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Discusses cellular senescence mechanisms in wound healing. Factors that can cause a cell to develop a senescent phenotype; Senescence in fibroblasts; Phases of wound healing; Role of matrix metalloproteases in wound healing.

The article reports that a variety of experimental and disease related inflammatory processes are associated with elevated levels of free arachidonic acid and prostaglandins (PGs). Experimental inflammatory stimuli for human skin include ultraviolet light of various wavelengths, infra-red, nicotinic acid esters and anthralin. To date, however, a major problem associated with the evaluation of drug action in skin, whether inhibitory or stimulatory to PG biosynthesis, has been the absence of a suitable technique for introducing drugs and recovering mediators from skin.

A variety of chemical stimuli, including tetrahydrofurfuryl nicotinate (Plummer et al, 19771 and anthralin (Barrel a!., 1982) are known to increase the levels of arachidonic acid and various prostanoids recovered from the fluid of suction blisters raised on human and animal skin. Recently we have demonstrated that the skin of mini-pigs behaves qualitatively and quantitatively, in a pharmacological manner similar to human skin with respect to the above two stimuli (Chatelus et al., 1982) However, the present studies with these two drugs suggest that the selection of the vehicle in which the drug is applied to the skin is of paramount importance since, as will be presented below, significant pharmacological effects of the vehicles can he detected on the levels of various prostanoids measured. [ABSTRACT FROM AUTHOR]

Psoriatic human hair follicle keratinocytes can he brought to culture under the same conditions as normal control hair follicle keratinocytes. In comparison with control cultures derived from non-psonatics there are significant differences. However, no significant differences are found between cultures derived from either psoriatic involved or uninvolved skin. Some characteristics of psoriatic Lesions are also encountered in the cultures. However, in contrast to the situation in a psoriatic lesion, cultures of psoriatic keratinocytes differentiate to a higher extent than comparable control cultures. A psoriatic morphology is therefore not completely formed, Whether this is due to the absence of a psoriatic dermis or to the fact that differentiation iii culture is incomplete remains to be investigated. [ABSTRACT FROM AUTHOR]

A variety of experimental and disease induced inflammatory skin reactions are associated with elevated levels of free arachidonic acid and various prostaglandins (Harnmcrström et al .,1975; Hensby et at., 1983). We were therefore interested to evaluate the action of several known inhibitors of prostaglandin biosynthesis and also drugs used to treat skin inflammatory reactions for their ability to inhibit prostaglandin biosynthesis in human skin. For this purpose, we have developed a new model in human skin based upon the previous observation that non-steroid (Hensby et at. 1983; Plumrner et al., 1978 Black et al., 1978) and corticosteroid (Black, Greaves & Hensby, 1980) anti-inflammatory drugs could significantly reduce the elevation of prostaglandins in human skin due to topical tetrahydrofurfuryl nicotinate or UV-B. Our model is based upon the ability of tetrahydrofurfuryl nicotinate (applied topically under occlusion and in the form of a solid cellulose mixed ester vehicle) to evoke a several-fold increase in the levels of free arachidonic acid and prostaglandins. In addition to the evaluation of non-steroid anti-inflammatory drugs and corticosteroid drugs, we have examined the effect of two other drugs, namely dapsone and thalidomide, frequently used as skin anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

The 15-lipoxygenase from soya bean has been claimed to represent a rapid assay procedure for drugs and chemical agents that inhibit other lipoxygenase products (Kingston, 1981). Although the exact role of products derived from skin lipoxygenase enzymes is not well established, many of these products, e.g. leukotriene B4, have inflammatory characteristics that warrant further examination (Camp, 1982). We have therefore started to evaluate anti-inflammatory drugs in vitro for their ability to inhibit soya bean 15-lipoxygenase, before appraising their effects in vivo in animal and human skin. [ABSTRACT FROM AUTHOR]

Investigates the role for prostanoids in various human skin diseases. Details on the pharmacology of many prostanoids; Quantitative analysis of prostaglandins; Levels of the various prostanoids in both vitiligo and tuberculin.

Presents a study which aim to correlate the chemical structure of steroid derivatives with receptor affinity. Identification of lipophilicity as a measure of the affinity of a substance for non-polar solvents; Association of the concept of quantitative structure activity relationships (QSAR) with the ability to establish mathematical relationships between chemical structure and biological activity; Use of reversed phase high performance liquid chromatography in the study.

