Pathogenesis Of Venous Ulceration Research Articles

MicroRNA-34 Family Enhances Wound Inflammation by Targeting LGR4

Venous ulcers are the most common type of human chronic nonhealing wounds and are stalled in a constant and excessive inflammatory state. The molecular mechanisms underlying the chronic wound inflammation remain elusive. Moreover, little is known about the role of regulatory RNAs, such as microRNAs, in the pathogenesis of venous ulcers. We found that both microRNA (miR)-34a and miR-34c were upregulated in the wound-edge epidermal keratinocytes of venous ulcers compared with normal wounds or the skin. In keratinocytes, miR-34a and miR-34c promoted inflammatory chemokine and cytokine production. In wounds of wild-type mice, miR-34a-mimic treatment enhanced inflammation and delayed healing. To further explore how miR-34 functions, LGR4 was identified as a direct target mediating the proinflammatory function of miR-34a and miR-34c. Interestingly, impaired wound closure with enhanced inflammation was also observed in Lgr4 knockout mice. Mechanistically, the miR-34-LGR4 axis regulated GSK-3β-induced p65 serine 468 phosphorylation, changing the activity of the NF-κB signaling pathway. Collectively, the miR-34-LGR4 axis was shown to regulate keratinocyte inflammatory response, the deregulation of which may play a pathological role in venous ulcers.

The value of regulated upon activation normal T cell expressed and secreted in the pathogenesis of varicose ulcer of lower limbs

To study the effectiveness of RANTES in the pathogenesis of venous ulceration. 40 Chronic venous insufficiency (CVI) individuals were enrolled in the study and separated into the ulceration group (n=20) and non-ulceration group (n=20), according to CVI with or without ulceration, 10 healthy individuals were enrolled as control group. The expression of RANTES mRNA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) in blood. Immunohistochemical staining of RANTES were carried in normal skin, in the tissue at the brim of ulceration and in the tissue of cured or curing ulceration. In ulceration group, the expression of RANTES mRNA in blood increased obviously. Compared with the other two groups, they were significant different (P < 0.05). The difference was also significance in the other two groups (P < 0.05). The average number of RANTES positive expression in normal skin is 28 +/- 13, in the tissue at the brim of ulceration is 107 +/- 44, and in the tissue of cured or curing ulceration is 35 +/- 20. There are significant difference between normal skin and the tissue at the brim of ulceration (P < 0.05). The average number of RANTES positive expression in the tissue of cured or curing ulceration is lower than that's in the tissue at the brim of ulceration. The high expression of RANTES may be one of the important mechanisms of varicose ulcer.

Local metabolic, pathophysiological and histological changes in venous ulcers

The pathogenesis of venous ulceration is not completely understood. The aim of this research was to measure and compare various parameters in ulcers caused by abnormalities in superficial venous (SU) versus deep venous flow (DU), to determine possible differences in their pathogenesis. Analysis of venous blood gases and levels of anaerobic metabolites from the ulcer site were measured in SU (n=8) and DU patients (n=8) and compared with control samples from the contralateral healthy limb. Histological examination via electron microscopy was also performed in tissue samples from the ulcer sites in SU (n=2) and DU (n=2) patients. The SU group had significantly lower values of partial oxygen pressure (pO2) and oxygen saturation (sO2), and significantly higher values of partial pressure of carbon dioxide, bicarbonate concentration and total carbon dioxide versus control samples. The DU group had significantly higher values of pO2 and sO2 versus controls. Elevated levels of pyruvate (P < 0.01) and lactate (P < 0.05) were found in DU ulcer blood samples taken after 30 min of passive standing (static shear), as compared with control blood samples. However, no significant histological differences between SU and DU samples could be distinguished via electron microscopy. Differences in levels of venous blood gases and anaerobic metabolites indicate a potential difference in the causation and development of superficial versus deep venous caused ulcers. This may have clinical significance for the diagnosis and treatment of these conditions.

