The irritant potential of n-propanol (nonanoic acid vehicle) in cumulative skin irritation: a validation study of two different human in vivo test models.

BACKGROUND/PURPOSE: Human in vivo cumulative irritation tests with low-grade irritants simulate real-life exposure to skin irritants. The test outcome depends not only on the substance tested but also on the design of the assay. More than one experimental irritant is usually used because chemicals have diverse mechanisms of action on the skin. We used sodium lauryl sulfate (SLS) and nonanoic acid (NON) in three different concentrations plus their vehicles, water and n-propanol, respectively, to validate our test models and to optimize test concentrations. METHODS: Healthy volunteer forearm skin was exposed in two different cumulative test models: a repeated open model (ROAT) and an exaggerated wash test model. ROAT: 10-min daily exposures for 5+4 days (no irritation on weekend) to SLS 0% (water), 0.5%, 1.0% and 2.0% on the right arm and NON 0% (n-propanol neat), 10%, 20% and 30% on the left arm. Wash test: induction of irritation by three daily washings for 6 days and maintenance of the dermatitis by two daily washings for 12 days with SLS 0%, 5%, 10% and 15% or NON 0%, 30%, 40% and 50%. Reactions were evaluated clinically and instrumentally (transepidermal water loss, colorimetry and hydration) at sequential time points. Additionally, for the wash test, subjective pain scores were obtained from the volunteers. RESULTS: In the ROAT, n-propanol exhibited irritation potential at the level of SLS 1.0% and, by visual scoring, was only found to be significantly different from the two highest concentrations of NON (20% and 30%). In the wash test, n-propanol was much less irritating than SLS, and it could only be distinguished statistically from NON (any concentration) by visual reading. For both test models, n-propanol, by instrumental measurements, was not significantly different from any NON concentration. CONCLUSION: In cumulative irritation test assays, n-propanol appears to be quite irritant itself and may thus be a significant contributor to NON irritation. Moreover, n-propanol was more irritant in the ROAT compared with the wash test.

[Buschke adult scleroderma as a rare differential stiff-man syndrome diagnosis]. / Scleroedema adultorum Buschke als seltene Differentialdiagnose des Stiff-man-Syndroms.

Stiff-man syndrome is a rare disorder of the central nervous system characterized by muscular rigidity and superimposed spasms. The etiology is still unknown and an autoimmune cause is discussed. Many differential diagnoses of muscular rigidity and of induration of the skin have to be considered. A 22 year old patient was admitted under suspicion of a stiff-man syndrome. He has had developed a painful rigidity of the trunk, starting in the neck. Massive stiffness of the trunk with pale appearance of the skin and a beginning disorder of swallowing and respiration were observed. Clinical investigation, EMG, cerebrospinal fluid and laboratory findings were all normal, thus excluding a stiff-man syndrome and other neuromuscular diseases. Skin biopsy showed typical changes of Buschke's scleredema adultorum, a rare connective tissue disorder of unknown etiology. Therapy with corticosteroide and ciclosporin led to a mild improvement of symptoms. Although rare, Buschke's scleredema adultorum should be regarded as a differential diagnosis of the stiff man syndrome.

Role of epidermal cell-derived alpha-melanocyte stimulating hormone in ultraviolet light mediated local immunosuppression.

Irradiation of the skin with ultraviolet light (UV) results in profound alterations of both local and systemic immune responses. These effects are largely mediated by soluble mediators released from epidermal cells in response to UV. It is well known that keratinocytes release increased amounts of cytokines upon UV-irradiation. UV-light also induces the release of the proopiomelanocortin (POMC)-derived peptide, alpha-melanocyte-stimulating hormone (alpha MSH), from keratinocytes, and upregulates the expression of POMC mRNA. alpha MSH exerts a variety of immunomodulating and antiinflammatory effects, mainly by virtue of its capacity to alter the function of antigen presenting cells and vascular endothelial cells. Within an in vivo mouse-model, both intravenous and topical application of alpha MSH resulted in inhibiting the induction, eliciting a contact hypersensitivity reaction, and inducing hapten-specific tolerance. These findings indicate that alpha MSH, released in the epidermis after UV irradiation, may contribute to UV-mediated immunosuppression. The therapeutic application of alpha MSH or alpha MSH-derived peptides may prove to be a useful approach for treating inflammatory skin diseases.

Alpha-melanocyte-stimulating hormone modulates activation of NF-kappa B and AP-1 and secretion of interleukin-8 in human dermal fibroblasts.

Alpha-melanocyte-stimulating hormone (alpha-MSH) has evolved as a mediator of diverse biological activities in an ever-growing number of non-melanocytic cell types. One mechanism by which alpha-MSH exerts its effects is modulation of AP-1 and NF-kappa B. These two transcription factors also play an important role in fibroblasts, in extracellular matrix composition, and in cytokine expression. By use of electric mobility shift assays, we demonstrate that alpha-MSH (10(-6) to 10(-14) M) activates AP-1 in human dermal fibroblasts, whereas coincubation with interleukin-1 beta (IL-1 beta) results in suppression of its activation. alpha-MSH also induces activation of NF-kappa B but does not modulate DNA binding on costimulation with IL-1 beta. Since AP-1 and NF-kappa B are key elements in controlling interleukin-8 (IL-8) transcription, human fibroblasts were treated with alpha-MSH and IL-1 beta for 24 hours, and cytokine levels in the supernatants were measured by ELISA. alpha-MSH alone had little effect, whereas coincubation with IL-1 beta led to marked downregulation of IL-8 secretion (at most 288 +/- 152 ng/mL) when compared to treatment with IL-1 beta alone (919 +/- 157 ng/mL). Our results indicate that alpha-MSH exerts modulatory effects on the activation of NF-kappa B and AP-1, and that it can regulate chemokine secretion in human dermal fibroblasts. These effects of alpha-MSH may have important regulatory functions in extracellular matrix composition, wound healing, or angiogenesis.

Aging and the skin immune system.

OBJECTIVE: To give a brief summary of age-related alterations that occur in the immune system (immunosenescence), with special regard to the skin immune system. DATA SOURCES: MEDLINE and institutional libraries were searched for relevant articles on immunosenescence and corresponding key words. DATA SYNTHESIS: The immune system of aged animals and humans undergoes alterations that may account for an increased susceptibility to certain infections, autoimmune diseases, or malignancies. However, some data on the parameters of immunosenescence are controversial. This appears to be caused by variations in study designs or by the many external influences that superimpose on intrinsic alterations of the immune system. Well characterized are age-related changes of T cells and cell-mediated immunity. With advancing age, human and murine T cells undergo a shift from the naive to the memory phenotype, associated with a change in cytokine profile. The cells also reveal reductions in the proliferative response to activation, in diversity of the T-cell receptor antigen repertoire, and in cytolytic activity. B cells of aging individuals show a restricted diversity of their antibody repertoire due to a decline in somatic mutations, resulting in a reduced response to certain viral infections or vaccinations. The number of Langerhans cells appears to decline with age, contributing to a reduced rate of sensitizations. Macrophages and keratinocytes also undergo age-related changes, although these are less well characterized. They entail alterations in cytokine production, which could play a role in increased susceptibility to endotoxins in elderly individuals. CONCLUSIONS: With aging, the skin immune system shows a decline in its adaptive capability, one of its outstanding qualities. Manipulations to revert age-related dysfunctions are being tested and may help to extend a healthy life.