Examines the inhibitory properties of anthralin on enzymes of the glycolytic pathway. Use of glucoses-6-phosphate dehydrogenase as a biochemical or biological event; Detection of low concentrations of anthralin; Solubility and stability of the compound in the medium.

Drug metabolizing enzymes, particularly those involved in the metabolism of carcinogenic chemicals, were characterized in cultured human keratinocytes. Using immunoblotting experiments, we analysed the expression of phase I enzymes, cytochrome P4501A1 (CYP1A1) and NADPH reductase, and phase II enzymes, phenol UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) isoform pi, in the presence of either classical inducers (i.e. 3-methylcholanthrene, dimethylbenz[a]anthracene, phenobarbital, and clofibrate) or all-trans retin-oic acid (RA). This study has shown that the expression of CYP1A1 and UGT is concomitantly induced by 3-methylcholanthrene, dimethylbenz[a]anthracene, and BA, and that of NADPH reductase is only enhanced by phenobarbital and RA. In contrast, the expression of GST pi was not affected by the inducers. Using the reverse transcriptase-polymerase chain reaction, we have demonstrated that the effects of 3-methylcholanthrene, dimethylbenz[a]anthracene and RA on CYP1A1 expression correlate with an increase of CYP1A1 mRNA level. Our results indicate that, with the exception of clofibrate, xenobiotics and RA differentially modulate the expression of drug metabolizing enzymes. [ABSTRACT FROM AUTHOR]

Keratinocyte/leucocyte interactions have become an area of intense investigations in the last decade. However, few convenient in vitro models are available at present. We have therefore designed a novel in vitro system for autologous human keratinocyte/leucocyte co-culture. Non-invasive epidermal cell sampling was achieved by using outer root sheath cells from hair follicles. After one passage, pure keratinocyte cultures (no Langerhans cells or melanocytes) were obtained. Co-culture experiments were performed on a Transwell system: keratinocytes were grown on the porous cupula, and then laid on to wells containing leucocytes. Alternatively, leucocytes can be added to the cupula when contact interactions between the two cell types are to be investigated. Using this system, we demonstrated that Phaesolus vulgaris phytohaemagglutinin-activated T lymphocytes (with 10% monocytes) in the lower compartment induced intercellular adhesion molecule 1 (ICAM-1) and HLA-DR expression, and inhibited methyl-³H-thymidine incorporation in normal human autologous keratinocytes cultured on the cupula. These changes were mediated by soluble factors (no cell contacts between keratinocytes and leucocytes), and required lymphocyte activation. This is the first direct in vitro evidence for leucocyte-induced lCAM-1 and HLA-DR expression on keratinocytes. This system is a potential tool for the study of keratinocyte/leucocyte interactions. The technique is easy to perform, keratinocyte and leucocyte responses can be assessed separately (proliferation, surface antigen expression), experiments within a given donor can easily be reproduced, and this model lends itself to a vast range of different experimental conditions. [ABSTRACT FROM AUTHOR]

Ornithine decarboxylase activity was measured in skin from 14 normal and 24 psoriatic subjects (with stable plaque type psoriasis vulgaris) using punch biopsies carried out immediately (o h) and 6 h after stimulation by cellotape stripping. At o h, no significant difference was found between normal and involved or uninvolved psoriatic skin, but a significant increase was measured 6 h after tape stripping. This increase was significantly greater in uninvolved and involved psoriatic skin compared with normal skin. Preliminary results indicated that these changes were localized in the epidermis. [ABSTRACT FROM AUTHOR]

A culture vessel consisting of two independent chambers separated only by the growth substrate is described. Cells may be cultured on both sides of the growth substrate. Culture medium and gas exposure can independently be controlled in both compartments. Human hair follicles have been used as source of keratinocytes and the bovine eye lens capsule has been explored as growth substrate. The presence of 5% CO in air in the lower compartment appears to have a significant effect on the morphology of the cultures. When the cultures are being exposed to air with 5% CO, the culture medium being applied in the lower compartment, formation of corneocytes characteristic for adult stratum corneum is induced, as evidenced by light and electron microscopy. To the knowledge of the authors, this stage of differentiation in vitro has not been obtained with previously described systems. Differentiation of the lower cell layers has been characterised with specific antibodies. The possible use of the system for applied and pure scientific research is discussed. [ABSTRACT FROM AUTHOR]

