Neurogenic control of blood flow and histamine release in psoriatic skin

Abstract

The manifestation of psoriasis represents an interaction between a genetically predisposed individual and environmental influences such as infections, trauma, stress, endocrine factors, sunlight and drugs. The cutaneous lesions are characterised by marked epidermal proliferation, complex alterations in epidermal differentiation, multiple biochemical, immunological, inflammatory and vascular abnormalities and a poorly understood relationship with the central and peripheral nervous system function. Hypothesis : Multiple observations are compatible with the existence of a peptidergic neurogenic mechanism in the pathophysiology of psoriatic plaque. Our hypothesis was that afferent nociceptive nerve-fibre endings in lesional skin are sensitised and activated by an unknown mediator. Via an axon-reflex mechanism in afferent C and A-delta fibre endings, these nerves release neuropeptides, which themselves have dilating effects and, in addition, may induce mast-cell degranulation/histamine release causing further vasodilatation. A pathological axon-reflex mechanism may thus contribute to the high blood flow and stimulate histamine release in lesional psoriatic skin. To test this hypothesis, a series of functional studies was conducted to elucidate whether local neurogenic peptidergic mechanisms are of importance for the maintenance of the increase in blood flow and whether such mechanisms may induce histamine release in psoriatic plaque. Methods : Healthy subjects and patients with untreated psoriatic lesions were examined. The microdialysis technique was evaluated for application in dermal skin through measurements of tissue perturbations induced by the microdialysis catheter. A new calibration technique, retrodialysis calibration, was tested and used to evaluate the concentration and release of histamine in lesional and non-lesional skin before and during the local stimulation and inhibition of nociceptive afferent nerves. The short term application of topical capsaicin was used to excite such neurones. Long-term treatment with capsaicin which desensitises nociceptive fibres or local anaesthesia was used to inhibit the activity. A laser Doppler technique was used to measure changes in perfusion before and after the provocations and 133Xenon clearance methodology was used to estimate skin blood flow. Results : Perfusion, blood flow, histamine concentration and histamine release increased in lesional skin as compared with non-lesional tissue. The inhibition of nervous activity by topical local anaesthesia decreased the perfusion and augmented the concentration of histamine but did not change the histamine release in lesional skin. No changes in these parameters were found in non-lesional skin. The stimulation of C-fibres by short-term capsaicin treatment increased the perfusion and the concentration and release of histamine in both lesional and non-lesional skin. Long-term capsaicin treatment reduced the perfusion in lesional skin and increased it in lesion-free skin. Conclusion : The results are compatible with the hypothesis that a pathological axon reflex may contribute to the high blood flow in lesional psoriatic skin. In contrast, the increase in histamine release, is mediated either not at all or only to a minor extent by neurogenic mechanisms.