transforming-growth-factor-beta and Leg-Ulcer

Topics: Administration, Topical; Blood Physiological Phenomena; Epidermal Growth Factor; Fibroblast Growth Factors; Growth Substances; Humans; Leg Ulcer; Leukocytes, Mononuclear; Platelet-Derived Growth Factor; Transforming Growth Factor beta; Wound Healing

To characterise the histological and cytokinetic characteristics of purely ischaemic ulcers and the processes that underpin healing following successful revascularisation.. Prospective observational study.. Biopsies were taken immediately pre- and 6 weeks following successful revascularisation of solely ischaemic ulceration. They were evaluated for morphological differences using H&E staining for the platelet derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), TGFbeta receptorIII (TGFbetaRIII), transforming growth factor beta 1 and 3 (TGFbeta1 and TGFbeta3) and von Willebrand factor (vWF) expression using immunohistochemistry. Localisation and quantification of these growth factors and receptors was assessed systematically by three independent investigators who were blinded to the timing of biopsy.. Pre-operatively, small vessel vasculitis, necrosis and infection with a profuse neutrophil and macrophage infiltrate was observed in all samples. Post-operative biopsies revealed a proliferation of new capillaries in and around the ulcer edge and base. vWF staining confirmed an endothelial layer within these new vessels. Following successful revascularisation there was less infection and inflammation with minimal vasculitis. These newly formed capillaries had increased staining for TGFbeta3, PDGFR and TGFbetaRIII with staining for PDGFR also localised to dermal fibroblasts which were larger and more numerous. Accelerated epithelial cell proliferation was observed with detachment from the underlying dermis.. Healing of purely ischaemic ulcers is characterised by vasculogenesis associated with increased presence of the proangiogenic cytokines PDGF and TGFbeta3. These findings show promise for the use of growth factor manipulation to aid healing in ischaemic ulcers.

Topics: Adult; Aged; Aged, 80 and over; Female; Follow-Up Studies; Humans; Ischemia; Leg; Leg Ulcer; Male; Middle Aged; Prospective Studies; Receptors, Growth Factor; Transforming Growth Factor beta; Wound Healing

Cutaneous leg ulcers are common in sickle cell anaemia and their risk might be genetically determined. Sickle cell anaemia patients were studied to examine the relationship of leg ulcers with haemolysis and with single nucleotide polymorphisms (SNPs) in candidate genes that could affect sickle vasoocclusion. Leg ulcer patients had lower haemoglobin levels and higher levels of lactate dehydrogenase, bilirubin, aspartate transaminase and reticulocytes than did control patients with sickle cell anaemia but without leg ulcers. Age-adjusted comparisons showed that sickle cell anaemia-alpha thalassaemia was more frequent among controls than cases. These results strongly suggested that the likelihood of having leg ulcers was related to the intensity of haemolysis. 215 SNPs in more than 100 candidate genes were studied. Associations were found with SNPs in Klotho, TEK and several genes in the TGF-beta/BMP signalling pathway by genotypic association analyses. KL directly or indirectly promotes endothelial nitric oxide (NO) production and the TEK receptor tyrosine kinase is involved in angiogenesis. The TGF-beta/BMP signalling pathway modulates wound healing and angiogenesis, among its other functions. Haemolysis-driven phenotypes, such as leg ulcers, could be improved by agents that reduce sickle erythrocyte density or increase NO bioavailability.

Topics: Adult; Anemia, Sickle Cell; Bone Morphogenetic Proteins; Female; Genotype; Glucuronidase; Hemolysis; Humans; Klotho Proteins; Leg Ulcer; Male; Phenotype; Polymorphism, Single Nucleotide; Receptor, TIE-2; Thalassemia; Transforming Growth Factor beta

Hepatocyte growth factor (HGF) is a multifunctional cytokine that is involved in recovery process after organ injuries.. We studied HGF and the membrane bound receptor, c-met locally in patients who suffered from chronic leg ulcers (> or =1 year) caused by venous insufficiency.. Skin biopsies from the edge of the ulcers were taken from patients (n=13) and studied by immunohistochemical staining for detection of HGF and c-met. Skin biopsies from healthy volunteers (n=10) were used as the control material. Ulcer secretion from chronic ulcers (n=11) was examined for the presence of HGF by ELISA and the concentration of HGF was compared with acute ulcers in healthy controls (n=10) and in patients operated for a non-invasive breast cancer (n=12).. We observed that c-met expression in the ulcer area increased significantly in chronic ulcers compared to controls (p=0.005). Concentration of ulcer-HGF in the patients with chronic ulcer was significantly higher than acute ulcers (p<0.01). The biological activity of HGF in ulcer secret was assessed in-vitro in transferred, mouse skin epithelial cell monolayer. Enhanced migration and morphologic changes were seen after adding ulcer secret from acute ulcers (> 1 ng/mL) that was inhibited by anti-HGF antibodies. No biological activity was observed by adding ulcer secret from chronic ulcers irrespective HGF concentration.. We conclude that in chronic skin ulcers decreased biological activity of endogenous HGF and overexpression of c-met is seen which might explain fibrosis and delayed recovery. Administration of exogenous active HGF might contribute to accelerated healing in these patients.

Topics: Adult; Animals; Biopsy; Blotting, Western; Breast Neoplasms; Case-Control Studies; Cell Line; Cell Movement; Cytokines; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Leg Ulcer; Male; Mice; Proto-Oncogene Proteins c-met; Skin; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ulcer; Venous Insufficiency; Wound Healing

Topics: Growth Substances; Humans; Leg Ulcer; Leukocyte Elastase; Transforming Growth Factor beta; Wound Healing

Treatment of leg ulcers should consider two aspects, i.e. the exact underlying condition (main cause and contributing factors) and local conditions. Compression therapy remains the corner-stone of the therapeutic concept. A compression of 35 mmHg at the distal calf improves insufficient venous function. A systolic ankle pressure of < or = 80% of blood pressure (ankle-arm-index < or = 0.8) requires reduction of compression therapy. At an ankle pressure below 80 mmHg compression should not be used. If superficial reflux is the major cause of chronic venous insufficiency, vein stripping should be considered. Contributing diseases like heart insufficiency, anemia or diabetes may require general medical care. Local contributing factors like reduced mobility of the ankle joint and lymphostasis may require physical therapy, and calcification of the wound bed should be excised. Local treatment considers ulcer bed and border. The ulcer bed needs debridement and moist wound care. Infection is treated with systemic antibiotics, according to the antibiogram. Tetanus immunization is required for all leg ulcer patients. Some centers report good results with endoscopic subfascial decision of perforator veins, paratibial fasciotomy and excision of fibrous tissue. Local application of recombined growth factors is currently under clinical evaluation. Adjuvant pharmacotherapy plays a minor role in the treatment of venous leg ulcers. An efficient treatment of the underlying cause combined with optimal wound care are the key to therapeutic success.

Topics: Anti-Bacterial Agents; Bandages; Debridement; Humans; Leg Ulcer; Platelet-Derived Growth Factor; Practice Guidelines as Topic; Pressure; Tetanus Toxoid; Transforming Growth Factor beta; Venous Insufficiency; Wound Infection

Topics: Angiogenesis Inducing Agents; Blood Platelets; Endothelial Growth Factors; Humans; Ischemia; Leg; Leg Ulcer; Platelet-Derived Growth Factor; Prospective Studies; Transforming Growth Factor beta

Topics: Fibrin; Fibrinogen; Growth Substances; Humans; Leg Ulcer; Macromolecular Substances; Transforming Growth Factor beta