The efficiency of the outgrowth of human epidermal and hair-follicle-sheath keratinocytes was studied using three different growth substrates: plastic, type-I collagen and bovine eye lens capsules (the Epicult system). It was shown that the eye lens capsule is the best substrate, since a higher percentage of cultures showed outgrowth, and the outgrowth of epidermal keratinocytes was much more rapid. This effect is related to the faster migration (not proliferation) of cells grown on lens capsules as compared to the two other substrates. The view that lens capsules can replace the basement membrane present in vivo was supported by the finding that two basement-membrane components, i.e., laminin and fibronectin, are present on lens capsules. It was shown that, in cultures grown on lens capsules, bullous-pemphigoid antigen is restricted to the basal layer, indicating that the differentiation of these cells is comparable to that of keratinocytes grown on irradiated, non-viable pig dermis. [ABSTRACT FROM AUTHOR]

Monohydroxy acids (HETEs) and leukotriene B4 (LTB4) metabolites of arachidonic acid were measured in skin of healthy volunteers after ultraviolet B irradiation, and in the uninvolved skin of psoriatics after topical dithranol application. Exudate was collected from suction bullae on control and inflamed abdominal skin, and analysed for 12-HETE and PGE2 by GC-MS and LTB4 by bioassay. 12-HETE and PGE2 were raised at 24 h but not at 72 h after u.v.B irradiation: control and 24 h values were 13.7 and 41.5 ng ml-1 (P less than 0.05, n = 6) for 12-HETE respectively, and 4.5 and 30.2 ng ml-1 (P less than 0.01, n = 6) for PGE2. Dithranol application raised PGE2 levels from 23.1 ng ml-1 in control exudate to 62 ng ml-1 (P less than 0.01, n = 6) at 24 h before declining to base levels at 72 h. However, 12-HETE was raised at 72 h (200 ng ml-1, P less than 0.01, n = 5) but not at 24 h (104 ng ml-1) compared to control levels (50 ng ml-1, n = 5). The levels of the LTB4 were low (less than 100 pg ml-1), and no significant increases were observed. Arachidonic acid in inflamed skin can be metabolised by the cyclo-oxygenase and lipoxygenase pathway. It is probable that the lipoxygenase product 12-HETE is involved in these inflammatory reactions. [ABSTRACT FROM AUTHOR]

Focuses on the mechanism or mode of action of the drug anthralin. Efficacy of the drug in psoriasis; Disadvantages of the medication such as staining and irritation; Subjection of anthralin to light-catalysed oxidation and/or chemical decomposition.

CD 271 possesses a potent anti- inflammatory activity in a large number of models particularly when compared with known reference anti-inflammatory agents. Retinoids (all-trans retinoic acid, 13 cis retinoic acid and Etretinate) show very weak or no activity. In view of these properties of CD 271, an enhanced therapeutic value can be anticipated in the treatment of skin diseases such as acne and psoriasis. [ABSTRACT FROM AUTHOR]

In model systems where anthralin and butanthrone have a high anti-proliferative activity, e.g., inhibition of keratinocyte metabolism in culture or inhibition of ornithine decarboxylase induction in vivo, CD 003 is inactive. However, in the skin disease psoriasis there is both an inflammatory as well as a differentiation/proliferation component, and consequently we have evaluated anthralin and butanthrone for their potential in vivo antiinflammatory activities. In addition, we have compared a new analogue, substituted at C, with these two compound. Our results support the belief that modification of the anthralin structure can result in the formation of less toxic, less irritant and less staining analogues, which maintain or significantly improve upon the topical antiinflammatory properties of anthralin. The possibility that such analogues will be of use in the treatment of skin diseases with a major inflammatory component is at present being investigated. [ABSTRACT FROM AUTHOR]

Examines the determination of anthralin in commercial ointments. Use of high performance liquid chromatography; Employment of two different methods of extraction and chromatography; Differences between the stated and the actual compositions of the creams.