Blockade of Mast Cell Activation Reduces Cutaneous Scar Formation

Abstract

Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound.

The Role of Chemokines in Fibrotic Wound Healing

“…Compared with the control, the treatment causes a significant decrease in scar width along with accelerated collagen re-organization. 72 We previously reported upregulated SDF-1/ CXCR4 signaling during wound healing in burn patients. In paired HTS and site-matched NS sections from recovering burn patients, SDF-1 was expressed in the epidermis, dermis, hair follicles, blood vessels, and sweat glands of NS; however, significantly upregulation occurred in HTS tissue compared with NS from the same patients.…”

Chemokine Involvement in Fetal and Adult Wound Healing

“…39 The chemokine MCP-1 has been shown to be a potent attractant for mast cells, which are increasingly considered to be important mediators in wound healing. 40 Mast cells degranulate after injury releasing multiple proinflammatory mediators and vasoactive amines 41 and have also shown to be abundant in both keloids and hypertrophic scars. 42 Mast cells also release chemokines such as IL-8, MIP-1a, and MIP-1b independent of degranulation, when stimulated through the activation of the CD30 pathway.…”

“…42 Mast cells are also increased in the skin in chronic skin inflammatory conditions, for example, psoriasis, basal cell carcinoma, and chronic ulcers. Disodium cromoglycate, a pharmacologic inhibitor of mast cell activation and degranulation, has been used to decrease the amount of inflammatory cytokines such as IL-1b and chemokine CXCL1 (Murine IL-8) 41 in the wounds, which resulted in the augmented healing response, characterized by improved collagen fiber organization and reduction in wound scar width, without negative effects on wound breaking strength. These data demonstrate that chemokine regulation can offer a potential therapeutic benefit for wound healing.…”

Mast cell concentration and skin wound contraction in rats treated with Ximenia americana L

“…Chen et al 22 blocked the degranulation of mast cells in wound repair using cromolyn disodium and observed a reduction in healing time. However, there was no increase in the inflammatory phase in this experiment, which may indicate the modulatory ability of these cells in the healing process.…”