vasoactive-intestinal-peptide and Skin-Diseases

Neuropeptides (NP) are a heterogeneous group of proteins functioning as neurotransmitters, neuromodulators and neurohormones. More than fifty of these molecules have been described, and some have been detected in human skin through immunochemistry and radioimmunoassay. In this article we attempt to study the role played by some of these substances such as substance P (SP), calcitonin gene related peptide (CGRP), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), somatostatin (S), and neurotensin (N). Several NP induce inflammatory response with edema and erythema. They can also induce the release of histamine by mastocytes, regulate cutaneous blood flow, and participate in sweat regulation and nociception. They also exert their action over several cells that participate in immunity, acting as mitotic, and chemotactic factors, inhibiting or stimulating inflammatory mechanisms. Specific NP have their receptors on epidermal cells. We will also try to study certain diseases in which NP play an important role in inducing or alleviating lesions, such as psoriasis, atopic eczema, alopecia areata, vitiligo, nodular prurigo, aquagenic pruritus, hypertrophic scars and other entities.

Topics: Calcitonin; Humans; Neuropeptide Y; Neuropeptides; Neurotensin; Skin Diseases; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Neuropeptides are neurotransmitters and neurohormones that play a role in various cutaneous functions. Keratinocytes and dermal endothelial cells are able to synthesize neuropeptides which are transported by nerve fibers or immune cells. Specific receptors for neuropeptides are also present on cutaneous cells. Neuropeptides intervene as neurogenic modulators of inflammatory reactions and therefore participate in the pathogenesis of skin diseases. An increasing body of evidence supports the setting up of clinical trials using topically neuropeptide agonists and/or antagonists in the treatment of chronic inflammatory skin disorders such as post-herpetic neuralgia, prurigo nodularis, localized pruritus, psoriasis, atopic dermatitis, contact dermatitis, cold urticaria, nostalgia paresthetica, diabetic neuropathy, Raynaud's phenomenon. In the near future, neuropeptides will represent a new approach to skin therapy.

Topics: Animals; Calcitonin Gene-Related Peptide; Forecasting; Humans; Neuropeptides; Skin; Skin Diseases; Tachykinins; Vasoactive Intestinal Peptide

Neurokinins are a family of peptides which are released from sensory nerves. This family involves substance P, neurokinin A and B which stimulate neurokinin-NK1, -NK2 and -NK3 receptors respectively. The neurokinins as well as C.G.R.P. (calcitonin gene related peptide) and V.I.P. (vasoactive intestinal peptide) are the mediators of the non adrenergic non cholinergic (N.A.N.C.) nervous system. All these peptides can be released by nerve fibres innervating the skin. They are mainly inflammatory mediators. At skin level, the neurokinin induce itch, wheal and flare. Itch and flare are partly due to histamine release from mast cells in response to substance P.

Topics: Amino Acid Sequence; Animals; Calcitonin Gene-Related Peptide; Edema; Erythema; Histamine Release; Humans; Mast Cells; Molecular Sequence Data; Neurons, Afferent; Pruritus; Receptors, Tachykinin; Skin; Skin Diseases; Tachykinins; Vasoactive Intestinal Peptide

Information concerning GEP hormones has progressively advanced since the initial discovery of a GEP hormone, secretin, in 1902. Studies in this area flourished with the advent of radioimmunoassay, and have provided an understanding of the secretion, regulation, metabolic actions, and role in certain diseases of major GEP hormones. Measurement of GEP hormones has achieved importance in clinical medicine and allowed understanding of the pathophysiology of several clinical disorders. The decade to come should witness additional advances in this rapidly expanding field.

Topics: Chemical Phenomena; Chemistry; Cholecystokinin; Diabetes Mellitus; Diarrhea; Endocrine System Diseases; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Hypoglycemia; Motilin; Neoplasms; Neurotensin; Pancreatic Polypeptide; Peptic Ulcer; Secretin; Skin Diseases; Somatostatin; Substance P; Vasoactive Intestinal Peptide

We analysed vasoreactions and sensations of atopic eczema (AE) patients and healthy controls after intracutaneous (i.c.) injection of vasoactive intestinal polypeptide (VIP) and acetylcholine (ACh). Blood flow was measured by laser Doppler flowmetry (LDF). Plasma extravasation and flare size were evaluated planimetrically, and sensations were recorded using visual analog scales. Three groups of subjects (controls, AE patients suffering from acute eczema and AE patients during a symptom-free period) were investigated. We administered VIP separately at concentrations of 1.5 x 10(-7), 1.5 x 10(-6) and 1.5 x 10(-5) M and in combination with ACh (5.5 x 10(-6) M) into the volar forearm of the subjects. Both substances led to an increase in LDF measurements and induced a wheal and flare reaction. Blood flow was elevated as a function of dose after a single VIP application in all groups. Compared with healthy controls, a significant increase in blood flow was measured after combined VIP and ACh administration in AE patients suffering from acute AE, whereas flare area and plasma extravasation were significantly reduced after single VIP and combined VIP and ACh injections, respectively. In all groups, VIP induced dose-dependent pruritus. Compared with a control stimulus (0.9% sodium chloride and ACh), combined injections of VIP and ACh had no additional effect on the magnitude of the sensation. In AE patients, the intensity was similar to that experienced by the control subjects, but the quality of sensation was different: ACh induced pain in the control subjects, pruritus in AE patients, and a mixture of pain and itching in AE patients showing no symptoms. Our results suggest that VIP- and ACh-induced skin reactions and the quality of the sensations depend on the activity of the atopic eczema. Confirming our former studies, AE patients develop a different quality of sensation after ACh administration and also after administration of VIP combined with ACh. Therefore, we suggest that ACh might be involved in the pathomechanisms of pruritus in AE.

