic intestinal mucosal injury. CONCLUSION: Luminal short chain fatty acids can induce dose-dependent intestinal mucosal injury in newborn rats, resembling the pathology seen in neonatal necrotizing enterocolitis. Overproduction/accumulation of short chain fatty acids, but not lactic acid, in the proximal colon and/or distal ileum may play a role in the pathogenesis of necrotizing enterocolitis in premature infants.     

Polyunsaturated fatty acids in erythrocyte and plasma lipids of children with severe protein–energy malnutrition

The fatty acid composition of plasma cholesterol esters, plasma phospholipids, erythrocyte phosphatidylcholine and erythrocyte phosphatidylethanolamine was investigated in severely malnourished Nigerian children with kwashiorkor (n = 12) and marasmus (n = 32). Normally nourished children from the same area (n = 23) served as controls. The malnourished children showed a significant reduction of highly polyunsaturated fatty acids in cholesterol esters, phospholipids and phosphatidylcholine. No differences between the groups were found in erythrocyte phosphatidylethanolamine. Children with kwashiorkor had lower levels of linoleic acid metabolites and docosahexaenoic acid than marasmic children. The results suggest that the kwashiorkor syndrome is associated with impaired desaturation and elongation of PUFA and/or increased lipid peroxidation.     

Cis- and trans-isomeric fatty acids in plasma lipids of newborn infants and their mothers

The proportionate fatty acid composition of plasma lipids was determined by high-resolution gas-liquid chromatography in 30 pairs of mothers and their term infants at the time of birth. Trans-fatty acids were found at similar percentage levels in maternal and infantile plasma, evidence for the first time of their placental permeability. In umbilical plasma, linoleic and alpha-linolenic acids contributed markedly smaller portions to total fatty acids, in contrast to clearly higher proportions of their long-chain polyunsaturated metabolites (LCP). Significantly larger percentage values in cord than in maternal plasma were found for those LCP that are structural components of brain lipids, which may reflect a discriminating placental transport mechanism for certain physiologically important LCP.     

多不饱和脂肪酸与注意缺陷多动障碍

注意缺陷多动障碍(attention deficit hyperactivity disorder,ADHD)是儿童青少年期常见的心理行为障碍,其主要临床特征为注意力不集中、活动过度和行为冲动.ADHD的发病机制及病因至今不明,多数学者认同ADHD是生物-心理-社会因素共同作用形成的疾病模型.生物学因素包括生物化学、遗传学、免疫学、神经系统发育障碍、脑电生理、影像学等.近年来,人体营养状况与精神心理健康的关系愈来愈引起研究人员注意,也不断有学者报道儿童青少年营养状况与ADHD存在一定的相关性,其中多见多不饱和脂肪酸(polyunsaturated fatty acid,PUFA)与ADHD关系的研究,以及锌元素、镁元素在脂肪酸(fatty acid)与ADHD中的作用.本文在查阅相关文献基础上,仅就此方面做一综述.