Abstract
BackgroundHypertrophic scar formation may be related to cutaneous neurogenic inflammation (CNI) through the substance P-neurokinin 1 receptor (SP-NK1R) signaling pathway. As a widely used drug in aesthetic clinical work, botulinum toxin type A (BTX-A) has a therapeutic effect on scars, but the actual mechanism remains unclear. This study aimed to clarify the potential mechanism by which BTX-A inhibits CNI in hypertrophic scars both in vitro and in vivo.MethodsTissue samples were obtained from surgical excisions. Immunohistological analysis was used to locate SP in human hypertrophic scars and normal skin. RT-PCR and western blot analysis were used to evaluate the expression of collagens after SP/BTX-A treatment. A rabbit ear scar model was used to explore the in vivo effect of BTX-A on scar treatment.ResultsSP and NK-1R were overexpressed in hypertrophic scars compared to normal skin tissues. Collagen secretion of hypertrophic scar-derived fibroblasts increased with increasing doses of SP. However, BTX-A may downregulate collagen expression through SP-NK1R pathway with or without the presence of SP inducing agent capsaicin. Meanwhile, SP inhibited the expression of NK-1R, and this inhibition was blocked by pretreatment with BTX-A. In vivo, intralesional BTX-A injection can also reduce the volume of scars and inhibit collagen secretion. Capsaicin may cause more severe scar manifestations, while the therapeutic effect of BTX-A remains.ConclusionOur research confirms that CNI stimulates fibroblasts during scar formation, while BTX-A can reduce collagen secretion by inhibiting the SP-NK1R signaling pathway, thus identifying a novel therapeutic target for this benign solid skin tumor.
Highlights
Hypertrophic scarring is a fibrous hyperproliferative disease secondary to skin injury characterized by excessive fibroblasts and extracellular matrix (ECM) deposition, which resembles the process of benign solid tumor formation [1, 2]
Immunofluorescence showed the distribution of TRPV1 aligned with that of substance P (SP), which verified the overexpression of SP in hypertrophic scar tissue (Figure 1)
Expression of SP, calcitonin gene-related peptide (CGRP), and NK-1R in Human Hypertrophic Scar and Normal Skin Tissue Samples. Both RT-PCR and western blot showed a significant increase (p < 0.0001) in the concentration of SP-related mRNA and proteins (SP, CGRP, NK-1R) in hypertrophic scar tissue compared to the normal samples (Figure 2)
Summary
Hypertrophic scarring is a fibrous hyperproliferative disease secondary to skin injury characterized by excessive fibroblasts and extracellular matrix (ECM) deposition, which resembles the process of benign solid tumor formation [1, 2]. Neurogenic inflammation (NI) has been proven to contribute to the formation of hypertrophic scars [3, 4]. A large number of macrophages and lymphocytes accumulate around the wound surface to initiate an inflammatory response, and fibroblasts subsequently secrete abundant disorderly arranged collagens, which eventually lead to scar formation [6]. In the scar healing process, the mechanical force generated by wound contraction may stimulate mechanosensitive nociceptors on sensory fibers to induce the secretion of SP and calcitonin gene-related peptide (CGRP) from peripheral nerve endings, thereby upregulating the expression of TGF-β and NGF in a variety of cells, including skin fibroblasts [7]. Hypertrophic scar formation may be related to cutaneous neurogenic inflammation (CNI) through the substance P-neurokinin 1 receptor (SP-NK1R) signaling pathway. This study aimed to clarify the potential mechanism by which BTX-A inhibits CNI in hypertrophic scars both in vitro and in vivo
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