A potential role of interferon-γ in the pathogenesis of venous leg ulcers

Venous leg ulcer is the most severe expression of chronic venous insufficiency. Venous ulcerations are always associated with venous ambulatory hypertension, but the exact mechanism leading from pathological hemodynamics in venous circulation to the necrotic lesions in the skin still remains undiscovered. It has been shown that tissue injury in venous ulcer patients was induced by leukocytes. However, though infiltrating leukocytes have at their disposal a powerfully cytotoxic arsenal, it has not been discovered which molecular mechanisms may contribute to the skin damage. The search for this hypothetical factor responsible for the development of ulceration should be focused on mechanisms leading to apoptosis of keratinocytes, on pathogenesis of related dermatological pathologies, on other pathologies associated with epithelial lesions, and on mechanisms responsible for the expression of adhesion molecules. A thorough review of the literature, with special regard to cytokines, has revealed that proinflammatory cytokine--interferon-gamma (INFgamma)--could be a pivotal cytokine in the pathogenesis of venous ulceration. This cytokine, however, has not been investigated in venous leg ulcer patients before. INFgamma is a glycoprotein with numerous immunological and antiproliferative activities. The most important message from recent investigations is the fact that INFgamma seems to be the main mediator of keratinocyte apoptosis. INFgamma mediates also leukocyte chemotaxis, and enhances the expression of adhesion molecules involved in the pathophysiology of chronic venous insufficiency. Therapeutic injections of interferons can result in skin necrosis. If it were proven that INFgamma was responsible for the development of venous leg ulcers, this fact would have important clinical consequences. In such a case, anti-INFgamma agent could be used, either in the management of active ulceration, or in the prevention of recurrent ulcer.

Venous ulcer: epidemiology, physiopathology, diagnosis and treatment

This review discusses the epidemiology, pathogenesis, diagnosis and current therapeutic options for venous ulcer. Venous ulcer is a severe clinical manifestation of chronic venous insufficiency (CVI). It is responsible for about 70% of chronic ulcers of the lower limbs. The high prevalence of venous ulcer has a significant socioeconomic impact in terms of medical care, days off work and reduced quality of life. Long-term therapeutics are needed to heal venous ulcers and recurrence is quite common, ranging from 54 to 78%. Thrombophlebitis and trauma with long-term immobilization predisposing to deep venous thrombosis are important risk factors for CVI and venous ulcer. The most recent theories about pathogenesis of venous ulcer have associated it with microcirculatory abnormalities and generation of an inflammatory response. Management of venous leg ulcers is based on understanding the pathogenesis. In recent years novel therapeutic approaches for venous ulcers have offered valuable tools for the management of patients with this disorder.

Treatment of venous ulcers

Underlying the pathogenesis of venous ulceration is venous hypertension. Therefore, the use of multilayered compression therapy is the gold standard in the treatment of a venous ulcer. As treatment progresses, an important determinant of response is wound assessment, which should be performed on initial visit and subsequently thereafter. Among the methods to assess improvement are digital photography and planimetry, which are objective methods to measure response to treatment and rate of wound healing. Lack of improvement over a 2- to 4-week period is predictive of eventual lack of response to therapy and suggests the need for adjunctive methods to achieve success, such as oral pentoxifylline, tissue-engineered skin, or skin grafting.

A Reduction in Serum Cytokine Levels Parallels Healing of Venous Ulcers in Patients Undergoing Compression Therapy

Introduction vascular endothelial growth factor (VEGF) and tumour necrosis factor alpha (TNFα) have been specifically implicated in the tissue damage associated with chronic venous disease (CVD). Furthermore, production of both factors is known to be upregulated in vessel wall cells subject to hypertension. The aim of this study was to determine the local venous levels of VEGF and TNFα in limbs with venous ulcers before and after treatment with graduated compression. Patients and methods eight patients with venous ulcers and 8 patients with varicose veins only were included in the study. For ulcer patients, serum samples were taken from the superficial veins in lower limbs and repeated after 4 weeks of treatment with 4-layered graduated compression. Serum from the arms of the same patients served as controls. Determination of the concentrations of VEGF and TNFα proteins were performed with sandwich enzyme-linked immunosorbent assays. Results both groups of patients had elevated levels of VEGF and TNFα. In patients with venous ulcers there was a reduction in the levels of both cytokines to below control values with treatment. These changes correlated with healing of the ulcers as determined by reduction in ulcer size. Conclusion these data, for the first time, suggest a central role for both TNFα and VEGF in the pathogenesis of venous ulceration which may constitute a causative link between venous hypertension and tissue pathology.

Lipodermatosclerosis and the significance of proteolytic remodeling in the pathogenesis of venous ulceration (Review).

