Skin Barrier and Lipid Metabolism
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PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/19370 Please be advised that this information was generated on 2021-10-01 and may be subject to change. Epidermal barrier dysfunction New insights and opportunities for therapeutical intervention Kucháreková M. ■ Epidermal barrier dysfunction: New insights and opportunities for therapeutical intervention Thesis University Medical Centre Nijmegen, the Netherlands With summary in Dutch -224 p, © 2003 ISBN ■ 90-9017339-0 NUR ■ 876 Druk ■ Ipskamp Printpartners, Enschede Vormgeving ■ Milan Tjioe No part of this book may be reproduced by any mechanical, photographic or electronic process, nor may it be stored in a retrieval system, transmitted, or otherwise copied for public or private use, without written permission of the author. Epidermal barrier dysfunction New insights and opportunities for therapeutical intervention Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen Proefschrift ter verkrijging van de graad van doctor aan de Katholieke Universiteit Nijmegen, op gezag van de Rector Magnificus Prof. dr. C.W.P.M. Blom volgens besluit van het College van Decanen in het openbaar te verdedigen op donderdag 4 december 2003 des namiddags om 3.30 uur precies door Martina Kucháreková Geboren op 5 juni 1971 te Zvolen, Slowakije Promotor: Prof. dr. dr. P.C.M. van de Kerkhof Copromotor: Dr. P.G.M. van der Valk Dr. J. Schalkwijk Manuscriptcommissie: Prof. dr. D.J. Ruiter (voorzitter) Prof. dr. Y. Hekster Prof. dr. P.J. Coenraads (RUG) Twijfel is ‘t begin van wijsheid (René Descartes) Voor mijn ouders Venované mojim rodičom CONTENTS Chapter 1 General Introduction 9 1.1 Structure and function of the epidermis 11 1.2 Selected inflammatory skin disorders associated with an altered 21 epidermal barrier 1.3 Methodology 37 1.4 Aims and questions of this thesis 43 Chapter 2 Skin barrier and lipid metabolism 61 2.1 Lack of upregulation of epidermal fatty acid binding protein (E- 63 FABP) in dithranol induced irritation 2.2 Epidermal expression of epidermal fatty acid binding protein (E- 75 FABP) distinguishes atopic dermatitis from psoriasis vulgaris Chapter 3 Epidermis as a barrier to microorganisms 85 3.1 Specific upregulation of epidermal host-defence proteins in psoriasis 87 compared to atopic dermatitis Chapter 4 Novel therapies on irritant contact dermatitis: Experimental 99 and clinical studies 4.1 The effect of a PDE-4 inhibitor (cipamfylline) in two human models 101 of irritant contact dermatitis 4.2 Effect of a lipid-rich emollient containing ceramide 3 in experimentally 115 induced skin barrier dysfunction 4.3 A randomized comparison of an emollient containing skin-related 133 lipids with a petrolatum-based emollient as adjunct in the treatment of chronic hand dermatitis 7 Chapter 5 Clinical aspects and topical treatment of dithranol irritation 147 as a unique form of irritant contact dermatitis 5.1 The effects of topical corticosteroids and a coal tar preparation on 149 dithranol induced irritation in patients with psoriasis 5.2 Dithranol irritation in psoriasis treatment: a study in 68 inpatients 159 5.3 Skin irritation during treatment of chronic plaque psoriasis with short 169 contact dithranol versus calcipotriol ointment Chapter 6 General Discussion 179 6.1. Barrier repair strategies in the treatment of irritant contact 183 dermatitis 6.2. Barrier repair strategies in the treatment of atopic dermatitis 190 6.3. Barrier repair strategies in the treatment of psoriasis 192 General conclusions 194 Summary 201 Samenvatting 207 List of publications 213 Curriculum vitae 216 Dankwoord 218 Colour Illustrations 221 7 8 1 General Introduction 8 Chapter 1 General Introduction 10 11 Chapter 1 General Introduction 1.1 STRUCTURE AND FUNCTION OF THE EPIDERMIS 1.1.1. Anatomy and organisation of human epidermis 1 The normal epidermis is a non-vascularized, terminally differentiating, stratified squamous epithelium, which is supplied of nutrients by diffusion through the underlying dermis and through the basement membrane. The major cell, making up 95% of the total, is the keratinocyte and its differentiation product, the corneocyte. Originating from a pool of cells with a limited proliferative potential, called transient amplifying cells, the newly formed keratinocytes move from the epidermal basement membrane towards the skin surface in two weeks. Microscopically we can distinguish the epidermis in four layers: stratum basale or stratum germinativum, stratum spinosum, stratum granulosum, and stratum corneum (SC). The stratum basale consists of a continuous one cell thick layer, attached to the basement membrane by hemidesmosomes and integrin