EXTRAVASATION OF MACROMOLECULES AND POSSIBLE TRAPPING OF TRANSFORMINGGROWTH-FACTOR-BETA IN VENOUS ULCERATION

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 bin d or trap growth factors. We have compared the tissue distribution of fibrin cuffs, plasma proteins, procollagen, and transforming growth fa ctors (TGF-beta 1 and TGF-beta 2) within venous ulcers and normally he aling graft donor sites. In venous ulcers, the papillary dermis and th e ulcer bed contained convoluted capillaries with phosphotungstic acid haematoxylin-positive pericapillary fibrin cuffs. By immunohistochemi cal staining, the cuffs were positive for actin, and contained massive ly redundant lamellae of basement membrane material which stained posi tive for type IV collagen. Extravasated factor XIIIa and alpha(2)-macr oglobulin were present within the fibrin cuffs. Increased numbers of t ype I procollagen positive fibroblasts, and increased TGF-beta 1 immun oreactivity were present within the fibrin cuffs, but not in the provi sional matrix in the ulcer bed around the cuffs. In contrast, in norma lly healing graft donor sites, tortuous capillaries and fibrin cuffs w ere 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 cr itical in wound healing, such as TGF-beta, are present within venous u lcers, but are abnormally distributed. Their distribution within fibri n cuffs and co-localization with extravasated plasma proteins, particu larly alpha(2)-macroglobulin, which is a recognized scavenger molecule for TGF-beta and other growth factors, provides evidence for a possib le 'trapping' of growth factors in venous ulcers.