Increased levels of palmitoylethanolamide and other bioactive lipid mediators and enhanced local mast cell proliferation in canine atopic dermatitis

Abstract

BackgroundDespite the precise pathogenesis of atopic dermatitis (AD) is unknown, an immune dysregulation that causes Th2-predominant inflammation and an intrinsic defect in skin barrier function are currently the two major hypotheses, according to the so-called outside-inside-outside model. Mast cells (MCs) are involved in AD both by releasing Th2 polarizing cytokines and generating pruritus symptoms through release of histamine and tryptase. A link between MCs and skin barrier defects was recently uncovered, with histamine being found to profoundly contribute to the skin barrier defects.Palmitoylethanolamide and related lipid mediators are endogenous bioactive compounds, considered to play a protective homeostatic role in many tissues: evidence collected so far shows that the anti-inflammatory effect of palmitoylethanolamide depends on the down-modulation of MC degranulation.Based on this background, the purpose of the present study was twofold: (a) to determine if the endogenous levels of palmitoylethanolamide and other bioactive lipid mediators are changed in the skin of AD dogs compared to healthy animals; (b) to examine if MC number is increased in the skin of AD dogs and, if so, whether it depends on MC in-situ proliferation.ResultsThe amount of lipid extract expressed as percent of biopsy tissue weight was significantly reduced in AD skin while the levels of all analyzed bioactive lipid mediators were significantly elevated, with palmitoylethanolamide showing the highest increase.In dogs with AD, the number of MCs was significantly increased in both the subepidermal and the perifollicular compartments and their granule content was significantly decreased in the latter. Also, in situ proliferation of MCs was documented.ConclusionsThe levels of palmitoylethanolamide and other bioactive lipid mediators were shown to increase in AD skin compared to healthy samples, leading to the hypothesis that they may be part of the body’s innate mechanisms to maintain cellular homeostasis when faced with AD-related inflammation. In particular, the increase may be considered a temptative response to down-regulating the observed elevation in the number, functionality and proliferative state of MCs in the skin of AD dogs. Further studies are warranted to confirm the hypothesis.

Monocytes Are Recruited From Venules During Arteriogenesis in the Murine Spinotrapezius Ligation Model

“…These functions are consistent with the observed increase in mast cells associated with collateral arterioles following ligation treatment. Local proliferation of mast cells in skin was recently documented in a canine model of dermatitis(34). Our EdU proliferation assay results suggest these cells are capable of local proliferation in skeletal muscle.…”

Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders

“…It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathological conditions. This may include pathologies as osteoarthritis [19], atopic dermatitis [20], epilepsy [21], degenerative myelopathy [22], some neuroinflammatory diseases (meningitis-asteritis and intraspinal spirocercosis) [23], and others [24]. It is important to remark that the information collected in studies with dogs with these pathologies is not only important for the development of Sativex in Veterinary Medicine but also for their equivalents in the human pathologies, thus representing suitable translational models for studying specific human pathologies.…”

Ultramicronized palmitoylethanolamide counteracts the effects of compound 48/80 in a canine skin organ culture model

“…[1][2][3] For example, in the lesioned skin of dogs affected with atopic dermatitis (AD), PEA levels are more than 30-fold higher than in normal nonatopic skin. 4 Such increases are generally considered to be a mechanism to maintain or restore cellular homeostasis in the face of external stressors. 5 A growing literature documents the beneficial effects of exogenously administered PEA in both in vitro and in vivo models of acute and chronic inflammation.…”

“…Their cytoplasmic secretory granules store a variety of bioactive mediators, such as biogenic amines, neuropeptides, cytokines and proteases. [10][11][12][13] MCs are a key player in innate and acquired immune responses, particularly in allergic reactions, including human and canine AD, 4,10,14,15 and are known to regulate skin vasodilation. 14,16 On activation, MCs undergo degranulation and release their granule content into the extracellular microenvironment.…”