摘要:

Antipsoriatic anthrones are probably the most commonly used topical agents in the treatment of psoriasis. There is growing evidence that the biochemical basis for their mechanism of action at the molecular level is related to their redox activity leading to the production of active oxygen species, which include singlet oxygen, superoxide anion radical, and hydroxyl radical. These species are involved in a variety of oxidative effects affecting cellular targets that have been implicated both in the mode of action and the skin-irritating properties of antipsoriatic anthrones: interaction with DNA, inhibition of various enzyme systems associated with cell proliferation and inflammation, such as glucose-6-phosphate de-hydrogenase and 5-lipoxygenase, and destruction of membrane lipids. Furthermore, the application of this information to the design of novel derivatives is discussed. In particular, compounds with diminished oxygen radical-generating properties have been developed, which may permit a separation of antipsoriatic and inflammatory effects. Some of the novel anthrone analogs which produced significantly less amounts of oxygen radicals than dithranol compared favorably in biological tests with this known antipsoriatic drug as an alternative method of treating psoriasis.

ISSN:1660-5527    

DOI:10.1159/000211326

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The number of mast cells is increased in psoriatic lesions and this is particularly prominent in their early phase. Mediators released by mast cells may interfere with various aspects of cutaneous inflammation and epidermal proliferation. Therefore, the aim of the present investigation was to find out whether a 4-week treatment period with Tiacrilast, a highly potent inhibitor of mast cell degranulation, might have anti-psoriatic potential. A total of 31 patients with plaque-type psoriasis were evaluated after treatment with a 3% Tiacrilast hydrogel and hydrogel alone, in a double-blind, placebo-controlled, within-patient comparative study. No statistically significant improvement of the Tiacrilast-treated plaques compared to the hydrogel-treated sites could be demonstrated. Therefore, the present study does not provide evidence of a potential role of mast cell degranulation in the treatment of psoriasis.

ISSN:1660-5527    

DOI:10.1159/000211327

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

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 [I4C]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.

ISSN:1660-5527    

DOI:10.1159/000211328

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

It is known that keratinocytes produce and secrete interleukin-1 (IL-1) de novo and that this process can be enhanced by various stimulators. IL-1 has been shown to be a potent proin-flammatory cytokine which mediates inflammation in various cutaneous disorders. It has also been demonstrated that γ-interferon (IFN-γ) which is released from infiltrated T cells can be detected in inflamed lesional sites. In order to understand the effects of IFN-γ on IL-1 production by keratinocytes in such inflammatory lesions, normal human keratinocytes (NHKs) and human squamous cell carcinoma cell line (HSC-1) cells were cultivated with recombinant human IFN-γ (rIFN-γ) and IL·1 levels were measured by ELISA. The effects of antipsoriatic agents such as hydrocortisone (HC), cyclosporine A(CsA), 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and its analogue MC903 on IL-1 production by keratinocytes were also investigated. IL-1 release by both NHK and HSC-1 cells was accelerated by stimulation with rIFN-γ dose-dependently, although IL-1α was released only transiently by rlFN-γ-stimu-lated NHKs in serum-free keratinocyte growth medium containing HC. Antihuman IFN-γ antibody inhibited IL-lα release by HSC-1 cells stimulated with rIFN-γ, suggesting that IL-1α release from keratinocytes is upregulated by IFN-γ. HC (5 μg/ml), 1,25(OH)2D3 (10-6M) and MC903 (10-6 M), but not CsA (5 μg/ml), inhibited IL-lα production by HSC-1 cells stimulated with 100 U/ml of rIFN-γ. Since IL-l plays an important role in the initiation of cutaneous inflammation, its downregulation may prevent inflammation and thereby at least partly account for the clinical effectiveness of these agents in the treatment of psoriasis.

ISSN:1660-5527    

DOI:10.1159/000211329

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Two human skin recombinants, the epidermis reconstructed on the deepidermized dermis (RE-DED) or on fibroblast-populated collagen matrix (Living Skin Equivalent, LSETM), were used to study the irritating effect of sodium lauryl sulfate (SLS). The extent of cytotoxicity induced after a 24-hour exposure period to increasing concentrations of SLS (0-5%) was evaluated on the basis of (1) morphological perturbations, (2) changes in the expression of differentiation-specific protein markers (keratin 1, 10, 6, 16, involucrin and transglutaminase), (3) cell membrane integrity (LDH leakage) and (4) release of proinflammatory mediators (PGE2, IL-1, IL-6 and IL-8). SLS induced significant changes in epidermal morphology and changes in the expression and localization of differentiation-specific protein markers when applied topically in concentrations higher than 1 % on RE-DED and higher than 0.1% on LSE. The exposure of both human skin recombinants to SLS resulted in a dose-dependent release of LDH, PGE2 and IL-1α and in an increase in keratinocyte intracellular IL-1 levels. Upon application of 5% SLS on RE-DED the total (intra- and extracellular) IL-1 levels remained high but due to cell damage the intracellular IL-1 level was markedly decreased and the extracellular IL-1 level increased. Similar observations have been made with LSE after application of 0.5% SLS. However, with LSE the extracellular IL-1α levels were found to be about 100 times lower than those measured with RE-DED. Exposure of LSE to SLS induced a marked increase of IL-6 production in fibroblasts incorporated in the collagen matrix. Contrary to LSE, both intra- and extracellular levels of IL-6 were low in unexposed controls and were only marginally modulated by the exposure of the RE-DED to SLS. In addition, a dose-dependent increase in IL-8 release was observed upon application of SLS on RE-DED. The results of the present study indicate that concentrations of SLS required to induce epidermal irritancy in vitro approximate those inducing irritation in human skin in vivo. All parameters used in the present study for evaluation of toxicity can serve as useful endpoints for screening of contact skin irritancy in vitro. Compared to RE-DED, the LSE seems to be more susceptible to SLS. The differences in sensitivity between LSE and RE-DED can be ascribed to reported differences in their stratum corneum barrier function.

ISSN:1660-5527    

DOI:10.1159/000211330

出版商:S. Karger AG    

年代:1995

数据来源: Karger

ISSN:1660-5527    

DOI:10.1159/000211331

出版商:S. Karger AG    

年代:1995

数据来源: Karger

ISSN:1660-5527    

DOI:10.1159/000316435

出版商:S. Karger AG    

年代:1995

数据来源: Karger

ISSN:1660-5527    

DOI:10.1159/000316436

出版商:S. Karger AG    

年代:1995

数据来源: Karger

ISSN:1660-5527    

DOI:10.1159/000211332

出版商:S. Karger AG    

年代:1995

数据来源: Karger

ISSN:1660-5527    

DOI:10.1159/000211333

出版商:S. Karger AG    

年代:1995

数据来源: Karger