Exogenous Administration of Substance P Enhances Wound Healing in a Novel Skin-Injury Model

Abstract

Soft tissue injury accounts for approximately 44% of all wounds in both the military and civilian populations. Following injury to soft tissue, Substance P (SP) and other neuropeptides are released by cutaneous neurons and modulate the function of immunocompetent and inflammatory cells, as well as epithelial and endothelial cells. The interaction between these components of the nervous system and multiple target cells affecting cutaneous repair is of increasing interest. In this report, we describe the effects of SP on wound repair in a novel, laser-induced, skin-wound model. Gross and histologic examination of laser-induced injury revealed that exogenously administered SP affects wound healing via neurite outgrowth, in addition to adhesion molecule and neurokinin-1 receptor involvement in vivo. All SP effects were decreased by pretreatment with Spantide II, an SP antagonist. The elucidation of SP-mediating mechanisms is crucial to firmly establishing the involvement and interaction of the peripheral nervous system and the immune system in cutaneous repair. Findings presented here suggest that SP participates in the complex network of mediators involved in cutaneous inflammation and wound healing.

Immunoregulatory Effects of Neuropeptides on Endothelial Cells: Relevance to Dermatological Disorders

“…It is thought that the angiogenesis is in part the result of substance P-induced production and migration of endothelial cell progenitor cells from the bone marrow into injured peripheral tissue [82], as well as dermal microvascular endothelial cell proliferation [83]. The observation that substance P improves wound healing has been made previously [84] but the ability to induce angiogenesis may, in part, be responsible for this phenomenon. Also, as discussed above, the connection between angiogenesis and chronic inflammation has come to light.…”

IL-10 Function, Regulation, and in Bacterial Keratitis

“…74,75 This study 73 revealed that the SP injection had a localized effect and increased growth factors such as hepatocyte growth factor (HGF) in both the normal and infected cornea. Unfortunately, this effect was overwhelmed by a pro-inflammatory cytokine response, leading to increased stromal destruction, higher bacterial plate counts, and a decrease in M2 arginase-producing cells (critical to disease resolution through production of anti-inflammatory mediators such as IL-10).…”

“…These data, based on experimental modeling, also led us to conclude that treatment with SP to hasten wound closure was contraindicated clinically in the cornea in the presence of a bacterial infection. 75 …”

Inflammatory and Angiogenic Abnormalities in Diabetic Wound Healing: Role of Neuropeptides and Therapeutic Perspectives

“…Impaired neurogenic inflammation, due to diabetic neuropathy, contributes to enhanced susceptibility for diabetic foot ulcer. The neuropeptides known to be involved in impaired diabetic wound healing are substance P [99,211] and neuropeptide Y [100,212]. Further research is needed in order to evaluate the effect of the addition of neuropeptides to impaired wound healing and possibly consider this approach as a future therapy.…”

“…Neuropeptides mediate their actions by binding to specific receptors found on various cells in the skin, including immune cells, Langerhans cells, EC, mast cells, fibroblasts and keratinocytes [98]. Several neuropeptides are involved in wound healing, including substance P (SP), neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) [99][100][101] (Table 1).…”