Low Humidity Stimulates Epidermal DNA Synthesis and Amplifies the Hyperproliferative Response to Barrier Disruption: Implication for Seasonal Exacerbations of Inflammatory Dermatoses

Abstract

Although seasonal changes in humidity are thought to exacerbate various skin diseases, whether these flares can be attributed to prolonged exposure to extremes in environmental humidities has not been studied systematically. We recently showed that prolonged exposure to high versus low humidities induced profound changes in epidermal structure and permeability barrier homeostasis. Therefore, we asked here whether comparable extremes in humidity could initiate not only homeostatic, but also potentially pathophysiologic alterations. We showed first that exposure to low humidity increases epidermal DNA synthesis in normal murine epidermis. Moreover, exposure to a low humidity for 48 h further amplifies the DNA synthetic response to barrier disruption, resulting in marked epidermal hyperplasia. Additionally, exposure to a dry environment for 48 h prior to barrier disruption results in dermal mast cell hypertrophy, degranulation, as well as histologic evidence of inflammation. To demonstrate the role of changes in external moisture on these phenomena, we applied either an occlusive, water-impermeable plastic membrane, Petrolatum, or a nonocclusive humectant, both to nonperturbated and to perturbed skin. All three forms of treatment prevented the epidermal hyperplasia and dermal mast cell hypertrophy and degranulation induced by exposure to low humidity. These studies indicate that (i) exposure to changes in environmental humidity alone induces increased keratinocyte proliferation and markers of inflammation, and (ii) that these changes are attributable to changes in stratum corneum moisture content. Finally, these studies provide evidence that changes in environmental humidity contribute to the seasonal exacerbations/amelioration of cutaneous disorders, such as atopic dermatitis and psoriasis, diseases which are characterized by a defective barrier, epidermal hyperplasia, and inflammation.

Filaggrin Genotype in Ichthyosis Vulgaris Predicts Abnormalities in Epidermal Structure and Function

“…Prior studies have shown that prolonged exposure of normal skin to reduced environmental humidity stimulates mast cell infiltration. 74 Furthermore, we observed an inverse relationship between FLG gene dose and skin surface pH in all FLGdeficient patients, with double-allele subjects displaying the greatest elevations in skin surface pH ( Figure 2E). This increase in skin surface pH could reduce the activity of ceramide-generating hydrolases, 55,75 accounting for the observed delay in maturation of extracellular lamellar bilayers in IV ( Figure 5, D and E).…”

Environmental risk factors and their role in the management of atopic dermatitis

“…However, higher humidity may also provoke perspiration, which can be irritating and aggravate pruritus. A study in murine models showed that low humidity induces epidermal DNA synthesis, causes mast cell degranulation, and leads to epidermal hyperplasia in response to barrier disruption [91]. Another study demonstrated that transferring mice from a humid to dry environment resulted in increased acute TEWL, which may be explained by altered distribution of epidermal lamellar bodies encountered on electron microscopy [92].…”

Basis for the barrier abnormality in atopic dermatitis: Outside-inside-outside pathogenic mechanisms

“…9,12 Decreased SC hydration is not merely of cosmetic concern because it alone suffices to stimulate epidermal hyperplasia and early evidence of inflammation, such as mast cell degranulation, even in normal skin. 25 Whether additional defensive functions of the SC, such as antioxidant or UV defense, also fail in patients with AD remain unknown. Nevertheless, AD can be viewed as a disease of broad barrier failure.…”

“…32 NS is characterized by severe AD, mucosal atopy, and anaphylactic reactions to food antigens. 25,26 Residual lymphoepithelial Kazal-type trypsin inhibitor expression in NS correlates inversely with excess SP activity within the outer epidermis, 33 resulting in a severe permeability barrier defect and dramatic thinning of the SC because of unrestricted, SP-dependent degradation of lipid-processing enzymes and corneodesmosome-constituent proteins, respectively. 33,34 Pertinently, several European, American, and Japanese case-control studies of patients with AD or mucosal atopy have found an increased frequency of single nucleotide polymorphisms (Glu420Lys) in SPINK5.…”