Decrease In Plasma Fibronectin Research Articles

Plasma Fibronectin as a Novel Predictor of Coronary Heart Disease: A Retrospective Study.

Although fibronectin has been associated with the pathogenesis of atherosclerosis, little is currently known about the relationship between plasma fibronectin and coronary heart disease (CHD). This retrospective study aimed to determine the predictive value of plasma fibronectin for CHD and its severity. A total of 1644 consecutive patients who underwent selective coronary angiography were recruited into the present study. The characteristics and results of the clinical examination of all patients were collected. Logistic regression analyses were performed to determine the predictive value of plasma fibronectin for the presence and severity of CHD. Compared with non-CHD patients, the CHD patients showed significantly higher plasma levels of troponin I and creatine kinase isoenzyme, along with lower plasma levels of fibronectin. However, no significant differences were detected in plasma fibronectin among patients with different grades of CHD. The logistic regression model showed that plasma fibronectin remained an independent predictor of CHD after adjustment with a 1.39-fold increased risk for every 1 SD decrease in plasma fibronectin. Nevertheless, plasma fibronectin could not predict the severity of CHD determined by the number of stenosed vessels and the modified Gensini score. This study demonstrated that lower plasma fibronectin might be an independent predictor of CHD, but it may be of no value in predicting the severity of CHD.

Decreased Plasma Fibronectin Leads to Delayed Thrombus Growth in Injured Arterioles

Plasma fibronectin (FN) is decreased in several clinical conditions. We were interested to study the thrombotic and hemostatic consequences of the decrease in plasma FN (pFN), the role of FN splice variants in thrombosis, and to examine whether pFN incorporates into thrombi in vivo. We compared the thrombotic response to a vessel injury in FN heterozygous (FN+/-) mice and corresponding FN+/+ mice. Although normal thrombosis in venules was observed, a decrease to half in the pFN concentration in FN+/- mice caused a delay in the appearance of thrombi in arterioles and consequently a delay in their occlusion. We were able to rescue the thrombotic defect in the FN+/- mice by infusion of rat pFN. Additionally, we could show intense incorporation of fluorescent pFN-coated microspheres into the developing thrombi. Moreover, we found that mice expressing FN without the EIIIA or EIIIB domains specific to cellular FN including platelet FN had no thrombotic defect. Mice heterozygous for FN have a striking defect in thrombus initiation and growth in arterioles attributable to the decrease of pFN. Our study is an example of haploid insufficiency for FN, and it emphasizes the fundamental role of this plasma protein in thrombosis in the arterial system.

FIBRONECTIN PREVENTS D-galactosamine/Lipopolysaccharide-induced lethal hepatic failure in mice

Plasma fibronectin (FN) has a broad range of biological functions involved in cellular adhesion, motility, differentiation, apoptosis, hemostasis, wound healing, reticuloendothelial system function, and ischemic injury. In this study, we examined the effects of FN on D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant liver failure in mice. Female Balb/c mice received intraperitoneal injection of 50 mug/kg of LPS and 400 mg/kg of GalN simultaneously. Thirty minutes before GalN/LPS administration, human plasma FN (FN group) or the same dose of human serum albumin (control group) was given intravenously. GalN/LPS induced a marked decrease in plasma FN, which was reversed by FN pretreatment. The survival rate of the FN group was markedly improved in a dose-dependent manner compared with that of the control group (survival rate 0%). FN prevented increases in the concentrations of serum enzymes and total bilirubin related to liver injury. FN pretreatment significantly suppressed tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-6 levels, and enhanced IL-10 levels in serum and liver tissue compared with the control group. Moreover, TUNEL staining, caspase 3 and 8 activities, and necrosis in the remnant liver were significantly decreased in the FN-treated rats compared with the controls. Furthermore, FN pretreatment inhibited the activation of nuclear factor (NF)-kappaB and increased the expression of Bcl-xL protein in liver tissue. These results suggest that FN protected against GalN/LPS-induced liver failure by a mechanism involving inhibition of NF-kappaB activation, which caused down-regulation of TNF-alpha and involved up-regulation of IL-10, and elevation of Bcl-xL induced a blockage of apoptotic signals, by which apoptosis of hepatocytes caused by GalN/LPS was suppressed.

Plasma fibronectin in asthmatic patients and its relation to asthma attack.

This study investigated the relation between asthma attacks and levels of plasma fibronectin (FN) and serum eosinophilic cationic protein (ECP) in patients with bronchial asthma in order to clarify the role of FN in the airway inflammation of bronchial asthma. Plasma levels of FN were significantly higher (P < 0.025) in patients with bronchial asthma than in healthy controls. They were also significantly higher (P < 0.05) in non-atopic asthmatics than in atopic asthmatics. Furthermore, plasma FN was lower during the attack than the non-attack stage (P < 0.025), and a significant increase of plasma FN was noted (P < 0.05) in asthmatics who had more severe and more frequent attacks. Serum levels of ECP were significantly higher during the attack than the non-attack stage (P < 0.005). An increase of plasma FN in the non-attack stage after attacks showed a significant correlation (P < 0.05) with a decrease of serum ECP. These observations clearly indicate that the decrease in plasma FN associated with attacks is closely related to aggravation of airway inflammation, and that the increase in plasma FN in the non-attack stage reflects chronic airway inflammation. These results suggest that the fluctuation in plasma levels of FN may be one of the factors affecting allergic inflammation and attacks in bronchial asthma.

Hemostatic changes after dietary coenzyme Q10 supplementation in swine.

