Abnormal proinflammatory and stressor environmental with increased the regulatory cellular IGF-1/PAPP-A/STC and Wnt-1/ß-Catenin canonical pathway in placenta of women with Chronic venous Disease during Pregnancy.

Lower limbs venous insufficiency refers to a wide variety of venous disorders grouped by the term of chronic venous disease (CVD). Hemodynamic and hormonal changes related to pregnancy period, may promote the development of CVD affecting approximately 1 in 3 women. It has been shown that the presence of this condition is associated with damage and placental suffering. Thus, taking IGF-1/PAPP-A/STC-2, inflammatory cytokines production, PI3K/Akt and Wnt/ ß-catenin pathways as a part of the alterations that occurs in the placenta due to CVD, the aim of this study will be to examine the main components of these pathways. Genic and protein expression of PAPP-A, STC-2, IGF-1, IRS-4 Wnt-1, ß-catenin, c-myc, Cyclin D1, IL-4/IL-6 and PI3K/Akt/mTOR pathway will be analysed through RT-qPCR and immunohistochemical techniques in women with CVD (n=62) and pregnant women without this condition (HC) (n=52). PAPP-A, IGF-1, IL-4, IL-6, IRS-4, PI3K, Akt, mTOR, Wnt-1, ß-catenin, c-myc and Cyclin D1 expression were found to be increased in women with CVD, whereas STC-2 were decreased in this group, compared to non-affected women. Our study has demonstrated that IGF-1/PAPP-A/STC-2 axis, PI3K/Akt and Wnt/ß-catenin pathways, along with c-myc, Cyclin D1 and inflammatory cytokines are altered in placenta women with CVD. These results extent the knowledge that CVD is associated to a placenta damage with abnormal tissue environment and cellular regulation.

[Granulocytes function in patients with chronic venous insufficiency followed by chronic wounds]. / Funktsional'naia aktivnost' kletok granulotsitarnogo zvena bol'nykh s dlitel'no nezazhivaiushchimi ranami na fone khronicheskoi venoznoi nedostatochnosti.

AIM: To analyze efficiency of ozone therapy, ultrasound and cryotherapy for infected and purulent wounds due to chronic venous insufficiency. MATERIAL AND METHODS: There were 127 patients with chronic venous insufficiency followed by chronic wounds. Efficacy of systemic and local ozone therapy was assessed. De Sole method was used to analyze chemiluminescent and spontaneous activity of neutrophils of peripheral blood. RESULTS: Advanced generation of active forms of oxygen was revealed in patients with chronic wounds and chronic venous insufficiency. Complex ozone therapy including intravenous administration of ozonized autologous blood, oxygen-ozone and ultrasonic exposure of the wound and cryogenic stimulation reduce painful period up to 3.1±0.6 days, accelerate epithelialization of the wound and normalize release of active forms of oxygen.

The Role of Endothelial Dysfunction and Inflammation in Chronic Venous Disease.

Chronic venous disease is a potentially prevalent and debilitating condition affecting millions of individuals, mostly in Western world. Predisposing genetic and environmental factors contribute to its development. However, the main etiology remains to be elucidated. An extensive literature search was conducted in Medline using the following key words algorithm: ("Chronic venous disease" OR "Chronic venous insufficiency" OR "varicose veins") AND ("endothelial dysfunction" OR "inflammation"). Besides being a multifactorial disease, it is now recognized that the hallmark of chronic venous disease pathophysiology likely remains in inflammation, possibly triggered by sustained venous hypertension and valvular incompetence. Shear stress changes are directly sensed by endothelial cells, leading to its activation and subsequent recruitment of leukocytes and release of proinflammatory agents. Dysfunctional endothelium has a pivotal role perpetuating the inflammatory cascade, with consequent pathological venous changes and chronic venous disease worsening. Endothelial dysfunction may be the central player in the link between varicose veins and deep vein thrombosis. In this article, we aim to analyze the crucial role of endothelial activation in the persistent inflammatory cycle that characterizes chronic venous disease.

[CHANGES OF PH AND CYTOLOGICAL PICTURE AT VARIOUS STAGES OF WOUND HEALING IN PATIENTS WITH VENOUS GENESIS TROPHIC ULCERS OF THE LOWER LIMBS].

