G. Varvara

Vascular Endothelial Growth Factor (VEGF), Mast Cells and Inflammation

Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis, therefore blocking angiogenesis has led to great promise in the treatment of various cancers and inflammatory diseases. VEGF, expressed in response to soluble mediators such as cytokines and growth factors, is important in the physiological development of blood vessels as well as development of vessels in tumors. In cancer patients VEGF levels are increased, and the expression of VEGF is associated with poor prognosis in diseases. VEGF is a mediator of angiogenesis and inflammation which are closely integrated processes in a number of physiological and pathological conditions including obesity, psoriasis, autoimmune diseases and tumor. Mast cells can be activated by anti-IgE to release potent mediators of inflammation and can also respond to bacterial or viral antigens, cytokines, growth factors and hormones, leading to differential release of distinct mediators without degranulation. Substance P strongly induces VEGF in mast cells, and IL-33 contributes to the stimulation and release of VEGF in human mast cells in a dose-dependent manner and acts synergistically in combination with Substance P. Here we report a strong link between VEGF and mast cells and we depict their role in inflammation and immunity.

Impact of mast cells on the skin.

When through the skin a foreign antigen enters it provokes an immune response and inflammatory reaction. Mast cells are located around small vessels that are involved in vasaldilation. They mature under the influence of local tissue to various cytokines. Human skin mast cells play an essential role in diverse physiological and pathological processes and mediate immediate hypersensitive reaction and allergic diseases. Injection of anti-IgE in the skin or other agents that directly activate mast cells may cause the decrease in vascular tone, leakage of plasma and may lead to a fall in blood pressure with fatal anaphylactic shock. Skin mast cells are also implicated as effector cells in response to multiple parasites such as Leishmania which is primarily characterized by its tissue cutaneous tropism. Activated macrophages by IFNγ, cytotoxic T cells, activated mast cells and several cytokines are involved in the elimination of the parasites and immunoprotection. IL-33 is one of the latest cytokines involved in IgE-induced anaphylaxis and in the pathogenesis of allergic skin disorders. IL-33 has been shown in epidermis of patients with psoriasis and its skin expression causes atopic dermatitis and it is crucial for the development of this disease. Here we review the impact of mast cells on the skin.

Impact of Capsaicin on Mast Cell Inflammation

Mast cells are inflammatory cells, and they are prominent in inflammatory diseases such as allergy and asthma. Mast cells possess high-affinity receptors for IgE (FCεRI) and the cross-linking of these receptors is essential to trigger the secretion of granules containing arachidonic acid metabolism [such as prostaglandin (PG) D2, leukotriene (LT) B4, and LTC4], histamine, cytokines, chemokines, and proteases, including mast cell-specific chymases and tryptases. Activation of mast cells provokes the secretion of cytokines and mediators that are responsible for the pathologic reaction of immediate hypersensitivity. Sensory nerve stimulation by irritants and other inflammatory mediators provokes the release of neuropeptides, causing an increase in vascular permeability, plasma extravasation and edema. Trigeminal nerve stimulation actives dura mast cells and increases vascular permeability, effects inhibited by capsaicin. Capsaicin causes release of sensory neuropeptide, catecholamines and vasodilation. Several studies have reported that capsaicin is effective in relief and prevention of migraine headaches, improves digestion, helps to prevent heart disease, and lowers blood cholesterol and blood pressure levels. The findings reported in these studies may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders.

Impact of neuropeptide substance P an inflammatory compound on arachidonic acid compound generation

There is much evidence that neuropeptide substance P is involved in neurogenic inflammation and is an important neurotransmitter and neurmodulator compound. In addition, substance P plays an important role in inflammation and immunity. Macrophages can be activated by substance P which provokes the release of inflammatory compounds such as interleukins, chemokines and growth factors. Substance P is involved in the mechanism of pain through the trigeminal nerve which runs through the head, temporal and sinus cavity. Substance P also activates mast cells to release inflammatory mediators such as arachindonic acid compound, cytokines/chemokines and histamine. The release of these chemical mediators is crucial for inflammatory response. Among these mediators there are prostoglandins and leukotrines. Here we review the impact of substance P on inflammatory compounds.

IL-36 Receptor Antagonist with Special Emphasis on IL-38:

IL-36 is another family member of IL-1 and induces the production of proinflammatory cytokines and activates MAPK and NFκB pathways. IL-36 is a common mediator of innate and adaptive immune response and is inhibited by IL-36 receptor antagonist (RA). IL-36RA acts on IL-36 receptor ligand which exerts proinflammatory effect in vivo and in vitro. IL-38 binds to IL-36 receptor as does IL-36RA and has similar biological effects on immune cells. IL-38 is also a member of IL-1 cytokine and shares some characteristics of IL-1RA, binding the same IL-1 receptor type I. IL-38 plays a role in the pathogenesis of inflammatory diseases, exerting protective effect in some autoimmune diseases. Both IL-38 and IL-36RA have an anti-inflammatory biological effect, however in some cases have contrary effects.

