The pathogenesis of venous ulceration is thought to involve formation of pericapillary fibrin cuffs as a result of venous hypertension, and a recent hypothesis suggests that extravasated plasma proteins may bind or trap growth factors. We have compared the tissue distribution of fibrin cuffs, plasma proteins, procollagen, and transforming growth factors (TGF-beta 1 and TGF-beta 2) within venous ulcers and normally healing graft donor sites. In venous ulcers, the papillary dermis and the ulcer bed contained convoluted capillaries with phosphotungstic acid haematoxylin-positive pericapillary fibrin cuffs. By immunohistochemical staining, the cuffs were positive for actin, and contained massively redundant lamellae of basement membrane material which stained positive for type IV collagen. Extravasated factor XIIIa and alpha 2-macroglobulin were present within the fibrin cuffs. Increased numbers of type I procollagen positive fibroblasts, and increased TGF-beta 1 immunoreactivity were present within the fibrin cuffs, but not in the provisional matrix in the ulcer bed around the cuffs. In contrast, in normally healing graft donor sites, tortuous capillaries and fibrin cuffs were absent, factor XIIIa and alpha 1-macroglobulin were restricted to the lumina of vessels, and procollagen and TGF-beta immunoreactivity were present within the granulation tissue and adjacent dermal matrix at the wound margin. These observations suggest that growth factors critical in wound healing, such as TGF-beta, are present within venous ulcers, but are abnormally distributed. Their distribution within fibrin cuffs and co-localization with extravasated plasma proteins, particularly alpha 2-macroglobulin, which is a recognized scavenger molecule for TGF-beta and other growth factors, provides evidence for a possible 'trapping' of growth factors in venous ulcers.
Transforming growth factor-beta(2) promotes healing in a variety of animal models and exhibits clinical effects thought to be mediated by connective tissue formation. Two clinical trials were conducted to evaluate the safety and effect of transforming growth factor-beta(2) purified from bovine bone and delivered topically to venous stasis ulcers three times per week for up to 6 weeks by means of a lyophilized collagen vehicle. The first was an open-label trial comparing transforming growth factor-beta(2) purified from bovine bone (0.5 microg/cm(2)) with a placebo consisting of lyophilized collagen vehicle-without active drug. After no safety issues arose in that trial, a prospectively randomized, closed-label, observer-blinded, three-armed trial was conducted to compare bovine transforming growth factor-beta(2) (2.5 microg/cm(2)) with the collagen matrix placebo vehicle and with a standard dressing. Standardized elastic compression was applied to all test extremities. The rate of reduction of ulcer area as measured by planimetry was the primary measure of effect. No serious safety-related events occurred in either trial. Clinical evaluation suggested that improvement in the quality and quantity of granulation tissue appeared to precede epithelialization of ulcers treated with bovine transforming growth factor-beta(2). In both studies, treatment with bovine transforming growth factor-beta(2) appeared to have a positive effect on the rate of ulcer closure, whereas ulcers in the control groups continued to exhibit impaired healing. In the open-label study, the mean rate of closure of ulcers treated with bovine transforming growth factor-beta(2) was significantly greater than that of ulcers treated with placebo. There was likewise enhanced reduction in ulcer area in the ulcers treated with bovine transforming growth factor-beta(2) in the second trial. However, because of a higher variability in patient response and a greater placebo effect, the difference was not significant. The placebo was not worse than the standard care arm, thereby showing that the vehicle is not injurious to healing. The combined results of the two trials suggest that, at doses of 0.5 to 2.5 microg/cm(2), bovine transforming growth factor-beta(2) is safe as a topically applied agent in a collagen matrix vehicle and can have a positive effect on closure of venous stasis ulcers. Large multicenter trials appear to be indicated to evaluate fully the potential utility of transforming growth factor-beta(2) in accelerating closure of chronic dermal ulcers.
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