The analysis of 82 patients medical records with venous trophic ulcers (VTU) of the lower limbs were presenting. pH in patients with VTU determined in three locations: the surface of ulcers, venous modified and unmodified skin and ulcers. Cytological examination of secretions from wounds conducted in 32 (39.1%) patients using smears. In 19 (23.2%) patients prevailed exudation stage, in 37 (45.1%) ­ granulation, in 26 (31.7%) - epithelialization. At all stages of wound healing at a distance from the ulcers observed values change skin pH to the acid side. Typical sings of first phase of wound healing were degenerative­inflammatory and inflammatory type of cytogram, and for the granulation phase ­ inflammatory­regenerative and regenerative one.

Glycosaminoglycan sulodexide modulates inflammatory pathways in chronic venous disease.

Inflammation represents an important epiphenomenon in the etiopathogenesis of chronic venous disease, a worldwide debilitating condition affecting millions of subjects. The pathophysiology of chronic venous disease (CVD) is based on the hemodynamic abnormalities in conjunction to alterations in cellular and extracellular matrix biocompounds. The endothelial dysfunction results from early perturbation in the endothelium linked to glycocalyx injury and promoted by inflammatory cells and mediators (such as matrix metalloproteinases and interleukins), which lead to progressive dilation of the vein resulting in chronic venous insufficiency. Activated leukocytes during the inflammatory process release enzymes, free radicals, chemokines and inflammatory cytokines in the vessel microenvironment, which are responsible for the changes of the venous wall and venous valve, reflux and venous hypertension, and the development/progression of tissue destruction and skin changes. Sulodexide, a highly purified mixture of glycosaminoglycans composed by 80% fast moving heparin and 20% of dermatan sulphate, exhibits anti-thrombotic and profibrinolytic properties, restoring also the essential endothelial glycocalyx. Glycosaminoglycan sulodexide has been also characterized to reduce the release of inflammatory cytokines/chemokines and to inhibit the matrix metalloproteinases-related proteolytic cascades, counteracting endothelial dysfunctions. The pleiotropic effects of sulodexide set the basis for a very promising agent in treating the spectrum of CVD.

Pediatric multiple sclerosis: pathobiological, clinical, and magnetic resonance imaging features.

In this article, the pathobiological, clinical, and treatment aspects of pediatric-onset multiple sclerosis (MS) are summarized, and the conventional magnetic resonance (MR) imaging (ie, T1-weighted, proton-density, and T2-weighted imaging) features of MS in children are discussed, as well as the application of MR imaging in the diagnosis of pediatric-onset MS and in prediction of MS in children with an incident central nervous system demyelination. Insights gained from studies comparing MR imaging features of pediatric-onset and adult-onset MS are presented.

[Trends in systemic inflammatory factors and aminoterminal brain natriuretic propeptide in the treatment of chronic heart failure].

AIM: To study trends in systemic inflammatory factors and aminoterminal brain natriuretic propeptide (NT-proBNP) in the blood of patients with stage IIA and IIB chronic heart failure (CHF) during therapy aimed at reducing venous congestion. MATERIAL AND METHODS: The study enrolled 52 patients with postinfarction cardiosclerosis (PICS). Clinical, echocardiographic and laboratory studies were conducted. The levels of TNF-alpha, IL-6, IL-10 and C-reactive protein (CRP) were measured by enzyme immunoassay. The concentration of endotoxin (ET) was estimated by the end-point chromogenic LAL test, that of NT-proBNP--by immunochromotographic assay. RESULTS: In the patients with CHF, clinical signs of pulmonary venous congestion are associated with a statistically significant increase in the blood levels of TNF-alpha and CRP, those of systemic venous congestion are related to a further rise in TNF-alpha levels and elevation of blood concentrations of NT-proBNP, ET and IL-10. Treatment-related reduction in pulmonary venous congection is associated with a decrease in the levels of TNF-alpha, CRP and IL-6; that in systemic venous congestion--with lower concentrations of NT-proBNP, TNF-alpha and ET. CONCLUSION: Specific changes in the levels of systemic inflammatory factors and NT-proBNP were found in patients with CHF in the presence of pulmonary and systemic venous congestion. Treatment aimed at elimination of the latter leads to reduction in the levels of systemic inflammatory factors and NT-proBNP.

[Remote results of using prostaglandins E1 and immunotherapy in combined modality treatment of various-aetiology trophic ulcers].

