ENHANCED EXPRESSION OF TRANSFORMING-GROWTH-FACTOR-BETA TYPE-I AND TYPE-II RECEPTORS IN WOUND GRANULATION-TISSUE AND HYPERTROPHIC SCAR

In the present study we have analyzed and compared, by immunohistochem istry and in situ hybridization, the expression pattern of the R4/ALK5 transforming growth factor (TGF)-beta type I receptor (RI) and the TG F-beta type II receptor (RII) in normal human skin, in wounded skin at various stages during the transition of wound granulation tissue to s car, and in long-persisting post-bum hypertrophic scars. In normal hum an skin, expression of RI and RII was clearly visible in the epidermis , in epidermal appendages, and in vascular cells, although only a smal l number of dermal fibroblasts revealed detectable levels of TGF-beta receptor expression, In contrast, granulation tissue fibroblasts showe d strong expression of both TGF-beta receptor types, although in norma l-healing excisional wounds their density decreased during granulation tissue remodeling, However, in post-burn hypertrophic scars, RI-and R II-overexpressing fibroblasts were found in high densities up to 20 mo nths after injury. From these findings we suggest that the repair proc ess of deep wounds involves the transformation of a subset of fibrobla stic cells toward an increased TGF-beta responsiveness and a transient accumulation of these cells at the wound site, In addition, our study provides evidence that excessive scarring is associated with a failur e to eliminate TGF-beta receptor-overexpressing fibroblasts during gra nulation tissue remodeling, which leads to a persistent autocrine, pos itive feedback loop that results in overproduction of matrix proteins and subsequent fibrosis.