Our study indicated that activated leukocytes traverse perivascular cuffs and release active TGF-beta(1). Positive TGF-beta(1) staining results of dermal fibroblasts were observed and suggest that fibroblasts are the targets of activated interstitial leukocytes. Increased protein production, despite normal levels of gene transcripts in patients in classes 5 and 6, suggests that alternate mechanisms other than gene transcription regulate protein production. A potential mechanism for quick access and release is storage of TGF-beta(1) in the extracellular matrix. IMG labeling to collagen fibrils support this possibility. Furthermore, TGF-beta(1) was exclusively elevated in areas of clinically active disease, indicating a regionalized response to injury. These data suggest that alterations in tissue remodeling occur in patients with CVI and that dermal tissue fibrosis in CVI is regulated by TGF-beta(1).