Skin pharmacology : the official journal of the Skin Pharmacology Society最新文献

The essential fatty acid, linoleic acid (LA), is required for the epidermal barrier and LA is also the precursor fatty acid for arachidonic acid (AA). Both fatty acids are imported from systemic sources, because AA is also not synthesized in the epidermis. The present studies were undertaken to compare the uptake and incorporation into cellular lipid of these fatty acids and to determine whether they compete with one another in these processes in relation to keratinocyte differentiation. The incorporation of [14C]LA and/or [14C]AA into phospholipids and triglycerides was examined in keratinocytes cultured under submerged and lifted conditions. In submerged (less well-differentiated) cultures, more LA was incorporated into phospholipids than AA, while AA was incorporated into triglycerides to a greater extent. When given together, neither fatty acid influenced the total and/or relative uptake and lipid distribution of the other. Compared to submerged cultures, the uptake of LA increased 2-fold in lifted (differentiated) cultures, while the uptake of AA was unchanged. Lifting increased the proportion of AA incorporated into phospholipids, but did not alter the distribution of LA among phospholipids or triglycerides. These data suggest that the essential fatty acids, LA and AA, which are destined for different metabolic roles within the keratinocyte do not compete with one another during their uptake and distribution among cellular lipid species. Furthermore, as keratinocytes differentiate in culture, their increased requirement for LA for the synthesis of barrier lipids may be achieved through the preferentially enhanced uptake and lipid incorporation.

Differences in the skin surface lipid content (SSL) and the dynamic friction coefficient (mu) were investigated with respect to age, sex, and anatomical region in 29 volunteers. The group consisted of (a) 7 young adult females (24.9 +/- 1.1 years old, mean +/- SD), (b) 7 old females (75.3 +/- 2.4 years old), (c) 7 young adult males (28.7 +/- 0.5 years old), and (d) 8 old males (73.8 +/- 1.9 years old). Measurements were obtained on 11 anatomical regions, namely, the forehead, upper arm, volar and dorsal forearm, postauricular, palm, abdomen, upper and lower back, thigh, and ankle. Skin surface lipid content data were compared with mu measurements to determine the relative contribution of the former to frictional properties of skin. mu and SSL were not statistically different between age groups on all regions except for the ankle, where lipid content was lower in the elderly. Similarly, mu did not vary between sex groups. Skin surface lipid content was statistically lower on the forehead, dorsal forearm and postauricular area in females. Both parameters, however, showed considerable regional variability. A significant linear correlation was established between mu and SSL combining all regions from all volunteers. When mu was plotted against SSL among individual anatomic sites, only the forehead and postauricular area showed significant linear correlations between the two parameters. These data suggest that surface lipid content plays a limited role in frictional properties of skin.

The measurement of transepidermal water loss (TEWL) is an important noninvasive method in order to assess the barrier function of the stratum corneum. As a consequence, TEWL has been found to be a very useful technique for studying skin irritation induced by various physical and chemical effects. Exposure of the skin to chemicals (detergents) and physical conditions (occlusion and stripping) generally results in an increase of TEWL. Until recently the only commercially available TEWL instrument was the Evaporimeter developed by ServoMed (Sweden). The instrument is based on the open chamber system with two humidity and temperature sensors which measure the water evaporation gradient at the surface of the skin. Recently a new commercially available instrument based on the same physical principle of measurement was developed by Courage and Khazaka (Tewameter, FRG). Our aim in this study has been to compare the measuring capacities of both instruments. The accuracy, sensitivity, variability and reproducibility of both instruments were compared in vivo under identical conditions on normal skin and skin damaged by external conditions. The influence of external and environmental factors such as air and probe temperature, relative humidity, air turbulence and pressure of application was evaluated for both instruments. Finally, the two instruments were compared in practice when following the increase in TEWL of the skin after stripping, occlusion and exposure to irritant household detergents. A very good correlation (r = +0.97) was found between the results of the two instruments over a wide range of TEWL values.

Dapsone (4,4'-diaminodiphenylsulfone) is effective in treating inflammatory skin diseases. Several lines of evidence suggest that the anti-inflammatory properties of this sulfone are partially due to modulation of functions of polymorphonuclear leukocytes (PMN). The goal of the present investigation is therefore to ascertain possible inhibitory effects of dapsone upon human 5-lipoxygenase (5-LOX) pathway. PMN of healthy donors were pretreated with dapsone in different concentrations (1.6-100 microM) for 5 min following by adding Ca ionophore A 23187 (10 microM) and subsequent incubation for 10 min. Thereupon the eicosanoids were assessed by reversed-phase high-performance liquid chromatography (RP-HPLC). Dapsone exhibited dose-dependent inhibitory activity showing 50% inhibition at 15 microM for leukotriene B4 (LTB4) with 5 x 10(6) PMN. The IC50 (half maximum inhibition concentration) of dapsone for 5-hydroxyeicosatetraenoic acid (5-HETE) and omega-OH-LTB4 amounted to similar values (5-HETE: 9 microM; omega-OH-LTB4: 11 microM). The inhibition of the conversion of arachidonic acid to several eicosanoids mainly suggests an effect on the 5-LOX enzyme. The comparison of inhibition values between intact PMN and a cell-free system (by sonification) indicates an additional effect of dapsone upon enzymes other than 5-LOX. Since the concentrations used are comparable with therapeutic conditions, dapsone may exert part of its anti-inflammatory effect by prevention of the generation of 5-LOX metabolites.