receptors. The basal cells are small and cuboidal and have large, dark-staining nuclei. Immediately above the basal cell layer, the differentiating keratinocytes enlarge and form a layer, which is called the stratum spinosum because of the many desmosomes. In this layer the protein involucrin is expressed. The stratum granulosum consists of cells with microscopically visible intracellular structures called keratohyalin granules, which contain many proteins needed for terminal differentiation. This is the last living layer which is very active. The cytoplasm of these cells also contains lamellar granules or bodies. The outermost layer of the epidermis is the stratum corneum where cells (corneocytes) have lost nuclei and cytoplasmic organelles. The cells become flattened and have a highly insoluble cornified envelope within the plasma membrane, formed by cross-linking of the soluble precursor, protein. In many areas of the skin, especially of the palms and soles a fifth layer can be observed called the stratum lucidum. It is the lower part of the stratum corneum, which stains as a homogeneous eosinophilic zone. During the migration from the inner layer to the outer layers of the epidermis, the keratinocytes undergo the following processes of proliferation and differentiation. Epidermal proliferation Corneocytes are continuously shed from the skin surface and replaced by cells from deeper layers. The increase of keratinocytes by proliferation in the basal and first suprabasal layer is under normal circumstances perfectly in balance with the loss from the outermost layer. This process is not observed by the naked eye and therefore it is called ‘desquamatio invisibilis’. In normal skin only 5-10 % of the basal cells is actively cycling.2 Several skin condition including psoriasis3 and wound healing are characterized by a strong increase of cycling cells. This phenomenon, called hyperproliferation, may serve the aim to repair, structurally and functionally, a damaged stratum corneum as quickly as possible. It may, however, also be a consequence of pathological processes, harmful to the subject. In irritant 10 11 Chapter 1 General Introduction contact dermatitis (ICD), environmental influences are responsible for damage to either the cellular or the intracellular compartment. It may result in an increase in cellular proliferation. This adaptive response may be caused by a direct interaction of irritants with the keratinocytes or by effects on the intercellular lipid domain and subsequent functional disturbances. Increased permeability for water may be a trigger for increased proliferation.4 Because corneocytes lack a nucleus, adaptive phenomena are the result of cellular responses in deeper layers. The stratum corneum is called a dead layer, but it should be realized that the stratum corneum contain many active enzymes in order to desquamate in the extremely orchestrated way as it does. In this thesis skin irritation by sodium lauryl sulfate (SDS) and dithranol is studied. SDS brings about strong effects on the skin barrier in contrast with dithranol. Both are, however, strong irritants inducing hyperproliferation.5;6 Epidermal differentiation As the epidermal keratinocytes move through the epidermis after losing their attachment to the basal lamina, they undergo the complex process of terminal differentiation, also known as keratinization, to produce SC. During this process plasma membrane is replaced by a tough, insoluble proteinaceous envelope. This layer, which is called the cornified envelope, consists of cross-linked proteins. First the proteins involucrin, envoplakin, and periplakin are sequentially cross-linked by epidermal transglutaminases (TGases), that promote the formation of disulphide and (-glutamyl)lysine isopeptide bonds. Proteins such as loricrin, elafin, S100, and small proline-rich region proteins (SPRRs) are incorporated later to form a mature envelope.7-9 This leads to a highly rigid insoluble structure, which is embedded in lipids from the plasma membrane and lipids secreted by the granular cells. During epidermal differentiation, epidermal lipids undergo a dramatic change both in composition and localisation resulting from activities of multiple enzymes.10 Basal and spinous cells show a complex lipid composition with phospholipids as the major constituents. The phospholipids contain a high proportion of linoleic acid. With progressive differentiation of the epidermis into the stratum, a marked decrease in phospholipids is observed while the amount of sphingolipids (ceramides and glucosylceramides) and cholesterol proved to be increased.11;12 At the end of the differentiation, the content of ceramides and neutral lipids is increased from the inner to the