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.