Title:
The Roles of SDF-1/CXCR4, MCP-1/CCR2 and CCL5/CCR5 Chemokine Pathway in Hypertrophic Scarring

Authors:
Hirokatsu Umeyama, Jie Ding, Antoinette Nguyen, Servet Elcin Alpat, Josue R Silva, Peter Kwan, Munetomo Nagao, Masahiro Tachi, Edward E. Tredget, Canada

Abstract:

Hypertrophic scars are a dermal form of fibroproliferative diseases that develop after skin trauma to the deep dermis. Dysfunction of the chemokine network can result in prolonged inflammation, abnormal blood vessel development, and a fibrotic wound-healing environment. To understand the role of the chemokine signaling in pathological scar formation, the inhibitory effects of scar formation by chemokine inhibitors of AMD3100, Maraviroc, and CAS445479-97-0 were investigated using a mouse model of dermal fibrosis, in which human split-thickness skin grafts were transplanted into full-thickness excision wounds in the dorsal of athymic nude mice, and the human skin grafts developed scars morphologically and histologically similar to human hypertrophic scars. The mice were treated with one of chemokine inhibitors from 5 days after grafting daily for 1 week and thereafter once a week. Mouse wounds were monitored, and scar tissues were collected at 2, 6, and 12 weeks after grafting for further histological and biochemical analysis. AMD3100 and Maraviroc reduced wound contraction. AMD3100 improved collagen orientation and up-regulated mRNA level of decorin in the early phase of wound healing. AMD3100, CAS445479-97-0 and Maraviroc reduced scar thickness, macrophage recruitment and myofibroblast formation, and down-regulated gene expressions of type I collagen in the early phase, heat shock protein 47 in the late phase, alpha-smooth muscle actin, and connective tissue growth factor throughout the whole phase of wound healing. Blocking chemokine pathways significantly improved scars in this dermal fibrotic model, which can be potential therapeutic targets for hypertrophic scars.

DOI: http://dx.doi.org/10.51505/ijmshr.2021.5215