The purpose of this study was to assess short- and long-term efficacy of combined-modality therapy (comprising PGE1-group preparations and immunocorrection) used to treat indolent trophic ulcers in patients presenting with chronic venous insufficiency (CVI) and cutaneous angiitis. Examined herein were both immediate and remote therapeutic outcomes obtained in patients suffering from indolent trophic ulcers secondary to CVI (post-thrombophlebic disease [PTPD] and varicose disease [VD]), as well as ulcers resulting from vasculitis or vasculopathy. The conventional therapy was supplemented with infusion of PGE1-group preparations and immunocorrection. Also investigated were the indices of microcirculation and the immune status, the percentage of the trophic ulcers having healed, the trophic-ulcer recurrence rate in the remote period, feasibility offurther performing a radical surgical intervention, the patients' quality of life after the treatment, and the need for repeat therapeutic courses according to the regimen proposed. The use of PGE1-group preparations in a combination with immunocorrection confirmed high efficacy of the treatment for various-aetiology trophic ulcers (with the preserved arterial blood flow). The trophic ulcers were observed to epithelialize rapidly following the initiation of treatment, thus making it possible to appropriately prepare the patient suffering from varicose disease for further surgical management. The remote-period evidence clearly showed that the use of the proposed therapeutic regimen had eventually led to a considerable improvement in the patients' quality of life, dramatically decreasing the recurrence rate of trophic ulcers in patients with PTPD and vasculopathies, and thus may safely be recommended both for prevention of ulcer relapses and as part of maintaining therapeutic courses. The detected deviations in the immune status of the patients afflicted with vasculitis and those suffering from CVI confirmed the need for immunocorrection.

Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy.

OBJECTIVE: Elevated inflammatory cytokine levels have been implicated in the pathogenesis of non-healing chronic venous insufficiency (CVI) ulcers. The goal of this study was to determine the protein levels of a wide range of inflammatory cytokines in untreated CVI ulcer tissue before and after 4 weeks of high-strength compression therapy. These levels were compared to cytokines present in healthy tissue. METHODS: Thirty limbs with untreated CVI and leg ulceration received therapy for 4 weeks with sustained high-compression bandaging at an ambulatory wound center. Biopsies were obtained from healthy and ulcerated tissue before and after therapy. A multiplexed protein assay was used to measure multiple cytokines in a single sample. Patients were designated as rapid or delayed healers based on ulcer surface area change. RESULTS: The majority of pro-inflammatory cytokine protein levels were elevated in ulcer tissue compared to healthy tissue, and compression therapy significantly reduced these cytokines. TGF-beta1 was upregulated in ulcer tissue following compression therapy. Rapid healing ulcers had significantly higher levels of IL-1alpha, IL-1beta, IFN-gamma, IL-12p40, and granulocyte macrophage colony stimulating factor (GM-CSF) before compression therapy, and IL-1 Ra after therapy. IFN-gamma levels significantly decreased following therapy in the rapidly healing patients. CONCLUSION: CVI ulcer healing is associated with a pro-inflammatory environment prior to treatment that reflects metabolically active peri-wound tissue that has the potential to heal. Treatment with compression therapy results in healing that is coupled with reduced pro-inflammatory cytokine levels and higher levels of the anti-inflammatory cytokine IL-1 Ra.

Dermal pathology, cellular biology, and inflammation in chronic venous disease.

The pathophysiology of venous dermal pathology in chronic venous disease (CVD) is reflective of a complex interplay that involves sustained venous hypertension, inflammation, cytokine and matrix metalloproteinase (MMP) activation, and altered cellular function. Endothelial expression of specific adhesion molecules recruits leukocytes, and diapedesis of these cells into the dermal microvasculature promotes an inflammatory response with activation of cytokines and proteinases. Altered cell function enhances a state of vulnerability in the surrounding tissues initiating specific changes associated with venous disease. Ultimately, the persistent inflammatory-proteinase activity leads to advanced chronic venous insufficiency (CVI) and ulcer formation.

Thrombus resolution and vein wall injury: dependence on chemokines and leukocytes.

Chronic venous insufficiency resulting in post-thrombotic syndrome occurs commonly after acute deep vein thrombosis, and is a prevalent cause of vascular disease morbidity in the community. Therefore, a better understanding of the pathophysiologic mechanisms that promote the development of chronic venous insufficiency could lead to novel approaches to interrupt the natural history and prevent post-thrombotic syndrome. In this paper, we will review the evidence that venous thrombus resolution is an inflammatory process that is dependent on chemokines and leukocytes.

Effects of acute global venous obstruction and unfractionated heparin on muscle cytokine synthesis.

