Abstract
Simple SummaryIn the present work, we developed an experimental preclinical model of skin with cutaneous field cancerization after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice). We observed impairments in the transepidermal water loss, stratum corneum hydration, and surface pH. We also detected a marked hyperkeratotic hyperplasia of the epidermis, induction of keratinocyte hyperproliferation, incidental actinic keratosis, and in situ squamous cell carcinomas in the UV-B light-irradiated groups. In this context, the association between the permeability barrier impairment and keratinocyte hyperproliferation might be considered a new target in the management of skin with cutaneous field cancerization. As current therapeutic approaches to actinic keratosis and cutaneous field cancerization only focus on the direct antineoplastic, immunomodulatory, or photodynamic effects of approved topical drugs, this mouse model of skin with cutaneous field cancerization might be helpful for both the identification and screening of potentially new preventive strategies or treatments (e.g., skin barrier therapies).Chronic ultraviolet B (UV-B) irradiation is known to be one of the most important hazards acting on the skin and poses a risk of developing photoaging, skin with cutaneous field cancerization (CFC), actinic keratosis (AKs), and squamous cell carcinomas (SCCs). Most of the UV-B light is absorbed in the epidermis, affecting the outermost cell layers, the stratum corneum, and the stratum granulosum, which protects against this radiation and tries to maintain the permeability barrier. In the present work, we show an impairment in the transepidermal water loss, stratum corneum hydration, and surface pH after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice) of skin with CFC. Macroscopic lesions of AKs and SCCs may develop synchronically or over time on the same cutaneous surface due to both the presence of subclinical AKs and in situ SCC, but also the accumulation of different mutations in keratinocytes. Focusing on skin with CFC, yet without the pathological criteria of AKs or SCC, the presence of p53 immunopositive patches (PIPs) within the epidermis is associated with these UV-B-induced mutations. Reactive epidermis to chronic UV-B exposure correlated with a marked hyperkeratotic hyperplasia, hypergranulosis, and induction of keratinocyte hyperproliferation, while expressing an upregulation of filaggrin, loricrin, and involucrin immunostaining. However, incidental AKs and in situ SCC might show neither hypergranulosis nor upregulation of differentiation markers in the upper epidermis. Despite the overexpression of filaggrin, loricrin, involucrin, lipid enzymes, and ATP-binding cassette subfamily A member 12 (ABCA12) after chronic UV-B irradiation, the permeability barrier, stratum corneum hydration, and surface pH were severely compromised in the skin with CFC. We interpret these results as an attempt to restore the permeability barrier homeostasis by the reactive epidermis, which fails due to ultrastructural losses in stratum corneum integrity, higher pH on skin surface, abundant mast cells in the dermis, and the common presence of incidental AKs and in situ SCC. As far as we know, this is the first time that the permeability barrier has been studied in the skin with CFC in a murine model of SCC induced after chronic UV-B irradiation at high doses. The impairment in the permeability barrier and the consequent keratinocyte hyperproliferation in the skin of CFC might play a role in the physiopathology of AKs and SCCs.
Highlights
The skin is constantly exposed to external damage, such as ultraviolet A (UV-A) and ultraviolet B (UV-B) radiation
cutaneous field cancerization (CFC), excluding incidental actinic keratosis (AKs) and in situ squamous cell carcinomas (SCCs) patches (Figure A1 and Table A1), were mainly correlated with: (1) hypergranulosis with orthokeratotic acanthosis; (2) hyperkeratosis; (3) increased vascularity consisting of ectatic blood vessels in the upper dermis; and (4) abundant mast cells in the dermis (Figure A2 and Table A1)
Significantly increased in both groups exposed to chronic UV-B light (26.78 ± 1.28 g/m2 /h, 100 mJ/cm2, p < 0.001; 29.9 ± 1.55 g/m2 /h, 150 mJ/cm2, p < 0.001) with respect to the nonirradiated group (9.39 ± 0.38 g/m2 /h) (Figure 1B), there was a significant decrease in stratum corneum hydration level (25.19 ± 1.24, 100 mJ/cm2, p < 0.001; 18.86 ± 1.39, 150 mJ/cm2, p < 0.001) in a dose-dependent manner with respect to the control group
Summary
The skin is constantly exposed to external damage, such as ultraviolet A (UV-A) and ultraviolet B (UV-B) radiation. The epidermis protects the body from UV-B radiation, and from other outside hazards such as pathogenic microorganisms [2], toxic chemicals [3], allergens [4], mechanical insults [5], etc In addition to this antimicrobial, chemical, and physical barrier, the skin must prevent both water and electrolyte loss from the internal milieu, which is defined as the permeability barrier. The regulation of water release from the organism into the atmosphere, known as transepidermal water loss (TEWL), is the main skin function because it is crucial to maintaining the homeostasis of the internal milieu [6,7,8] This permeability barrier is constituted by extracellular lipid membranes (extracellular lamellar bilayers), containing cholesterol, free fatty acids, and ceramides [7], and structural proteins, such as filaggrin, loricrin, and involucrin [9], located at the stratum corneum. Both conditions, age [10,13] and chronic UV-B light exposure [14,15], show permeability barrier derangements
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