Inhibitor Effect of Antioxidant Flavonoids Quercitin, and Capsaicin in Mast Cell Inflammation

Mast cells are essential not only for allergies but also for innate and acquired immunity, autoimmunity and inflammation, and they are recognized as a new type of immunoregulatory cells capable of producing different cytokines. Natural compounds have long been recognized to possess anti-inflammatory, antioxidant and anticancergenic activity. Quercitin is an inhibitor for mast cells and is a potent antioxidant, cytoprotective and anti-inflammatory compound and has a negative effect on intracellular regulator signal events initiated by FceRI receptor cross-linking and other activating receptors on mast cells. These observations candidate quercitin as a therapeutic compound in association with other therapeutic molecules. Capsaicin is a compound derived from peppers, especially capsicum, and is involved in stimulating circulation aiding digestion and relieving pain. Capsaicin receptor sub type I (VRI) is expressing in neurons and is present in a number of brain nuclei and in non-neuronal tissues, mediating inflammatory response. Capsaicin is involved in migraine, allergic symptoms, arthritis pain and gastric secretion. In this paper we review the biological effects of quercitin and capsaicin.

Impact of Mast Cells in Rejection of Allografts

Mast cells in the tissue are located close to nerves in and around the small vessels where they orchestrate important immune response after antigen recognition through Toll-like receptors. Mast cells can activate T and B lymphocytes and dendritic cells and have been postulated to act directly within tissue allografts and/or to induce indirect effects via inflammatory mediator release, therefore they have been shown to play an indispensable role in allograft tolerance. Major limitation in the success of transplantation is the immune response of the recipient to the donor tissue. The failure of tissue grafting is caused by an inflammatory reaction called rejection. Mast cells play a role during immune response and are elicited with transplanted allograft and also may exhibit their immune-regulatory effects directly through secretion of modulatory cytokines and activation of metabolic pathways. However, the role of mast cells in transplantation is poorly understood. The most severe rejection episodes have been found in patients with an increased number of mast cells. Mast cell mediators which can activate latent forms of TGF-β or increase angiotensin II levels are capable of inducing fibrosis through various mechanisms, activating fibroblasts and inducing collagen synthesis. Mast cells are also implicated in regulatory T-cell functions and are required to sustain peripheral tolerance via Treg, therefore there is an interaction between mast cells and Treg cells. Treg create IL-9 in enhancing mast cell growth and Chemotaxis, suggesting that Treg and mast cells form a functional unit that mediates graft tolerance. In this study we concentrate our attention on the role of mast cells in rejection of allografts and try to understand the role of mast cell-related immune mechanisms in organ transplantation.

Impact of immunity in autism spectrum disorders

Autism spectrum disorders (ASDs) are childhood psychopathologies characterized by having difficulties in social interaction, verbal and non-verbal communication as well as sensor motor movements. Evidence suggests that in ASDs environmental toxicant exposure, genetic and mitochondrial dysfunction are involved associated with abnormal immune response with allergic problems and elevated serum IgE. ASDs present the major cytokine and chemokine dysfunction in CNS and is mediated by an increase of pro-inflammatory cytokine levels in the brain, such as TNF, IL-1, IFN-γ, IL-6, IL-8 and others. Mast cells, which are also implicated in ASDs, are worsened by stress and produce proinflammatory cytokines and can be stimulated by neurotensin in the brain and gut, contributing also to the inflammatory response. However, the exact etiology of ASDs remains largely unknown.

Soft-Tissue Healing and Impression Technique in Implant Dentistry: A Case Report

The present clinical report describes a technique for aesthetic restoration of single dental implants in the anterior area. One objective of implant therapy in anterior areas is the achievement of an aesthetic result, which is highly dependent on the condition of the peri-implant soft tissue. A 22-year-old woman presented with right maxillary lateral incisor agenesis. An implant was placed, and a transfer impression technique carried out. The model was used to construct the custom abutment, provisional crown, and metal substructure. The metal substructure was covered with a waxed collar with the same emergence profile as the provisional restoration. The abutment and the provisional crown were placed, and after soft-tissue healing, an impression was taken using the waxed metal framework as coping. This final impression also registered and transferred the architecture of the soft peri-implant tissues. This clinical report describes an impression technique that accurately duplicates the peri-implant tissue profile. The final prosthesis is therefore shaped according to the interim prosthesis, for ideal contour and soft-tissue position. This technical procedure requires minimal chair time and is cost effective, as fewer components are used during the treatment.