Phlegmasia cerulea dolens is a devastating complication of massive deep venous thrombosis, which is clinically characterized by massive lower extremity tissue edema and subsequent arterial insufficiency. These experiments evaluated the local tissue effects of acute global venous obstruction combined with partial arterial ischemia. Experiments were performed to assess the effects of heparin on the cytokine response to simultaneous venous and partial arterial obstruction. Murine hind limbs were subjected to conditions of unilateral venous occlusion and partial tourniquet limb ischemia, which was confirmed by laser Doppler imaging (LDI). Mice underwent either hind limb venous obstruction with intravenous unfractionated heparin (200IU/kg) or intravenous saline 5min before venous occlusion. Sham-treated mice were subjected to anesthesia alone without venous occlusion. After 3hr, the mice were killed and tissue was harvested for measurement of edema (wet to dry weight ratio, W/D), muscle viability, indices of local thrombosis (thrombin-antithrombin complex [TAT]), and cytokine analysis for growth-related oncogene-1 (GRO-1) and interleukin-6 (IL-6, protein via enzyme-linked immunoassay and mRNA via reverse transcriptase polymerase chain reaction). Bleeding time and volume were documented in saline- and heparin-treated mice to confirm systemic anticoagulation. Administration of intravenous heparin resulted in a marked increase in bleeding time and volume. LDI confirmed venous obstruction and ongoing arterial inflow. Venous obstruction resulted in severe visible edema that correlated with a significantly higher W/D ratio but was not associated with a significant decrease in muscle viability. GRO-1 and IL-6 protein and mRNA levels were significantly elevated in the venous occlusion group compared to sham. Heparin therapy significantly decreased TAT3 levels but did not alter the profile of GRO-1 or IL-6 protein levels seen with venous occlusion. Venous occlusion with partial ischemia induces a unique and potent local cytokine expression. Heparin therapy did not ameliorate the cytokine response. These data indicate that heparin therapy does not modulate the cytokine response to venous obstruction.

Immune function of erythrocytes in patients with chronic venous insufficiency of the lower extremities.

BACKGROUND: The influence of inflammatory processes has been one of the hot topics in discussions of the etiology of chronic venous insufficiency (CVI). Erythrocytes are very important in controlling inflammatory immunity and innate immune reactions. The purpose of this study was to analyze the correlation between the development of CVI and the change of CD35, Fy6 on erythrocytes, and interleukin-8 (IL-8) levels. METHODS: A group of 43 patients with CVI were studied in parallel with 8 healthy individuals serving as control subjects. Control subjects were those with normal findings on lower extremity duplex examinations. We used an erythrocyte flow cytometer to examine the expression of both CD35 and Fy6 on red blood cells, and an enzyme-linked immunosorbent assay analysis method to measure plasma IL-8 levels. We also analyzed the change of IL-8 levels under the influence of erythrocytes using a modified method of the hemaimmune reaction. RESULTS: Compared with normal control subjects, CD35 expression increased significantly among patients with CVI classified as C4 without lipodermatosclerosis, but tended to decrease and reach the lowest level among patients classified as C5-C6. Fy6 expression increased significantly among patients in the early stages of CVI, but tended to decrease remarkably among patients classified as C5-C6. The inflammatory response intensified at the C5-C6 classification, where high levels of IL-8 coexisted with a low expression of Fy6. The increase in IL-8 in the CVI group was higher than in the control group in association with the complete blood cells, regardless of the presence of erythrocytes, when inactive tumour cells were added, whereas the level of IL-8 in the CVI group was significantly lower than in the control group. CONCLUSIONS: Abnormalities of erythrocyte innate immunity represents a fundamental derangement in CVI. These inadequate inflammatory responses may lead to local tissue and microvascular damage of the lower extremity.

Chronic venous insufficiency and the therapeutic effects of Daflon 500 mg.

Chronic venous insufficiency is linked to venous hypertension and forces of shear stress on the endothelium. Venous hypertension depends upon two forces: the weight of a column of blood from the right atrium transmitted through the valveless vena cava and iliac veins to the femoral vein, and pressure generated by contracting skeletal muscles of the leg transmitted through failed perforating veins. When valve failure occurs in superficial axial veins and perforating veins, the venous pressure in the veins and venules of the skin and subcutaneous tissue is raised. The skin changes in chronic venous insufficiency are directly related to the severity of the venous hypertension. Also, pathologic changes in the valves are linked to venous hypertension and leukocyte infiltration and activation. It is hypothesized that acute venous pressure elevations cause a shift in the venous hemodynamics with changes in wall shear stress. This initiates the inflammatory cascade. Daflon 500 mg ameliorates the effects of chronic inflammation. In randomized trials, 60 days of therapy with Daflon at a dosage of 500 mg 2 tablets daily was effective, in addition to elastic compression, in accelerating venous ulcer healing. Because venous insufficiency is linked to venous hypertension and an inflammatory reaction, it appears that Daflon 500 mg 2 tablets daily shows a great potential for accomplishing blockade of the inflammatory cascade.

