NK₁‐receptors mediate the proliferative response of human fibroblasts to tachykinins

Abstract

1The effect of synthetic tachykinin selective receptor agonists was studied on the growth of cultured human skin fibroblasts (HF). 2 Human fibroblasts were grown in serum-free conditions in the presence of natural tachykinins (substance P and neurokinin A) and of three synthetic agonists, [fl-Ala4, Sar9, Met (02) Cell proliferation was measured by percentage increase in cell number and by [3H]-thymidine uptake following 48 h exposure to agents compared to baseline condition. 3 Neurokinin A (NKA) and substance P (SP) significantly increased cell proliferation the threshold concentrations being 10-12 and 10-11 M, respectively. Addition of thiorphan to culture conditions enhanced the effect of SP but not of NKA.4 The selective NK1-receptor agonist produced a dose-dependent increase in cell proliferation as judged by total cell number and [3H]-thymidine uptake. No significant effect was observed with NK2-and NK3-receptor agonists. 5 These data indicate that the effect of SP on fibroblast proliferation is mediated by interaction with a NK1-receptor type and local metabolism can interfere with the full expression of this effect of SP on cell proliferation.

A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion formation and increases peritoneal fibrinolytic activity

“…These data provide the first evidence that activation of the NK-1R by tachykinins such as SP is involved in adhesion formation. The participation of the NK-1R in promoting adhesions is not surprising, because binding of an agonist such as SP to the NK-1R can initiate a wide range of potentially adhesiogenic effects, including production of inflammatory cytokines (41), stimulation of fibrosis (24), increased chemotaxis of neutrophils and macrophages (42,43), and mitogenesis of fibroblasts (28).…”

“…SP is known to play an important role in inflammatory (22,23), proliferative (24), and wound healing (25) processes. Known SP effects range from increasing inflammatory cytokine mRNA expression and secretion (26) to stimulating angiogenesis (27) and proliferation of fibroblasts (28). Neurons are the primary source of SP, but lymphocytes (29), monocytes (30), macrophages (30), and eosinophils (31) have been identified as additional sources.…”

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

“…Released neuropeptides may participate in many of the inflammatory processes that are crucial for normal wound healing, such as cell proliferation, cytokine and growth factor production, and neovascularization (854,968). Several clinical observations indicate that damage to the peripheral nervous system influences wound healing, resulting in chronic wounds within the affected area.…”

Joint immobilization reduces the expression of sensory neuropeptide receptors and impairs healing after tendon rupture in a rat model

“…14,15 Two weeks of immobilization appears to lead to a downregulation of SP-receptor mRNA levels, thereby possibly also negatively influencing the tissue repair process at this level.…”

“…[9][10][11] Thus, the SP-receptor, neurokinin 1 (NK 1 ), and the CGRP-receptor, calcitonin-receptor-like receptor (CRLR), including the receptor activity modifying protein (RAMP-1), have been reported to promote angiogenesis and tissue repair by stimulating proliferation of endothelial cells and fibroblasts. [12][13][14][15] In tendons, thus far only the SP-receptor (NK 1 ) has been detected, 16 but none of the SP-(NK 1 ) or the CGRP-(CRLR/RAMP-1) receptors have been analyzed in relation to activity and healing.…”