Topics: Acetylcholine; Adult; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Female; Humans; Hypersensitivity; Injections, Intradermal; Laser-Doppler Flowmetry; Male; Pruritus; Regional Blood Flow; Severity of Illness Index; Skin; Skin Diseases; Skin Tests; Vasoactive Intestinal Peptide

Epidermal Langerhans cells (LCs) are dendritic APCs that play an important role in cutaneous immune responses. LCs are associated with epidermal nerves and the neuropeptides vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) inhibit LC Ag presentation for Th1-type immune responses. Here, we examined whether PACAP or VIP modulates LC Ag presentation for induction of IL-17A-producing CD4(+) T cells. Treatment with VIP or PACAP prior to in vitro LC Ag presentation to CD4(+) T cells enhanced IL-17A, IL-6, and IL-4 production, decreased interferon (IFN)-γ and interleukin (IL)-22 release, and increased RORγt and Gata3 mRNA expression while decreasing T-bet expression. The CD4(+) T-cell population was increased in IL-17A- and IL-4-expressing cells and decreased in IFN-γ-expressing cells. Addition of anti-IL-6 mAb blocked the enhanced IL-17A production seen with LC preexposure to VIP or PACAP. Intradermal administration of VIP or PACAP prior to application of a contact sensitizer at the injection site, followed by harvesting of draining lymph node CD4(+) T cells and stimulation with anti-CD3/anti-CD28 mAbs, enhanced IL-17A and IL-4 production but reduced production of IL-22 and IFN-γ. PACAP and VIP are endogenous mediators that likely regulate immunity and immune-mediated diseases within the skin.

Topics: Animals; Antigen Presentation; Cytokines; Epidermis; Female; Langerhans Cells; Mice; Mice, Inbred BALB C; Mice, Transgenic; Pituitary Adenylate Cyclase-Activating Polypeptide; Skin Diseases; Th1 Cells; Th17 Cells; Vasoactive Intestinal Peptide

Merkel cells (MCs) are involved in mechanoreception, but several lines of evidence suggest that they may also participate in skin disorders through the release of neuropeptides and hormones. In addition, MC hyperplasias have been reported in inflammatory skin diseases. However, neither proliferation nor reactions to the epidermal environment have been demonstrated. We established a culture model enriched in swine MCs to analyze their proliferative capability and to discover MC survival factors and modulators of MC neuroendocrine properties. In culture, MCs reacted to bFGF by extending outgrowths. Conversely, neurotrophins failed to induce cell spreading, suggesting that they do not act as a growth factor for MCs. For the first time, we provide evidence of proliferation in culture through Ki-67 immunoreactivity. We also found that MCs reacted to histamine or activation of the proton gated/osmoreceptor TRPV4 by releasing vasoactive intestinal peptide (VIP). Since VIP is involved in many pathophysiological processes, its release suggests a putative regulatory role for MCs in skin disorders. Moreover, in contrast to mechanotransduction, neuropeptide exocytosis was Ca(2+)-independent, as inhibition of Ca(2+) channels or culture in the absence of Ca(2+) failed to decrease the amount of VIP released. We conclude that neuropeptide release and neurotransmitter exocytosis may be two distinct pathways that are differentially regulated.

Topics: Animals; Calcium Signaling; Cell Proliferation; Cells, Cultured; Skin; Skin Diseases; Swine; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide has been demonstrated to lack inherent effects on capillary permeability, but also to potentiate the oedema promoting actions of other inflammatory mediators or even to strongly reduce organ damage and subsequent oedema in ischemic models of the lung and heart. This study investigated the role of VIP on oedema in partial- and full-thickness skin burns of anaesthetised rats in vivo by spectrophotometrical quantification of Evans blue albumin. Results show that systemic VIP elicited a significant drop in mean arterial blood pressure versus saline (p<0. 001) and VIP antiserum (p<0.001) both in burned and non-burned animals. VIP also decreased heart rate versus saline (p<0.05) and anti-VIP (p<0.01) in non-burned and burned animals. EB-albumin in normal skin was significantly inhibited by VIP as compared to saline (p<0.05), but did not differ significantly from VIP-antiserum. A significant inhibition of EB-albumin extravasation versus saline was also seen following administration of VIP-antiserum (p<0.01). Similarly, VIP significantly reduced EB-albumin extravasation versus saline treatment in partial-thickness (p<0.01) and full-thickness burns (p<0.001), while VIP-antiserum had no significant effect on skin perfusion in any of the burned groups as compared to saline treatment. The present results show that systemic VIP is a potent inhibitor of burn oedema. This effect could be secondary to constriction of skin vessels as a result of VIP-induced systemic hypotension or be mediated by the interaction of VIP with other oedema promoting mediators released following a thermal trauma to the skin.

