EFFECT OF ENDOCANNABINOID SYSTEM AND CANNABIMIMETIC COMPOUNDS IN THE CONTROL OF MAST CELLS: POSSIBLE IMPLICATION IN ACUTE AND CHRONIC INFLAMMATION
De Filippis, Daniele (2009) EFFECT OF ENDOCANNABINOID SYSTEM AND CANNABIMIMETIC COMPOUNDS IN THE CONTROL OF MAST CELLS: POSSIBLE IMPLICATION IN ACUTE AND CHRONIC INFLAMMATION. [Tesi di dottorato] (Inedito)
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The present work aims to elucidate the emerging role played by cannabimimetic compounds in the control of mast cell activation. Mast cells are immune competent cells strategically located at sites directly interfacing with the external environment which, in case of injury, may regulate the immune response by the release of a plethora of both pre-formed and newly-synthesised mediators. However, although the main goal of mast cell activation is to initiate the inflammatory reaction, and thus to maintain internal homeostasis, the consequences of deregulated mast cell activation could led to chronically activate the inflammatory response, as it occurs in arthritis, inflammatory bowel diseases, atherosclerosis and asthma. Therefore, much effort has been made to develop compounds able to regulate mast cell degranulation. Several evidences suggested that cannabinoids as well palmitoylethanolamide (PEA), a fatty acid amide sharing several biological activities with cannabinoids, are considered as an emerging class of modulators of mast cell behaviour. We, firstly, focus our study on the effect of cannabimimetic compounds in the control of mast cell isolated both from human biopsies of endometritis and from rats and appropriately stimulated in vitro. Since to study mast cell functionality in vitro is sometime inappropriate in view of the considerable degree of mast cell heterogeneity, both in respect to their morphology, expression of proteins and, primarily, in respect to their different sensitivity to stimuli, therefore the study continued in an animal model of mast cell dependent chronic inflammation, as granuloma. The activation of endocannabinoid system or the up-regulation of PEA tone significantly reduced granuloma formation in rat through the control of mast cell activation preceding the release of pro-inflammatory and pro-angiogenic mediators. Moreover, our data evidenced that mast cells modulation by PEA resulted useful also in the management of pain associated to granuloma-formation. In fact PEA, through the control of the recognized “cross-talk” existing between mast cell-nerves, reduced mechanical allodynia in inflamed rats. These data are in well accordance with recently described deregulation of the neuro-immune axis occurring in the aetiology of inflammatory disease. The cannabimimetic control of neuro-immune axis was finally studied in a model of acute intestinal inflammation in mice. The administration of cannabidiol in septic mice, by the blockage of fatty acid amide hydrolase, prevented the activation of enteric glial cells in parallel to the immune cells (mast cell and macrophages) activation. The control of neuro-immune axis by cannabidiol finally resulted in its anti-inflammatory and protective effect in septic mice. According to the here reported evidences for a cannabimimetic control of mast cell, it is reasonable to propose these compounds, including PEA and its congeners, as possible candidate for treating several acute and chronic inflammatory diseases, recognizing in mast cell activation a common origin, such as dermatitis, inflammatory gastrointestinal syndrome and granuloma formation.
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