Abstract
Fibroblast migration is an important component of the tissue response during the repair process, and substance P (SP) has been shown to exert trophic effects. In the present study, cell migration was evaluated as the distance travelled by adherent human skin fibroblasts (HF) at 96 h and by the number of individual cells moving across a filter within 5 h.
In control conditions (1% calf serum) adherent fibroblasts moved from the starting line by approximately 700 μm. The addition of SP (10−11–10−7 M) increased HF mobilisation in a concentration-dependent manner, with maximal activity at 10−8 M (50% increase in migration over control). Migration of individual HF in suspension was also promoted by SP in a concentration-dependent manner, with an EC50 of 2.2×10−9 M. The response produced by the maximally effective concentration of SP was equal to 65 and 90% of the effect elicited by 100 ng/ml Platelet-Derived Growth Factor AB (PDGF A/B) on adherent and individual cells respectively. The synthetic NK1 receptor agonist [Sar9]SP-sulphone (10−11–10−6 M) reproduced the SP effect. The NK2 and NK3 receptor agonists [βAla8]NKA(4–10) and [MePhe7]NKB were devoid of any effect. The effect of SP was antagonised by two selective antagonists of NK1 receptors, namely (±) CP 96,345 (10−10–10−8 M) and FK 888 (10−9–10−7 M), while the NK2 receptor antagonist MEN 10627 (10−8–10−7 M) was not effective.
Our data indicate that SP is a potent effector of fibroblast migration and the NK1 receptor is responsible for this effect. These observations further support the specific role of the NK1 receptor in mediating the trophic function of SP at the cutaneous level.
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References
Augustin-Voss HA, Pauli BU (1992) Quantitative analysis of autocrine-regulated, matrix-induced and tumor cell-stimulated endothelial cell migration using a silicon template compartmentalisation technique. Exp Cell Res 198:221–227
Beresford IJM, Birch PJ, Hagan RM, Ireland SJ (1991) Investigation into species variants in tachykinin NK1 receptors by use of the non-peptide antagonist, (±) CP 96,345. Br J Pharmacol 104:292–293
Diemel LT, Brewster WJ, Femyhough P, Tomlinson DR (1994) Expression of neuropeptides in experimental diabetes; effects of treatment with nerve growth factor or brain-derived neurotrophic factor. Mol Brain Res 21:171–175
D'Orlean-Juste P, Dion S, Mizrahi J, Regoli D (1985) Effects of peptides and nonpeptides on isolated arterial smooth muscle: role of endothelium. Eur J Pharmacol 114:9–21
Foreman JC, Jordan CC (1984) Neurogenic inflammation. Trends Pharmacol Sci 5:116–119
Fujii T, Murai M, Morimoto H, Maeda Y, Yamaoka M, Hagiwara D, Miyake H, Ikari N, Matsuo M (1992) Pharmacological profile of a high affinity dipeptide NK1 receptor antagonist, FK 888. Br J Pharmacol 107:785–789
Fujita S, Shimizu T, Izumi K, Fukuda K, Sameshima M, Ohba N (1984) Capsaicin-induced neuroparalytic keratitis-like corneal changes in the mouse. Exp Eye Res 38:165–171
Hunt TK, La Van FB (1989) Enhancement of wound healing by growth factors. N Engl J Med 321:111–112
Jacques L, Couture R, Drapeau G, Regoli D (1989) Capillary permeability induced by intravenous neurokinins. Naunyn-Schmiedeberg's Arch Pharmacol 340:170–179
Kähler CM, Sitte BA, Reinisch N, Wiedermann CJ (1993) Stimulation of the chemotactic migration on human fibroblasts by substance P Eur J Pharmacol 249:281–286
Kingsnorth AN, Slavin J (1991) Peptide growth factors and wound healing. Br J Surg 78:1286–1290
Kjartansson J, Dalsgaard C-J, Jonsson C-E (1987) Decreased survival of experimental critical flaps in rats after sensory denervation with capsaicin. Plast Reconstr Surg 79:218–221
Lembeck F, Holzer P (1979) Substance P as a neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation. Naunyn-Schmiedeberg's Arch Pharmacol 310:175–183