The impact of gastrocnemius muscle cell changes in chronic venous insufficiency.

OBJECTIVE: To investigate the pathological and metabolic changes in the gastrocnemius muscle in patients with chronic vein insufficiency (CVI). METHOD: Thirty-six patients with varicose veins were investigated by ambulatory venous pressure (AVP) and duplex ultrasonography. Twelve age and height-matched controls were used for comparison. Patients and controls consented to participate in this study. Twenty-one patients with primary vein varicose (group AI) and 15 patients (group AII) with primary deep venous valve incompetence (DVI) underwent biopsies of the gastrocnemius muscle during operation. Adductor biopsies obtained from the same limbs served as a control group (group B) and specimens from controls subjects without venous disease served as the second control group (group C). All the specimens were investigated by superoxide dismutase (SOD), nitric oxide (NO), Na+-K+-ATPase, Ca2+-ATPase and lactic acid (LD) determinations. Samples were subjected to light and electron microscopy following H & E staining, special ATPase, cytochrome oxidase/succinate dehydrogenase (COX/SDH) stains. RESULTS: Normal muscle architecture was seen following H & E, ATPase and COX/SDH staining and normal cell metabolism was observed in specimens of groups B and C. In group A, pathological changes were encountered in the gastrocnemius muscle including disseminated myofibril atrophy, cell denaturation and necrosis, inflammatory cell infiltration, proliferation and dilation of interfascicular veins. ATPase staining (pH 9.4) demonstrated grouping of atrophic fibres, especially type I myofibril grouping, accompanied by moderate to severe atrophy of type II muscle fibres. However, no patient had selective type I fibre atrophy. Enhanced enzymatic activity in single or multiple myofibrils was demonstrated by COX/SDH staining in approximately half of the specimens in group AII. In group AII, electron microscopy showed swelling, myelin figure denaturation of mitochondria, disruption of the myofibrils and increased lipid droplets in the gastrocnemius muscle. Increased concentration of LD was found in most specimens from group A patients. There were also reductions of SOD, NO, biochemical activity of Na+-K+-ATPase, Ca2+-ATPase with increasing concentration of LD in these patients, most prominently in group AII. We found correlation between AVP assessments and the biochemical measurements as well as morphological appearances of the gastrocnemius muscle. CONCLUSION: Venous hypertension results in pathophysiological changes in the gastrocnemius muscles of patients with DVI, associated with decreased calf pump function.

An animal model of venous hypertension: the role of inflammation in venous valve failure.

BACKGROUND: Clinical observation suggests that chronic venous insufficiency is related to failure of venous valves. Duplex ultrasound studies of lower extremity superficial veins regularly show valve failure and venous reflux. Gross morphologic observation of venous valves in surgical specimens shows tearing, splitting, scarring, and disappearance of valves. HYPOTHESIS: Venous valve damage is acquired, linked with venous hypertension, and affected by inflammation. OBJECTIVE: The objective of this study was to investigate the inflammatory process in valve remodeling associated with acute and chronic venous hypertension. METHODS: A femoral arteriovenous fistula was created in study animals (Wistar rats, n = 60), and animals without an arteriovenous fistula were studied as controls (n = 5). At 1, 7, 21, and 42 days animals with the femoral arteriovenous fistula were anesthetized, and systemic pressure, the pressure in the femoral vein distal to fistula, and the pressure of the femoral vein in the contralateral hind limb were measured. Timed collection of blood backflow after division of the femoral vein distal to the fistula and in the alive, anesthetized animal was collected, measured, and calculated per unit time to be used as an indicator of valve insufficiency. The femoral vein distal to the fistula was harvested; valvular structures were examined and measured. Specimens were processed, and longitudinal sections were made and challenged with immunostaining antibodies against matrix metalloprotease (MMP)-2 and MMP-9. Sections were examined, and expression of molecular markers was determined by light absorption measurements after image digitization. RESULTS: One week after the procedure, all animals exhibited some degree of hind limb edema ipsilateral to the arteriovenous fistula. Pressure in the femoral vein distal to the fistula was markedly increased on average to 96 +/- 9 mm Hg. Reflux was increased in a time-dependent manner, with the 21-day and 42-day groups showing the highest values. Valves just distal to the fistula showed an increased diameter of the valvular annulus and a shortening of the annular height. Venous wall findings included fibrosis and fusion of the media and adventitia and scarring and disappearance of valves principally in the 21- and 42-day specimens. Immunolabeling for MMP-2 showed an increased level in the 21- and 42-day groups. MMP-9 showed an increased level at 1 day, followed by a more marked level in the 21- and 42-day groups. CONCLUSIONS: In this animal model of venous hypertension the findings of limb edema, increasing valvular reflux, and morphologic changes of increased annulus diameter and valve height are seen. Histologic changes included massive fibrosis of media and fusion with adventitia. Inflammatory markers MMP-2 and MMP-9 are strongly represented, and valve disappearance occurs after these markers are present. The gross morphologic changes seen are quite similar to those observed in human surgical specimens removed in treatment of venous insufficiency. CLINICAL RELEVANCE: When observed angioscopically at the time of vein stripping, saphenous vein valves show severe deformities including shortening, scarring, and tearing. The current model of induced venous hypertension demonstrates early venous valve changes that replicate those observed in humans. This observation provides a link from venous hypertension to an induced inflammatory reaction that stimulates the valve damage. Thus the model could be useful for defining the fundamental mechanisms that cause venous valve failure and varicose veins and in pharmacologic testing to prevent or treat venous insufficiency.

