Arachidonic acid metabolism in primary irritant dermatitis produced by patch testing of human skin with surfactants.

A clinical study was performed to determine the effects of patch testing human skin with four industrially used surfactants on erythema formation, transepidermal water loss, and the contents in suction blister fluids of primary proinflammatory mediators including arachidonic acid, eicosanoids, and IL-1 alpha, which were analyzed by quantitative gas chromatography/negative ion chemical ionization mass spectrometry and by an enzyme-immunoassay, respectively. Benzalkonium chloride (BKCI) and sodium lauryl sulfate (SLS) elicited erythema and caused increased transepidermal water loss, indicating a disturbance of the epidermal barrier. Triethanolamine (TEA) and Tween 80 did not evoke these gross symptoms of inflammation. Suction blister fluids collected after a 24-h application of BKCl, SLS, and Tween 80 contained significantly increased amounts of individual eicosanoids whereas TEA induced no response. The induced eicosanoid profile was characteristic for each compound, pointing to different cell types of skin to be involved in their production. The elevation of prostaglandin and LTB4 contents correlated with the induction of erythema and the impairment of the epidermal barrier as shown for BKCl and SLS and preceded the maximum of erythema formation. IL-1 alpha contents did not correlate with these gross symptoms of inflammation. The results of this in vivo study support those of a previous study using human keratinocytes in culture indicating the release of arachidonic acid and prostaglandins to be an early event involved in the interaction of keratinocytes with surfactants. Moreover, the in vivo data with human skin underscore the mechanistic relationship to the in vitro model and support the concept that arachidonic acid and eicosanoid release from keratinocytes can be used as a marker of primary skin irritation.

Mechanisms in tumor promotion: guidance for risk assessment and cancer chemoprevention.

In mouse skin, tumor development promoted by 'non-genotoxic' carcinogens is closely related to the wound response. In both cases endogenous factors such as cytokines and eicosanoids released primarily from 'activated keratinocytes' play a key role as mediators of inflammation and cellular hyperproliferation. The liberation of interleukin-1 alpha and arachidonic acid from human keratinocytes has been used as an in vitro parameter of irritancy. The results (from experiments with 15 different chemicals) being validated at present in a clinical study indicate a quantitative relationship between irritancy in vivo and mediator release in vitro. In the course of experimental skin carcinogenesis an overproduction of eicosanoids due to a constitutive overexpression of the corresponding enzymes (i.e. PGH synthase-II and 8- and 12-lipoxygenase) is observed. Enzyme inhibitors, for instance nonsteroidal antiinflammatory drugs (NSAIDs), exert a strong tumoristatic effect. Thus, the approach of multistage skin carcinogenesis provides a suitable animal model for a mechanistic evaluation and further improvement of chemopreventive measures such as the inhibition of colorectal tumor development in humans by NSAIDs ('aspirin effect').

Hair growth induction by substance P.

BACKGROUND: In vitro, some neuropeptides, including the tachykinin, substance P (SP), act as growth factors. The cyclic growth of the richly innervated hair follicle offers a model for probing such functions in a complex, developmentally regulated tissue interaction system under physiologic conditions. Dissecting the role of neuropeptides in this system may also reveal as yet obscure neural mechanisms of hair growth control. EXPERIMENTAL DESIGN: The neuropeptide-releasing neurotoxin, capsaicin was injected intradermally, or SP slow-release formulations were implanted subcutaneously in the back skin of C57BL/6 mice with all follicles in the resting stage of the hair cycle (telogen) in order to see whether this induced hair growth (anagen). In addition, the endogenous SP skin concentration and the activity of the main SP-degrading enzyme, neutral endopeptidase, were determined during the induced murine hair cycle by high performance liquid chromatography-controlled radioimmuno-assay (SP) or by fluorometry (neutral endopeptidase). RESULTS: Both capsaicin and SP induced significant hair growth (anagen) in the back skin of telogen mice. This was associated with substantial mast cell degranulation. The endogenous SP skin concentration showed significant, hair cycle-dependent fluctuations during the induced murine hair cycle, which were largely independent of the activity of neutral endopeptidase. CONCLUSIONS: SP may play a role in the neural control of hair growth. Whereas this pilot study does not address the underlying mechanisms of action, it demonstrates that SP has potential as a hair growth-stimulatory agent in vivo, and serves as a basis for exploring the role of tachykinins in epithelial-mesenchymal-neuroectodermal interaction systems like the hair follicle.