Dramatic Effect of Botulinum Toxin Type A on Hypertrophic Scar: A Promising Therapeutic Drug and Its Mechanism Through the SP-NK1R Pathway in Cutaneous Neurogenic Inflammation

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.

Potential therapeutic effect of NK1R antagonist in diabetic non-healing wound and depression

“…Momen ( 34 ) contributed the aprepitant-related angiogenesis to MMP-2, MMP-9, VEGF, and VEGFR. On the other hand, regulation of EGFR, Akt, and SIRT1 by NK1R blockade was also considered beneficial in terms of re-epithelialization and collagen deposition ( 35 – 37 ).…”

Machine learning and single‐cell transcriptome profiling reveal regulation of fibroblast activation through THBS2/TGFβ1/P‐Smad2/3 signalling pathway in hypertrophic scar

“…HS is a chronic skin condition characterized by the formation of fibrous lesions due to the excessive accumulation of fibroblasts and collagen 28 . This disease is caused by a combination of genetic, biomechanical, metabolic, endocrine and immunological factors 29 . Given its impact on physical, mental and social well‐being, HS has been recognized as a major challenge to global health in terms of unmet functional and psychosocial needs 1 .…”

Traditional Chinese medicine for hypertrophic scars—A review of the therapeutic methods and potential effects

“…Frontiers in Pharmacology frontiersin.org Zhang et al, 2022). The evidence that cutaneous neurogenic inflammation could stimulate fibroblasts during scar formation has been confirmed (Zhang et al, 2022).…”

“…Inflammation and the cutaneous nerve system play essential roles in wound healing and HS formation ( Yang et al, 2014 ; Li et al, 2015 ; Zhang et al, 2022 ). The evidence that cutaneous neurogenic inflammation could stimulate fibroblasts during scar formation has been confirmed ( Zhang et al, 2022 ).…”

“…Inflammation and the cutaneous nerve system play essential roles in wound healing and HS formation ( Yang et al, 2014 ; Li et al, 2015 ; Zhang et al, 2022 ). The evidence that cutaneous neurogenic inflammation could stimulate fibroblasts during scar formation has been confirmed ( Zhang et al, 2022 ). Neurogenic inflammation is an inflammatory process due to acute injury with the release of neuropeptides, especially neuropeptide substance p (SP), from sensory nerves ( Black, 2002 ).…”