Cellular and molecular mechanisms of venous leg ulcers development - the puzzle theory

• Published in: International angiology Vol. 29; no. 1; pp. 1 - 19
• Main Author: SIMKA, M
• Format: Journal Article
• Language: English
• Published: Torino Minerva Medica 01.02.2010; Edizioni Minerva Medica
• Subjects: Animals; Apoptosis; Biological and medical sciences; Blood and lymphatic vessels; Capillary Permeability; Cardiology. Vascular system; Chemotaxis; Cytokines - immunology; Dermatology; Disease Progression; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelium, Vascular - immunology; Erythrocytes - immunology; Erythrocytes - metabolism; Erythrocytes - pathology; Humans; Inflammation Mediators - immunology; Iron - metabolism; Keratinocytes - immunology; Keratinocytes - pathology; Macrophages - immunology; Medical sciences; Risk Factors; Skin involvement in other diseases. Miscellaneous. General aspects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Varicose Ulcer - etiology; Varicose Ulcer - immunology; Varicose Ulcer - metabolism; Varicose Ulcer - pathology; Varicose Ulcer - physiopathology; Venous Pressure; Iron overload; Leg ulcer; Skin disease; T-Lymphocytes; Venous insufficiency; Lower limb; Metabolic diseases; Cardiovascular disease; Venous incompetence; Venous disease; Leg; Vascular disease; T-Lymphocyte; Varicose veins; Ulcer; Apoptosis; Varix
• ISSN: 0392-9590; 1827-1839

This review presents a hypothetical model of the development of a venous leg ulcer. The primary pathology is venous hypertension that leads to increased capillary permeability, resulting in extravasation of erythrocytes. Macrophages produce proinflammatory cytokines, which enhance the expression of adhesion molecules in the endothelium of postcapillary venules and increase the recruitment of leukocytes to the pericapillary interstitium. Extravasated T lymphocytes stimulated by cytokines, which are produced by activated macrophages, differentiate toward the Th1 phenotype. In the case of excessive extracapillary passage of erythrocytes or impaired transport of ferric ions by macrophages, the accumulation of iron in the dermis can occur. In tissues with a high concentration of iron, T lymphocytes proliferate instead of undergoing apoptosis. This is possible due to the internalization of the INF-gR2 chain of the interferon-g receptor, the downregulation of inducible nitric oxide synthase expression in macrophages and the inactivation of the active site of caspases. Stimulated by interferon-g skin keratinocytes produce chemokines: CXCL9, CXCL10 and CXCL11, which attract T lymphocytes. Finally, positive feedback loops develop resulting in the migration of T lymphocytes toward the epidermis and in high local concentrations of interferon-g and keratinocyte-derived chemokines. T lymphocytes invading epidermis produce interferon-g and Fas ligand. High concentrations of interferon-g result in the overexpression of Fas by keratinocytes. Matrix metalloproteinases shed Fas ligand from T lymphocytes. The combined effect of Fas ligand and interferon-g on Fas-overexpressing keratinocytes results in their abundant apoptosis and dermo-epidermal detachment, which is clinically manifested as blister-like lesions that progress to chronic ulcerations.