Lindsay RM, Lockett C, Stemberg J, Winter J (1989) Neuropeptide expression in cultures of adult sensory neurones: modulation of substance P and calcitonin gene-related peptide levels by nerve growth factor. Neuroscience 33:53–65
Maggi CA, Borsini F, Santicioli P, Geppetti P, Abelli L, Evangelista S, Manzini S, Theodorsson Norheim E, Somma V, Amenta F, Bacciarelli C, Meli A (1987) Cutaneous lesions in capsaicin pretreated rats. Naunyn-Schmiedeberg's Arch Pharmacol 336:538–545
Maggi CA, Patacchini R, Rovero P, Giachetti A (1993) Tachykinin receptors and tachykinin receptor antagonists. J Auton Pharmacol 13:23–93
Maggi CA, Astolfi M, Giuliani S, Goso C, Manzini S, Meini S, Patacchini R, Pavone V, Pedone C, Quartara L, Renzetti AR, Giachetti A (1994) MEN 10627, a novel polycyclic peptide antagonist of tachykinin NK2 receptors. J Pharmacol Exp Ther 27:1489–1500
Mitsuhashi M, Payan DG (1987) The mitogenic effects of vasoactive neuropeptides on cultured smooth muscle cell line. Life Sci 40:853–861
Morbidelli L, Maggi CA, Ziche M (1993) Effect of selective tachykinin receptor antagonists on the growth of human skin fibroblasts. Neuropeptides 24:335–341
Nilsson J, Von Euler AM, Dalsgaard CJ (1985) Stimulation of connective tissue cell growth by substance P and substance K. Nature 315:61–63
Payan BG, Brewester R, Goetzl EJ (1983) Specific stimulation of human T lymphocytes by substance P. J Immunol 131:1613–1615
Regoli D, Drapeau G, Dion S, Couture R (1988) New selective agonists for neurokinin receptors: pharmacological tools for receptor characterisation. Trends Pharmacol Sci 9:290–295
Rhudy RW, McPherson JM (1988) Influence of the extracellular matrix on the proliferative response of human skin fibroblasts to serum and purified Platelet-Derived Growth Factor. J Cell Physiol 137:185–191
Robinson JP, Willars GB, Tomlinson DR, Keen P (1987) Axonal transport and tissue contents of substance P in rats with long-term streptozotocin-diabetes. Effects of the aldose reductase inhibitor “statil”. Brain Res 426:339–348
Scicchitano R, Bienenstock J, Stanisz AM (1988) In vivo immunomodulation by the neuropeptide substance P. Immunology 63:733–735
Snider RM, Constantine JW, Lowe III JA, Longo KP, Lebel WS, Woody HA, Drodza SE, Desai MC, Vinick FJ, Spencer RW, Hess H-J (1991) A potent nonpeptide antagonist of the substance P (NK1) receptor. Science 251:435–435
Van Rossum JM (1963) Cumulative dose-response curves. Techniques for making dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn Ther 143:299–330
Vedder H, Affolter H-U, Otten U (1993) Nerve growth factor (NGF) regulates tachykinin gene expression and biosynthesis in rat sensory neurons during early postnatan development. Neuropeptides 24:351–357
Walsh DA, Terenghi G, Polak JM (1994) Neural and vascular regulatory factors of the skin. J Eur Acad Dermatol Venereol 3:116–139
Wang ZY, Tung SRT, Strichartz GR, Hakanson R (1994) Investigation of the specificity of FK 888 as a tachykinin NK1 receptor antagonist. Br J Pharmacol 111:1342–1346
Ziche M, Morbidelli L, Pacini M, Geppetti P, Alessandri G, Maggi CA (1990a) Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res 40:264–278
Ziche M, Morbidelli L, Pacini M, Dolara P, Maggi CA (1990b) NK1 receptors mediate the proliferative response of human fibroblasts to tachykinins. Br J Pharmacol 100:11–14
Ziche M, Morbidelli L, Geppetti P, Maggi CA, Dolara P (1991) Substance P induces migration of capillary endothelial cells: a novel NK1 selective receptor mediated activity. Life Sci 48:PL7-PL11
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Parenti, A., Amerini, S., Ledda, F. et al. The tachykinin NK1 receptor mediates the migration-promoting effect of substance P on human skin fibroblasts in culture. Naunyn-Schmiedeberg's Arch Pharmacol 353, 475–481 (1996). https://doi.org/10.1007/BF00169165
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DOI: https://doi.org/10.1007/BF00169165