Immunocytochemical characterisation of the inflammatory cell infiltrate of varicose veins.

OBJECTIVES: To characterise the inflammatory cell infiltrate in varicose vein wall, and its relationship to the valve complex. DESIGN: A comparative study of the distribution of inflammatory cells in normal and varicose vein. MATERIALS: Specimens of proximal human long saphenous vein were obtained from patients with duplex Doppler confirmed long saphenous vein reflux (n=14). Control vein was obtained from patients undergoing coronary artery bypass without clinical evidence of venous insufficiency (n=6). Longitudinal 7 microm frozen sections of vein, displaying valve, were prepared. METHODS: Using immunohistochemistry, T-lymphocytes (CD3), macrophage/monocytes (CD68), neutrophils (CD15s) and mast cells (anti-mast cell tryptase) were identified. The number of cells per unit length vein were counted using light microscopy. RESULTS: There were significantly more mast cells and macrophage/monocytes in varicose vein as compared to control. There was a non-significant trend towards more T-lymphocytes in varicose vein. Few neutrophils were present in varicose or normal vein. The distribution of inflammatory cells with respect to the valve was not found to be significant. CONCLUSIONS: Varicose veins display a greater inflammatory cell infiltrate than normal vein. The key role of macrophage/monocytes and mast cells in tissue damage and remodelling should stimulate further research into whether they play a significant role in the development of chronic venous insufficiency.

Venous hypertension, inflammation and valve remodeling.

OBJECTIVES: To identify possible mechanisms for destruction of valves in chronic venous hypertension and the results of treatment with an anti-inflammatory micronized purified flavonoid fraction. MATERIAL AND METHODS: The saphenous vein valves in a rat model of venous hypertension caused by a femoral arterial-venous fistula were studied. Studies included femoral venous pressure, valve morphology, femoral venous reflux and selected molecular inflammatory markers as examined by immunohistochemistry. The effects of treatment with the anti-inflammatory micronized purified flavonoid fraction (S 5628, Servier, 50 and 100 mg/kg/day) were investigated. RESULTS: The femoral venous pressure was elevated close to arterial values for a period of 3 weeks. We then examined the morphology of the veins and selected molecular inflammatory markers were assessed. The results show that in this model venous reflux develops in response to venous hypertension. This can be inhibited by the administration of the anti-inflammatory micronized purified flavonoid fraction (S 5628, Servier, 50 and 100 mg/kg/day). The valve becomes incompetent by a combination of venous dilation and shortening of the valve leaflets. This is not inhibited by treatment with S 5628. The valve leaflets are infiltrated with granulocytes, monocytes and T-lymphocytes, and the endothelial cells express enhanced levels of P-selectin and ICAM-1. Cells in the valves are subject to extensive apoptosis although no enhancement of MMP 2,9 expression could be detected at the three-week time point examined in this study. CONCLUSIONS: These results indicate that in this model chronic elevation of venous pressure is associated with an inflammatory reaction in venous valves, a process that may lead to their dysfunction, reflux, and upstream elevation of venous pressure. These effects are mitigated by the anti-inflammatory micronized purified flavonoid fraction in a dose dependent manner.