title: The therapeutic potential of a C-X-C chemokine receptor type 4 (CXCR-4) antagonist on hypertrophic scarring in vivo.
abstract: Effective prevention and treatment of hypertrophic scars (HTSs), a dermal form of fibrosis that frequently occurs following thermal injury to deep dermis, are unsolved significant clinical problems. Previously, we have found that stromal cell-derived factor 1/CXCR4 signaling is up-regulated during wound healing in burn patients and HTS tissue after thermal injury. We hypothesize that blood-borne mononuclear cells are recruited into wound sites after burn injury through the chemokine pathway of stromal cell-derived factor 1 and its receptor CXCR4. Deep dermal injuries to the skin are often accompanied by prolonged inflammation, which leads to chemotaxis of mononuclear cells into the wounds by chemokine signaling where fibroblast activation occurs and ultimately HTS are formed. Blocking mononuclear cell recruitment and fibroblast activation, CXCR4 antagonism is expected to reduce or minimize scar formation. In this study, the inhibitory effect of CXCR4 antagonist CTCE-9908 on dermal fibrosis was determined in vivo using a human HTS-like nude mouse model, in which split-thickness human skin is transplanted into full-thickness dorsal excisional wounds in athymic mice, where these wounds subsequently develop fibrotic scars that resemble human HTS as previously described. CTCE-9908 significantly attenuated scar formation and contraction, reduced the accumulation of macrophages and myofibroblasts, enhanced the remodeling of collagen fibers, and down-regulated the gene and protein expression of fibrotic growth factors in the human skin tissues. These findings support the potential therapeutic value of CXCR4 antagonist in dermal fibrosis and possibly other fibroproliferative disorders.
authors.affiliation: Wound Healing Research Group, Division of Plastic and Reconstructive Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.forename: Zengshuan
authors.initials: Z
authors.lastname: Ma
authors.forename: Hongbin
authors.initials: H
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Kwan
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwashina
authors.forename: Heather A
authors.initials: HA
authors.lastname: Shankowsky
authors.forename: Donald
authors.initials: D
authors.lastname: Wong
authors.forename: Edward E
authors.initials: EE
authors.lastname: Tredget
mesh_terms: D000328:Adult; D000818:Animals; D017439:Cicatrix, Hypertrophic / Q000473:pathology / Q000517:prevention & control*; D020405:Dermis / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D016038:Skin Transplantation; D014945:Wound Healing / Q000187:drug effects*
chemical_list: C540323:CTCE-9908; D010455:Peptides; D019718:Receptors, CXCR4