The hamster flank organ model was used to measure the effects of clofibric acid on the in vitro uptake of sodium [1-14C] acetate into lipids. Clofibric acid produces a dose-dependent inhibition of lipogenesis in the hamster flank organ in vitro.

Skin sites on 8 test subjects were treated with moisturizers, and different electrical measuring methods were compared regarding their quality in the assessment of the induced changes in the stratum corneum hydration level. Low frequency susceptance measurements were found preferable to high frequency admittance measurements, and the advantages of monopolar measurements with the three-electrode system are described.

Topical steroid treatment is a common therapy for psoriasis. Steroids are known to bind to specific cytoplasmic receptors and to influence gene expression. We investigated the effects of the novel steroid derivative mometasone furoate on the expression of putative target genes in normal human epidermal cells (KC). Gene expression was measured by semiquantitative mRNA-PCR. In addition, cytokine receptor characteristics were assessed by ligand binding studies. We found a dose-dependent downregulation of proinflammatory mediators (IL-8, TNF alpha). Genes involved in growth regulation (HER-2, p53) were also modulated. IL-8 binding to KC was inhibited. We conclude that modulation of the expression of cytokine, cytokine receptor and growth factor genes may contribute to the antipsoriatic action of steroids.

Several novel inhibitors of human synovial fluid phospholipase A2 (HSF-PLA2) were evaluated in cellular models of inflammatory mediator release (murine macrophage and human neutrophil) and topical in vivo inflammatory skin models in mice to ascertain the scope of effects which might be observed for PLA2 inhibitors. Potent inhibition of HSF-PLA2 in vitro can be observed with compounds such as scalaradial and ellagic acid, which both have IC50 values of 0.02 microM (using autoclaved [3H]-arachidonic-acid (AA)-labelled Escherichia coli membranes as substrate). Luffariellolide, a manoalide analog, and aristolochic acid are less potent (IC50 = 5 and 46 microM, respectively) in this assay. An interesting observation is that ellagic acid in cellular assays does not inhibit macrophage eicosanoid production and only 30% inhibition of PAF biosynthesis can be obtained at 50 microM in the human neutrophil. Possibly due to its irreversible mechanism of action, scalaradial retained its potent activity in both the macrophage (IC50 for PGE2 production = 0.05 microM) and neutrophil assays (IC50 for PAF biosynthesis = 1 microM). Aristolochic acid is active in these cellular assays (macrophage IC50 = 2.5 microM and neutrophil IC50 = 100 microM), but is consistently less active than either scalaradial or luffariellolide. The relative potencies of these compounds were determined in several murine in vivo inflammatory models such as oxazolone contact hypersensitivity, AA-induced ear edema and phorbol ester (PMA)-induced ear edema. In the mouse model of oxazolone contact hypersensitivity, these PLA2 inhibitors have little effect (< or = 30% inhibition at 400 micrograms/ear) with scalaradial and luffariellolide being less effective than either aristolochic or ellagic acid. PMA-induced ear edema was effectively inhibited by scalaradial, luffariellolide and aristolochic acid (ED50 = 70, 50 and 50 micrograms/ear, respectively) whereas ellagic acid was less effective (ED50 = 230 micrograms/ear). In AA-induced ear edema, these PLA2 inhibitors had minimal effects, as would be expected for compounds which inhibit PLA2. These results, especially those of ellagic acid, suggest that caution should be taken in the extrapolation of potency against a purified human extracellular type PLA2 to the scope of activities these compounds might have in the cellular and in vivo models. The consistency of scalaradial and luffariellolide may be inherent to their irreversible mechanism of action, which is a factor to be accounted for in the extrapolation of enzyme data to cellular and in vivo models.

Porphyria cutanea tarda (PCT) is characterized by cutaneous symptoms in association with hepatic accumulation and urinary excretion of mainly uro- and heptacarboxyporphyrins. 24 PCT patients excreting urinary porphyrins between 1.9 and 5.8 mumol/24 h (normal < 0.2) were treated with chloroquine at a dose of 125 mg twice a week. During the first phase of therapy urinary porphyrin excretion transiently increased 1.1- to 2.9-fold indicating a phase of mobilization. A slight initial elevation was also found regarding the activities of serum aminotransferases reflecting the hepatotoxic effect of chloroquine. The clinical symptoms disappeared after a period ranging from 2 to 6 months, and after an average of 12 months the porphyrin excretion in all patients had returned to nearly normal values.

Salicylic acid (SA) and urea are widely used in topical preparations. Using a simple tape stripping technique the effect on the binding forces within the stratum corneum and the skin absorption of SA and urea were studied. The degree of stratum corneum removal was recorded by measuring the transmission through the tape with a digital light-measuring instrument. With successive stripping of the skin the amount of tissue adhering to the tape decreased. Exposure of the upper arm to 2% SA for 6 h increased the skin material on the tape strips significantly. No significant increase was recorded after 3-hour exposure, or after exposure to 0.5% SA. Neither did the exposure to 10% urea for 3 or 6 h influence the amount of skin adhering to the tape significantly. Radiochemical analyses showed that the amount of SA and urea in each of the first 6 tape strips was about 5-15 micrograms/cm2. This technique provides a useful tool to evaluate the binding forces within the stratum corneum in relation to absorption of topically applied substances.