Development of Mechanisms Associated With Neurogenic-Mediated Skin Inflammation During the Growthof Rats

Abstract

Neurogenic-mediated inflammation may be associated with several inflammatory skin diseases including atopic dermatitis. However, age-dependent differences in neurogenic-mediated skin responses are not fully understood. We compared skin plasma leakage in rats aged 2 and 8 wk, which was induced by topical capsaicin, topical formalin, and intracutaneous substance P, whose effects are mediated via tachykinin NK1 receptors. Evans blue dye extravasation served as an index of the increase in skin vascular permeability. Capsaicin, formalin, and substance P caused a skin response in a dose-dependent manner in both age groups. However, the skin response was much greater in adults than in pups. In addition, the localization of sensory C-fibers and tachykinin NK1 receptors in the skin was investigated by immunofluorescent staining with antisubstance P and antitachykinin NK1 receptor antibodies, respectively. Substance P-immunoreactive nerves were detected throughout the dermis and tachykinin NK1 receptors were mainly detected in blood vessel walls in the dermis in both age groups. However, they were more sparsely distributed in pups. In conclusion, the weak neurogenic-mediated skin inflammation in pups is probably because of immature neural mechanisms associated with skin inflammation such as reduced innervation of sensory C-fibers and low expression of tachykinin NK1 receptors. (Pediatr Res 67: 363-368, 2010) N eurogenic-mediated inflammation may be associated with several inflammatory skin diseases including atopic dermatitis (1). Immediately after stimulation of nerve endings of sensory C-fibers, antidromic conduction through afferent nerve collaterals causes the release of neuropeptides such as substance P and calcitonin gene-related peptide from nerve endings of sensory C-fibers. The released neuropeptides lead to pain, pruritus, vascular modulation (i.e. plasma leakage, vasodilation, and endothelial cell activation), and activation of immune cells including T-and B-cells, and mast cells (1-3).In animal experimental models, it is more difficult to elicit neurogenic-mediated skin inflammation in younger animals, particularly during the perinatal period. Fitzgerald and Gibson (4) showed that topical mustard oil and antidromic stimulation of the sciatic nerve of rats, which specifically stimulate sensory C-fibers in the skin, are incapable of producing plasma leakage in the paw until postnatal day 11. However, this is inconsistent with previous data that substance P-immunoreactive nerves are detected even in the skin of rats aged day 0 -1 (4,5). Schotzinger and Landis (5) reported increases in the number of substance P-immunoreactive nerves in rat skin, branching pattern of nerves, and substance P immunoreactivity throughout neonatal life that approach adult levels by postnatal day 21. Therefore, the histologic immaturity of sensory C-fibers may be one reason for the lack or reduced level of neurogenic-mediated skin inflammation in rat pups. Neurogenic-mediated skin inflammation is also likely to depend on the e...

Neuro-Inflammation in Pediatric Traumatic Brain Injury—from Mechanisms to Inflammatory Networks

“…To the best of our knowledge there have been no studies examining the scope of neurogenic inflammation in the pediatric population or in models of pediatric TBI. Previous research has demonstrated a reduced expression of NK1 receptors and reduced neurogenic inflammatory response in P16 pups compared to adult rats [155], implying the neurogenic inflammation observed in older rodents may not be replicated in younger animals. Nonetheless, numerous adult rodent studies have illustrated a positive association between injury severity and SP release, as well as therapeutic benefit, in the form of reduced BBB permeability and vasogenic edema, following NK1 receptor antagonism [156] or neuropeptide depletion with capsaicin [157].…”

Staphylococcal Enterotoxin B Causes Proliferation of Sensory C-Fibers and Subsequent Enhancement of Neurogenic Inflammation in Rat Skin

“…Localization of substance P, transient receptor potential channel vanilloid 1 (TRPV1), tachykinin NK1 receptors, endothelial cells, NGF, brain-derived neurotrophic factor (BDNF), and tumor necrosis factor (TNF)-a were examined using immunofluorescence staining methods, and fluorescence image analyses were performed according to our previous methods [22]. PBS containing 1.5% nonimmune goat serum (Vector Laboratories) or mouse serum (Vector Laboratories) was used for blocking unoccupied sites.…”

“…Enhancement of Neurogenic Plasma Leakage in the Skin by Intracutaneous SEB. Neurogenic microvascular leakage in the skin was measured by quantifying the extravasation of Evans blue dye induced by topical formalin, according to our previous study [22,25]. SEB (200 lg/mL) or PBS was administered intracutaneously to anesthetized rats of both age groups (6 per group), as described above.…”

“…There is a strong association between infection with S. aureus and acute and subacute skin symptoms, such as impetigized lesions, that are commonly seen in infants with atopic dermatitis [1,2], suggesting that staphylococcal infection, partially involving superantigen-mediated mechanisms, may also potentially contribute to exaggerated neurogenic inflammation in atopic dermatitis during infancy. However, we previously showed that innervation of sensory C-fibers and tachykinin NK1 receptors were relatively sparse in the normal skin of pups, compared with those in adults [22]. We therefore investigated age-related differences in the effects of SEB on mechanisms associated with neurogenic skin inflammation between preweaning and adult rats.…”

Evaluation through in vivo reflectance confocal microscopy of the cutaneous neurogenic inflammatory reaction induced by capsaicin in human subjects

“…This type of reaction may have a contributing role in the development and aggravation of psoriasis, 1-3 atopic dermatitis, 3-6 urticaria, 1 and perioral dermatitis. 9 Neurogenic-mediated inflammation increasingly appears to be a factor in the onset and evolution of various skin diseases, 4,5,[10][11][12] and the study of interactions between the nervous system and the skin is of great interest for the scientific world. 9 Neurogenic-mediated inflammation increasingly appears to be a factor in the onset and evolution of various skin diseases, 4,5,[10][11][12] and the study of interactions between the nervous system and the skin is of great interest for the scientific world.…”