Recombinant Neutral Endopeptidase Attenuates Substance P-Induced Plasma Extravasation in the Guinea Pig Skin

Rubinstein, Israel; Iwamoto, Itsuo; If, Ueki; Db, Borson; Ja, Nadel

doi:10.1159/000235122

Cited by 28 publications

(13 citation statements)

References 38 publications

(60 reference statements)

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“…The close association of SP and CGRP innervated mast cells with vasculature observed in this study supports the concept of axon reflex-mediated vasodilation in response to noxious stimuli (Lembeck and Holzer, 1979;Kiernan, 1975). Intradermal SP injection in rats causes mast cell histamine release, mimicking results of injection with histamine or the mast cell secretagogue compound 48/80 (Hagermark et al, 1978) and is attenuated in guinea pigs by the SP-cleaving enzyme neutral endopeptidase (Rubenstein et al, 1990). The role of SP and other tachykinins in this response has been well demonstrated, and the concomitant plasma extravasation is augmented by CGRP (Brain and Williams, 1985;Gamse and Saria, 1985).…”

Section: Discussionsupporting

confidence: 84%

Nerve‐mast cell interaction in normal guinea pig urinary bladder

Keith

Jin

Saban

1995

J of Comparative Neurology

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Urinary bladders of normal adult female guinea pigs were analyzed for anatomical evidence of nerve-mast cell interaction using light microscopy and electron microscopy. Nerves, ganglia, and individual nerve fibers were visualized on paraffin sections using immunohistochemistry with antisera against the neural antigens neurofilament protein and protein gene product 9.5, and sections were also immunoreacted with antisera against the neuropeptides substance P and calcitonin gene-related peptide. Separate mast cell populations were identified by counterstaining with toluidine blue and alcian blue. Mast cells of both types were found within nerves and intramural ganglia and were in close contact with individual nerve fibers displaying substance P- and calcitonin gene-related peptide-like immunoreactivity. Moreover, serotonin-immunoreactive mast cells were innervated with nerve fibers that reacted with antiserum against vasoactive intestinal polypeptide. At the ultrastructural level, these fibers were almost exclusively identified as unmyelinated primary sensory afferents. Mast cells contacted these fibers with lamellipodia that wrapped around and enclosed the fibers deeply within the cell. Close association between mast cells, nerves, and vessels was common. Ultrastructural evidence suggests that bidirectional communication occurs between nerve fibers and mast cells. These structures may participate in axon reflexes that regulate normal vascular and detrusor smooth muscle function and cause vasodilation, edema, inflammation, and bladder hyperreactivity. In summary, a close relationship exists between mast cells and peptidergic nerve fibers, including primary sensory afferents. Results suggest that bidirectional interaction could occur between nerves and mast cells.

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Section: Discussionsupporting

confidence: 84%

Nerve‐mast cell interaction in normal guinea pig urinary bladder

Keith

Jin

Saban

1995

J of Comparative Neurology

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“…5). The notion is also supported by our previous findings that NEP inhibitors increase the binding of SP in rat ileum [25], Our findings of potentiation of SP-induced neutro phil activation by the NEP inhibitor are in agreement with the findings that the NEP inhibitors enhance SPinduced responses in other tissues [26][27][28][29][30], These find ings are also in agreement with our previous findings that the NEP inhibitors increase vascular permeabil ity induced by tachykinins in guinea pig skin [20] and that recombinant human NEP decreases the response [31]. Our findings that inhibitors of kininase II or aminopeptidases did not affect the SP-induced neu trophil activation are also in agreement with the stud ies by other investigators [27,28] and our previous study [20], In addition, although kininase II hydro lyses SP [32], no significant kininase II activity was found to be present in human neutrophils [pers.…”

Section: Discussionsupporting

confidence: 93%

Neutral Endopeptidase Modulates Substance P-Induced Activation of Human Neutrophils

Iwamoto

Kimura

Yamazaki

et al. 1990

Int Arch Allergy Immunol

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Neutral endopeptidase (NEP; EC 3.4.24.11) is well recognized as a regulatory peptidase for substance P (SP)-induced responses in various tissues. To determine whether NEP regulates SP-induced activation of human neutrophils, we examined the effect of the NEP inhibitor phosphoramidon on SP-induced superoxide generation and chemotaxis in human blood neutrophils. SP (10^––6––10^––4M) induced superoxide generation and chemotaxis in the neutrophils dose dependently. The NEP inhibitor enhanced the SP-induced responses. Thus, phosphoramidon (10^––6M) shifted the dose-response curves of SP-induced superoxide generation and chemotaxis of the neutrophils to the left by 0.5–0.6 log. Phosphoramidon prevented the hydrolysis of SP by the neutrophils, the NEP activity of the neutrophils being assessed as 125 ± 13 pmol of SP/min/10⁶ cells. The N-terminal peptide SP_1–9 (up to 3 × 10^––⁴M), which was a major degrading product by NEP of the neutrophils, did not activate the neutrophils. We conclude that NEP modulates SP-induced activation of human neutrophils.

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“…Neutral endopeptidase modulates neurogenic inflammation by degrading tachykinins (24), and transient inhibition of neutral endopeptidase by phosphoramidon amplifies neurogenicmediated skin vascular permeability (13). We showed that phosphoramidon significantly enhanced plasma leakage in the skin induced by intracutaneous substance P in adult rats but not in pups, suggesting that the activity of neutral endopeptidase in the skin may increase with age.…”

Section: Discussionmentioning

confidence: 76%

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

et al. 2010

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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...

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Recombinant Neutral Endopeptidase Attenuates Substance P-Induced Plasma Extravasation in the Guinea Pig Skin

Cited by 28 publications

References 38 publications

Nerve‐mast cell interaction in normal guinea pig urinary bladder

Nerve‐mast cell interaction in normal guinea pig urinary bladder

Neutral Endopeptidase Modulates Substance P-Induced Activation of Human Neutrophils

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

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