Prepared by Joseph Raffetto, MD
Corresponding chapter in Handbook of Venous Disorders: Chapters 6 and 7
Burnand KG, Whimster I, Naidoo A, Browse NL. Pericapillary fibrin in the ulcer-bearing skin of the leg: the cause of lipodermatosclerosis and venous ulceration. Br Med J (Clin Res Ed) 1982; 16;285:1071-2.
Comment: This is a landmark article which defined the principle abnormality in the microcirculation of advanced venous disease, defining the fibrin cuff, which is an essential finding in patients with lipodermatosclerosis and venous ulcer.
Pappas PJ, DeFouw DO, Venezio LM, GortiR, Padberg FT Jr, Silva MB Jr, Goldberg MC, Durán WN, Hobson RW 2nd. Morphometric assessment of the dermal microcirculation in patients with chronic venous insufficiency. J Vasc Surg 1997;26:784-95.
Comment: This excellent basic science study performed morphometric analysis of venous tissue collected from patients with advanced chronic venous disease. The major findings determined that mast cells and macrophages are key leukocytes in the postcapillary venules, that fibroblasts were the most abundant cell type, that the interendothelial gap junctions were not widened, and that TGF-ß protein is overexpressed and likely involved in the tissue remodeling present in skin changes of advanced chronic venous disease.
Hasan A, Murata H, Falabella A, Ochoa S, Zhou L, Badiavas E, Falanga V. Dermal fibroblasts from venous ulcers are unresponsive to the action of transforming growth factor-beta 1. J Dermatol Sci 1997;16:59-66.
Comment: This study demonstrated that the transcription product of procollagen and TGF-ß are comparable in control and venous ulcerdermal fibroblasts. However, exogenous stimulation with TGF-ß demonstrated reduced collagen stimulation and was associated with reduced TGF receptors. These findings may explain the reduced healing of venous ulcers.
Raffetto JD. Dermal pathology, cellular biology, and inflammation in chronic venous disease. Thromb Res 2009;123 Suppl 4:S66-71.
Comment: This recent review article is an excellent review of the scientific data published on the current understanding of venous pathophysiology encompassing inflammatory activation, cytokine and growth factor involvement, matrix metalloproteinase mechanism in venous pathology, molecular changes including alterations in cell cycle proteins and the mitogen-activated protein kinase cascade leading to skin changes and ulcer formation.The article reviews possible targets in which therapeutic interventions could be applied in arresting the progression to venous ulceration.
Herouy Y, May AE, Pornschlegel G, Stetter C, Grenz H, Preissner KT, Schöpf E, Norgauer J, Vanscheidt W. Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: implications for venous ulcer formation. J Invest Dermatol 1998;111:822-7.
Comment: This clinical and basic scientific study demonstrated the importance of elevated expression, activity and location of matrix metalloproteinases in patients with advanced venous disease.
Zamboni P, Scapoli G, Lanzara V, IzzoM, Fortini P, Legnaro R, Palazzo A, Tognazzo S, Gemmati D. Serum iron and matrix metalloproteinase-9 variations in limbs affected by chronic venous disease and venous leg ulcers. Dermatol Surg 2005;31:644-9.
Comment: This study established the relationship between iron overload, matrix metalloproteinase expression, and skin changes in advanced venous disease
Pappas PJ, You R, Rameshwar P, Gorti R, DeFouw DO, Phillips CK, Padberg FT Jr, Silva MB Jr, Simonian GT, Hobson RW 2nd, Durán WN. Dermal tissue fibrosis in patients with chronic venous insufficiency is associated with increased transforming growth factor-beta1 gene expression and protein production. J Vasc Surg 1999;30(6):1129-45.
Comment: This elegant and important study demonstrated the importance of leukocytes producing TGF-beta and translocating in to the extracellular matrix to fibroblasts in patients with advanced chronic venous disease.
Raffetto JD, Gram CH, Overman KC, Menzoian JO. Mitogen-activated protein kinase p38 pathway in venous ulcer fibroblasts. Vasc Endovascular Surg 2008;42:367-74.
Comment: This study determined the importance of MAPK p38 asa key regulator of cell proliferation in venous ulcer fibroblasts.