Topics: Animals; Blood Pressure; Burns; Capillary Permeability; Coloring Agents; Edema; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Heart Rate; Hypotension; Immune Sera; Inflammation Mediators; Male; Rats; Rats, Sprague-Dawley; Skin; Skin Diseases; Sodium Chloride; Spectrophotometry; Vasoactive Intestinal Peptide; Vasoconstrictor Agents; Vasodilator Agents

Severe xerosis occurs in approximately 20% of human immunodeficiency virus seropositive patients. Changes in cutaneous innervation have been found in various inflammatory skin diseases and in xerotic skin in familial amyloid. We have therefore carried out a quantitative examination of the cutaneous peptidergic innervation in human immunodeficiency virus-associated xerosis. Immunohistochemistry and image analysis quantitation were used to compare total cutaneous innervation (protein gene product 9.5), calcitonin gene-related peptide, substance P, and vasoactive intestinal peptide peptidergic fibers, at two sites in the skin of human immunodeficiency virus-associated xerosis patients (upper arm, n = 12; upper leg, n = 11) and site-matched seronegative controls (upper arm, n = 10; upper leg, n = 10). Measurement of lengths of fibers of each type was carried out for each subject in the epidermis and papillary dermis, and around the sweat glands. Immunostained mast cells in these areas were counted. Epidermal integrity and maturation were assessed by immunostaining for involucrin. There were significant (Mann-Whitney U test; p < 0.02) decreases in total lengths of protein gene product 9.5 fibers in both epidermis/papillary dermis and sweat gland fields; of calcitonin gene-related peptide innervation in the epidermis/papillary dermis; and of substance P innervation of the sweat glands. There were no differences in the distribution of mast cells, or in the epidermal expression of involucrin. Depletion of the calcitonin gene-related peptide innervation may affect the nutrient blood supply of the upper dermis, and the integrity and function of basal epidermis and Langerhans cells. Diminished substance P innervation of the sweat glands may affect their secretory activity. Both of these changes may be implicated in the development of xerosis.

Topics: Adult; Aging; Anti-HIV Agents; Calcitonin Gene-Related Peptide; Disease Progression; Female; HIV Infections; Humans; Male; Middle Aged; Nervous System Physiological Phenomena; Peptides; Protein Precursors; Skin; Skin Diseases; Substance P; Thiolester Hydrolases; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

Topics: Calcitonin Gene-Related Peptide; Dermatology; Forecasting; Humans; Neuropeptides; Neurosecretory Systems; Skin; Skin Diseases; Substance P; Vasoactive Intestinal Peptide

Pieces of hairy skin tissue of fetal rat were transplanted into the anterior eye chamber of adult rats. The ability of autonomic and sensory nerve fibers from the host iris to innervate the grafted skin tissue was immunohistochemically and enzyme-histochemically examined using antisera against tyrosine hydroxylase (TH), substance P (SP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP), and a reaction medium for acetylcholinesterase (AchE). The grafted tissue was successfully implanted and connected with the host iris. Epidermis, dermis, subcutaneous tissue, hairs, hair follicles, sebaceous glands, and piloerector muscles developed in the graft. Two weeks after transplantation, TH-, SP-, and CGRP-immunoreactive fibers were observed in association with the blood vessels in the graft. Four weeks after transplantation, TH-immunoreactive fibers were distributed in the piloerector muscles, whereas SP- and CGRP-immunoreactive fibers were present around the hair follicles. VIP-immunoreactive and AchE-positive fibers were restricted to the host iris at all survival times. These results suggest that the outgrowth of autonomic and sensory nerve fibers from the host iris show target specificity for the grafted skin tissue.

Topics: Animals; Anterior Chamber; Antibodies, Monoclonal; Calcitonin Gene-Related Peptide; Female; Fetal Tissue Transplantation; Immunohistochemistry; Male; Rats; Rats, Inbred Strains; Skin; Skin Diseases; Skin Transplantation; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

Immunoreactivity to material like vasoactive intestinal polypeptide was found to occur within certain cellular elements of the epidermis in two patients out of four who had lesions of lichen sclerosus et atrophicus. No specific immunofluorescence to the material could be seen in the dermis, apart from single immunoreactive nerve fibers.

Topics: Adolescent; Adult; Animals; Atrophy; Female; Fluorescent Antibody Technique; Humans; Male; Middle Aged; Peptides; Rabbits; Rats; Sclerosis; Skin; Skin Diseases; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Adult; Aged; Diabetes Mellitus; Diagnosis, Differential; Female; Glucagonoma; Humans; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Skin Diseases; Somatostatinoma; Vasoactive Intestinal Peptide