The preceding stage of venous ulceration represents a scleroderma-like hardening of the skin called lipodermatosclerosis. Clinical stages such as lipodermatosclerosis and venous ulceration, which succeed one another are highly associated to chronic venous insufficiency. Lipodermatosclerosis is characterized by fibrous scar tissue of the reticular dermis built up of collagen bundles and loss of cellular components, whereas venous ulceration is characterized by total loss of epidermis and partially of matrix structures in the upper dermis. There is a growing recognition that an excessive proteolytic activity by proteases, in particular that of matrix metalloproteinases and fibrinolytic factors of the plasminogen activation system may be a key feature in the pathophysiological understanding of venous leg ulcer formation. Lipodermatosclerosis displays an intense ongoing proteolytic process by elevated matrix metalloproteinase activity, as recently shown on different molecular and biological levels. Elevated expression on mRNA and protein level of matrix metalloproteinases and fibrinolytic factors of the plasminogen activation system have been detected in liposclerotic skin lesions. In addition, matrix metalloproteinases were proteolytically activated confirmed by zymography experiments and collagen degradation assays. Therefore it is well conceivable, that proteolytic enzymes of matrix metalloproteinases could initiate an elevated turnover of the extracellular matrix with subsequent breakdown of the matrix scaffold finally resulting in venous ulceration.

The microcirculation in venous hypertension.

Venous ulceration is a common problem in western countries and results in large costs to healthcare systems. A number of hypotheses of the mechanisms of development of venous ulceration have been advanced, but this question has not been fully resolved. In recent years research effort has focused on the microcirculation of the skin and many methods of investigation have been employed to study this. Some of the principal findings described in published work are reviewed in this article. It seems unlikely from the available evidence that venous ulceration is attributable solely to failure of diffusion of oxygen and other small nutritional molecules to the tissues of the skin. The microvascular changes in the skin are characterised by activated endothelium and perivascular inflammatory cells. It is much more likely that leucocytes attach themselves to the cutaneous microcirculation, become activated and produce endothelial injury. Repeated over many months or years, this chronic inflammatory process leads to be tissues changes of lipodermatosclerosis. Although there is evidence of leucocyte involvement in the pathogenesis of venous ulceration, the exact mechanisms remain to be resolved. Improved treatment for patients may be devised once a better understanding of the basic causes of this condition has been reached.

The microcirculation in venous hypertension

To review the factors that result in skin ulceration of patients with chronic venous insufficiency. Index Medicus was searched using an on-line computer system for years 1966-1995 to identify articles relating to venous ulceration and the microcirculation. Articles and sections of articles relating to the mechanisms which cause venous ulceration and the efficacy of the treatment of venous ulceration have been included. It seems unlikely that venous ulceration is attributable to failure of diffusion of oxygen and other small nutritional molecules to the tissues of the skin. It is much more likely that neutrophils attach themselves to the cutaneous microcirculation, become activated and produce endothelial injury. Repeated over many months or years, this leads to the chronic inflammatory process of lipodermatosclerosis. The microvascular changes in the skin are characterised by activated endothelium and perivascular inflammatory cells. There is evidence of leucocyte involvement in the pathogenesis of venous ulceration. The exact mechanisms remain to be resolved. Improved treatment for patients may be devised with a better understanding of the basic causes of this condition.

Morphological Changes in Lipodermatosclerosis and Venous Ulcers: Light Microscopy, Immunohistochemistry and Electron Microscopy

Objectives: To demonstrate morphological changes in lipodermatosclerosis (LDS) and venous ulcers by histology, immunohistochemistry, electron microscopy and immunoelectron microscopy. Design: Single patient group study in patients with trophic skin changes in chronic venous insufficiency. Setting: Department of Dermatology, Medical University of Lübeck. Patients: Ten patients with venous leg ulcers. Interventions: Biopsies were taken from areas of LDS and compared with clinically normal-appearing skin of the affected leg and with ulcer tissue. Main outcome measures: Comparison of the morphological features on light and electron microscopy. Results: Superficial dermis. Histologically, the ulcer tissue and LDS skin show dilated tortuous vessels in a glomerulus-like arrangement in the superficial parts of the dermis. Ultrastructurally, the superficial vessels are surrounded by a cuff, which contains amorphous and basal membrane material and is most pronounced in LDS. Immunofluorescence studies reveal ill-defined perivascular staining after incubation with antibodies against fibrin(ogen), laminin and type IV collagen. The exact ultrastructural localization of type IV collagen within the perivascular cuff is observed by immunoelectron microscopy. Deep dermis. In deeper parts of the dermis, the vessels of both ulcer tissue and LDS are surrounded by cellular cuffs with pericytes, fibroblasts and compact collagen bundles. Conclusions: We suggest that the severe morphological changes in LDS and ulcer tissue play an important role in the pathogenesis of venous ulceration.

