We have analysed the endogenous retinoids present in whole mouse embryos from day 9 to day 14 of development and in individual components of the embryo at two stages, day 10.5 and day 13, by HPLC. We can only detect two retinoids, all-trans-RA (tRA) and all-transretinol (t-retinol), and t-retinol is 510-fold in excess over tRA. We cannot detect 9-cis-RA or any didehydroretinoids; thus mammalian embryos seem to differ in their retinoid content from other embryos such as chick, Xenopus, and fish. The levels of tRA do not change significantly over the 6 days of development analysed, whereas t-retinol rises sharply as the liver develops. Within the embryo, tRA is present at high levels in the developing spinal cord and at very low levels in the forebrain; indeed there is a gradient of endogenous tRA from the forebrain to the spinal cord. Other parts of the embryo had intermediate levels of tRA. When a teratogenic dose of RA was administered to day 10.5 embryos, the levels of tRA present in individual tissues of the embryo rose dramatically-from 175-fold to 1,400-fold-and the levels rose in all tissues not in any exclusive areas. We then determined which areas of the embryo were malformed by such a teratogenic dose. The lower jaw, palate, vertebrae, tail, and limbs were consistently abnormal, and since these areas received a dose of tRA no higher than any other it was concluded that cell-specific factors must determine the teratogenic response of these tissues. We then considered whether cellular retinoic acid-binding protein I or I1 (CRABP I or 11) played any role in this response by determining their relative levels in each of the tissues analysed. There was no correlation between the presence of CRABP I and 11 and the distribution of administered RA. Neither was there a clear correlation in detail between the presence of CRABP I and I1 and the sites of teratogenesis. We therefore conclude that other factors, for example, nuclear factors, must be responsible for the teratogenic response to RA. o 1995 Wiley-Liss, Inc.
1. Lipoxin A4 (LXA4) and lipoxin B4 (LXB4) have been evaluated for their capacities to modulate neutrophil (PMN) migration and endothelial cell adherence using compounds prepared by total chemical synthesis. 2. Increased PMN migration was seen with concentrations of LXA4 from 10(-9) mol/l to 10(-7) mol/l. LXA4 was 100-fold less potent than leukotriene B4 (LTB4) and it elicited only one-half of the maximal response of LTB4. 3. The (5S,6S,15S)-isomer of LXA4 induced only a weak migratory response and LXB4 was inactive, suggesting that the activity of LXA4 was stereospecific. 4. Modified chequerboard analysis indicated that LXA4 was a chemokinetic agent. 5. Preincubation of PMN with increasing concentrations of LXA4 induced a very similar dose- and time-dependent inhibition of the subsequent response to 10(-7) mol/l LTB4 or 10(-7) mol/l N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP). The inhibition was observed at 10(-10) mol/l LXA4; the concentration which produced 50% inhibition was 10(-8) mol/l and 100% inhibition of PMN locomotion occurred at 10(-6) mol/l LXA4. 6. The (5S,6S,15S)-isomers of LXA4 and LXB4 were 5- and 100-fold less potent than LXA4, respectively, in suppressing LTB4- or FMLP-induced PMN migration. 7. Preincubation of PMN with LXA4 led to a suppression of calcium mobilization, as assessed by Quin2-AM fluorescence, when the cells were subsequently stimulated under optimal conditions by LTB4 or FMLP. 8. These results suggest that the inhibitory activity of lipoxins may be related to the capacity of these molecules to regulate calcium ion mobilization.
Recruitment of inflammatory leucocytes to the airways may play a part in the pathogenesis ofasthma. As dietary enrichment with fish oil lipids can suppress leucocyte function, the effect of these lipids on asthma control and neutrophil function was studied in 20 subjects with mild asthma. Twelve subjects received capsules containing 3-2 g of eicosapentaenoic acid and 2-2 g of docosahexaenoic acid daily and eight subjects received placebo capsules containing olive oil for 10 weeks in a double blind fashion. Baseline specific airways conductance, airways responsiveness to histamine and exercise, diurnal peak expiratory flow, symptom scores, and bronchodilator use were measured. Neutrophil fatty acid composition was evaluated by gas chromatography, calcium ionophore induced neutrophil leukotriene (LT)B4 and LTB5 generation were measured by reverse phase high performance liquid chromatography and radioimmunoassay, and neutrophil chemotactic responses to formyl-methionyl-leucyl-phenylalanine (FMLP) and LTB4 were assessed by a microchemotaxis technique. Although the fish oil supplemented diet produced a greater than 10 fold increase in the eicosapentaenoic acid content of neutrophil phospholipids, there was no significant change in airways responsiveness to histamine or any change in any of the clinical measurements. After dietary supplementation with fish oil there was a 50% inhibition of total LTB (LTB4 + LTB5) generation by ionophore stimulated neutrophils and neutrophil chemotaxis was substantially suppressed. Neutrophil function remained unchanged in the placebo group. It is concluded that in subjects with mild asthma a fish oil enriched diet attenuates neutrophil function without changing the severity of asthma.
RA, in conjunction with Fgf-8, may be needed for the induction of the chick limb bud and the induction of Shh and Fgf-4 expression. The expression of Shh and Fgf-4 remains dependent upon the continued synthesis of RA within the limb bud. Didehydroretinoic acid is the major active retinoid in the stage 20 chick limb bud.
The effects of dietary supplementation with fish oil lipids on the airways responses to allergen and neutrophil biochemistry and function have been studied in 17 atopic asthmatic subjects. Nine subjects received 18 capsules of Max-EPA (3.2 g eicosapentaenoic acid and 2.2 g docosahexaenoic acid) a day and eight subjects received identical capsules containing olive oil, for 10 wk in a double-blind fashion. There were no differences between prediet values and those observed after dietary supplementation with Max-EPA or placebo in the dose of allergen causing an acute asthmatic response as assessed by a 35% fall in specific airways conductance (PD35), the extinction dose of allergen on skin prick testing, the histamine PD35, or the total serum IgE concentrations. Twelve of the 17 subjects developed late asthmatic responses after allergen challenge prediet. Six of these subjects received Max-EPA, and six received placebo capsules. As compared to prediet values, 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 (p less than 0.005) but not with placebo. The attenuation of the late response was not accompanied by any significant change in the clinical severity of disease as assessed by diurnal peak expiratory flow rates, symptom scores, or bronchodilator drug usage.(ABSTRACT TRUNCATED AT 250 WORDS)
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