The "trap" hypothesis of venous ulceration

The pathogenesis of venous ulceration is unknown. We propose that macromolecules leaking into the dermis as a result of venous hypertension bind to or "trap" growth factors and matrix material, which then become unavailable for tissue repair and for the maintenance of tissue integrity.

Peripheral nerve function in chronic venous insufficiency

Abnormalities of vasomotion, impairment of the venoarteriolar reflex and increased skin blood flow reported in the liposclerotic skin of patients with chronic venous insufficiency (CVI) suggest altered nervous control of the skin microcirculation. The aim of this study was to determine whether patients with CVI have a peripheral neuropathy. Forty patients with CVI and lipodermatosclerosis (LDS) and 35 age and sex-matched controls were examined for neuropathy using three modalities of testing. Threshold to warming was used to assess unmyelinated fibres, and threshold to cooling and vibration to assess myelinated fibres. Warming and cooling thresholds were measured on the sole of the foot by a purpose built, computer controlled instrument. The threshold to vibration was measured on the big toe using the Ohio Bio-thesiometer. A significantly raised threshold to warming and vibration was found in the CVI group compared to the normal controls [median threshold to warming (interquartile range) in CVI group = 5.3 (0.1-9.1) median threshold to warming (interquartile range) in controls = 1.21 (0.17-3.5), p = 0.005 and median threshold to vibration (interquartile range) in CVI group = 22 (13-31) median threshold to vibration (interquartile range) in controls = 12 (8.5-27.5), p = 0.024]. The thresholds to cooling was not statistically different in the two groups. This study demonstrates the presence of a peripheral neuropathy in patients with chronic venous insufficiency, and this may be important in the pathogenesis of venous ulceration.

Vasomotion in Venous Disease

Abnormalities of the capillary microcirculation may be important in the pathogenesis of venous ulceration. In this study the characteristics of capillary vasomotion in venous disease have been studied using laser Doppler flowmetry. The amplitude and frequency of vasomotion in the skin microcirculation as measured by laser Doppler flowmetry was determined in 101 subjects. These comprised 43 subjects with venous disease and lipodermatosclerosis (LDS), 14 subjects with uncomplicated varicose veins (VV), and 44 normal controls. In 43 of these 101 limbs, vasomotion was also measured after heating the skin to 43 degrees C. The resting laser Doppler flux was significantly higher in the LDS group compared to the other two groups (LDS median = 76, VV median = 47 (P less than 0.04), controls median = 49 (P less than 0.003]. The amplitude of vasomotive waves was significantly higher in the LDS group compared to controls (LDS median = 20, VV median = 8.3 (P less than 0.007), controls median = 14 (P less than 0.007), as was the frequency of vasomotion (LDS median = 3.3 waves/min, VV median = 2.5 (P = ns), controls median = 2.7 (P less than 0.007]. On heating the skin to 43 degrees C the frequency of the vasomotion increased significantly in the control (P less than 0.004) and VV (P less than 0.04) groups but not in the LDS group. The amplitude of the vaso-motion also increased significantly in the control (P less than 0.01) and VV (P less than 0.002) groups but not in the LDS group.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity in Oxygen Diffusion Around Venous Ulcers

The pathogenesis of venous ulceration is thought to involve the formation of fibrin cuffs around dermal capillaries. Consistent with a barrier effect of fibrin, it has been shown that the dermal diffusion of oxygen, as measured by transcutaneous oxygen pressure (TcPO2), is decreased in limbs affected by venous ulcer. However, it is unknown whether oxygen diffusion around the perimeter of venous ulcers is uniformly affected. In this study, we investigated TcPO2 values at four different quadrants around the ulcers of 14 patients, the contralateral leg of five patients with unilateral ulcers, and the leg of six normal individuals. These values were also compared to TcPO2 measurements at the chest. Our results indicate that, whereas TcPO2 values in limbs affected by venous ulcers are much lower than normal, there is a great deal of variability in oxygen diffusion around individual ulcers. These findings may represent a heterogeneity in the disease process affecting the leg.

A Study on the Effect of Hydroxyethylrutoside on Transcutaneous Oxygen Tension Measurements in Patients with Severe Venous Insufficiency

Chronic venous insufficiency is thought to cause tissue hypoxia and ulceration through pericapillary deposition of fibrin. Transcutaneous tissue oxygen tension measurements (TCpO 2) were made on 17 patients with severe venous insuffi ciency and repeated after three and six months of treatment with O-(B- hydroxyethyl)-rutosides, a drug recommended for treatment of venous insufficiency that is thought to enhance tissue fibrinolysis. After six month's treatment, TCpO 2 measurements were significantly better than inital values (0.01 &lt; p &lt; 0.05). This improvement in TCpO2 measurements is consistent with the hypothesis that O-(B-hydroxyethyl)-rutosides act by enhancing tissue fibrinolysis and might reduce the pericapillary fibrin that is thought to be a major factor in the pathogenesis of venous ulceration.

Fibrin- and Fibrinogen-Related Antigens in Patients With Venous Disease and Venous Ulceration

Abnormalities in systemic fibrinolysis have been implicated in the pathogenesis of venous ulceration. Patients with venous disease have a prolonged euglobulin lysis time and elevated plasma fibrinogen levels, yet little is known about the metabolism of fibrinogen and fibrin in such patients. In this study, we have used a technique that involves electrophoresis and densitometric analysis of captured fibrin-related antigens to measure the concentration and proportions of the individual fibrin and fibrinogen degradation products in patients with venous disease of the lower extremity. As a group, patients with venous disease had markedly elevated levels of total fibrin-related antigen and D-dimer, the terminal degradation product of cross-linked fibrin. Levels of D-monomer, the breakdown product of fibrinogen and non-cross-linked fibrin monomer, and a measure of fibrinogenolysis were normal in all patients. In patients with ulcers, the levels of D-dimer were disproportionately higher than expected from fibrin monomer levels. On an individual basis, significant elevations of D-dimer were present in six (55%) of the 11 patients with venous disease with ulcers and in three (43%) of the seven patients with venous disease without ulcers. We conclude that patients with venous disease have uniform evidence for enhanced fibrin formation, as evidenced by elevated levels of total fibrin-related antigen and D-dimer. This is regardless of whether the venous disease is accompanied by ulceration.

Impaired Postural Vasoconstriction: A Contributory Cause of Oedema in Patients with Chronic Venous Insufficiency

Dependent oedema is a common feature in patients suffering from venous insufficiency. Postural vasoconstriction which prevents oedema has been shown to be impaired in several conditions complicated by dependent oedema. We therefore investigated the postural vasoconstrictor response, foot swelling rate and capillary density in eight patients with venous insufficiency and seven normal controls. Foot skin blood flow was measured on the pulp of the big toe using laser–Doppler flowmetry with the foot at heart level (H) and placed approximately 1 metre below the heart (D). Postural fall in flow was calculated as (H – D) × 100/H. Foot swelling rate was measured simultaneously using a strain gauge Plethysmograph. Postural vasoconstriction was impaired in venous insufficiency at 62 ± 12% compared to 88 ± 4% in controls ( P &lt; 0.02). Capillary density in the forefoot was assessed using television microscopy and was significantly reduced in the venous insufficiency group at 26.83 ± 2.74 per mm2 compared to 36.96 ± 1.09 per mm2 ( P &lt; 0.01). These findings suggest impaired postural vasoconstriction may contribute to the formation of oedema characteristic of venous insufficiency. The apparent reduction in capillary density may be implicated in the pathogenesis of venous ulceration to which such patients are prone.

C-reactive protein levels in venous ulceration: An indication of infection?

The role of bacteria in the pathogenesis of venous ulcers is unclear. It is difficult to be clinically certain of the presence of infection. Routine bacteriology is often unhelpful, and any simple investigation that improves diagnosis in this situation would be of value. C-reactive protein (CRP) levels are useful in detecting infection in other situations, and they may be of value in this context as well. C-reactive protein levels were measured in 50 patients with venous leg ulcers and in 20 patients with active venous eczema. There was no elevation of CRP levels in patients with eczema alone, nor in the majority of patients with ulcers. Sixteen patients had raised CRP levels: 7 had clinically obvious infection, and 9 had erythematous skin of uncertain cause surrounding their ulcers. All had positive bacterial cultures from the ulcer base, with β-hemolytic streptococci the main contaminant. Treatment with an appropriate antibiotic reduced CRP levels to normal, cleared the bacteria from the ulcers, and was associated with resolution of erythema. CRP levels appear to distinguish between infectious and inflammatory causes of erythema in patients with gravitational disease.

The pathogenesis of venous ulceration: a hypothesis.

The pathogenesis of venous ulceration: a hypothesis.