Improved cardiovascular morbidity and mortality have been observed in several clinical studies of dietary supplementation with coenzyme Q10 (CoQ10). We elucidated the effect of CoQ10 on certain hemostatic parameters that may influence the progression of heart disease. Twelve Yorkshire swine were randomized to receive diet supplementation with either CoQ10 or placebo for 20 days. Blood samples were obtained at baseline and at the end of the feeding period. At the end of the protocol, there were no significant differences in hemostatic parameters in the placebo group. A significant increase in total serum CoQ10 level (from 0.39 +/- 0.06 to 0.96 +/- 0.04 microgram/ml, p < 0.001) was noted after the feeding period in the CoQ10-supplemented group. We observed significant inhibition of ADP-induced platelet aggregation (-9.9%) and a decrease in plasma fibronectin (-20.2%), thromboxane B2 (TXB2, -20.6%), prostacyclin (-23.2%), and endothelin-1 (ET-1, -17.9%) level. There were no changes in the plasma concentrations of the natural antithrombotics [antithrombin-III (AT-III), protein S, and protein C] after CoQ10 supplementation. CoQ10 supplementation in a dose of 200 mg daily is associated with mild antiaggregatory changes in the hemostatic profile. Clinical beneficial effects of CoQ10 may be related in part to a diminished incidence of thrombotic complications.

Effect of Fibronectin on C3b and Fc Receptor-mediated Phagocytosis by Peripheral Blood Monocytes in Uraemic Patients

The influence of human fibronectin was evaluated on the phagocytosis in vitro of C. albicans (C3b receptor-mediated) and IgG antibody-coated sheep erythrocytes (Fc receptor-mediated) by the peripheral blood monocytes of 40 uraemic patients undergoing periodic haemodialysis. Some nutritional parameters (albumin, transferrin, C4, C3, haematocrit, lymphocyte count, height and bodyweight) were also evaluated. Results showed significantly decreased plasma fibronectin (P less than 0.001) and reduced C3b receptor (R)- and FcR-mediated phagocytosis in uraemic patients (P less than 0.001). A strict correlation was found between fibronectin and C3bR-mediated phagocytosis (P less than 0.001) and between fibronectin and FcR-mediated phagocytosis (P less than 0.05). In 20 patients with decreased fibronectin concentrations and reduced phagocytic function, the in vitro incubation of peripheral blood monocytes with 50 micrograms/ml of purified fibronectin significantly enhanced C3bR-(P less than 0.001) but not FcR-mediated phagocytosis. Study of nutritional parameters in the uraemic patients revealed that values of fibronectin, C3, IgG and albumin were significantly reduced. Fibronectin correlated significantly (P less than 0.001) with C3. A good relationship (P less than 0.05) was also found between the plasma fibronectin and bodyweight loss. A greater incidence of infectious disease was observed in patients with decreased plasma fibronectin than in uraemic patients with normal values (P less than 0.05). The results suggest that a decrease in plasma fibronectin in uraemic patients could impair the peripheral blood monocyte phagocytic capacity and be potentially dangerous, predisposing the patient to infections. The determination of fibronectin concentration in these patients may, therefore, have a potential value as an indicator of peripheral blood monocyte phagocytic function.

Plasma fibronectin and fibronectin therapy in sepsis and critical illness.

Plasma fibronectin may be an important component of host defense in critically ill patients, particularly after trauma and during sepsis. This paper reviews recent studies that have sought to characterize the natural history of plasma fibronectin during sepsis, as well as those studies that tested the effect of therapy with concentrated fibronectin in sepsis. The decrease in plasma fibronectin that generally is seen in humans during sepsis probably is due to many factors, and it has been difficult to produce a similar pattern in animal models. Depletion of plasma fibronectin is not a sensitive or specific predictor of imminent sepsis, and once sepsis is established, the concentration of plasma fibronectin is no more sensitive a predictor of mortality than are many other clinical markers. Early, uncontrolled trials of therapy with a fibronectin concentrate in patients with sepsis appeared to indicate a propitious effect on organ function. However, more recent controlled trials have failed to show a significant effect of therapy with fibronectin concentrate on either organ function or patient survival.

Factor XIII as a modulator of plasma fibronectin alterations during experimental bacteremia.

Fibronectin is found in plasma as well as in association with connective tissue and cell surfaces. Depletion of plasma fibronectin is often observed in septic trauma and burned patients, while experimental rats often manifest hyperfibronectinemia with sepsis. Since Factor XIII may influence the rate of clearance and deposition of plasma fibronectin into tissues, we evaluated the temporal changes in plasma fibronectin and plasma Factor XIII following bacteremia and RE blockade in rats in an attempt to understand the mechanism leading to elevation of fibronectin levels in bacteremic rats, which is distinct from that observed with RE blockade. Clearance of exogenously administered fibronectin after bacteremia was also determined. Rats received either saline, Pseudomonas aeruginosa (1 X 10(9) organisms), gelatinized RE test lipid emulsion (50 mg/100 gm B.W.), or emulsion followed by Pseudomonas. Plasma fibronectin and Factor XIII were determined at 0, 2, 24, and 48 hours post-blockade or bacteremia. At 24 and 48 hr following bacteremia alone or bacteremia after RE blockade, there was a significant elevation (p less than 0.05) of plasma fibronectin and a concomitant decrease (p less than 0.05) of plasma factor XIII activity. Extractable tissue fibronectin from liver and spleen was also increased at 24 and 48 hours following R.E. blockade plus bacteremia. In addition, the plasma clearance of human fibronectin was significantly prolonged (p less than 0.05) following bacterial challenge. Infusion of activated Factor XIII (20 units/rat) during a period of hyperfibronectinemia (908.0 +/- 55.1 micrograms/ml) resulted in a significant (p less than 0.05) decrease in plasma fibronectin (548.5 +/- 49.9 micrograms/ml) within 30 min. Thus Factor XIII deficiency in rats with bacteremia may contribute to the elevation in plasma fibronectin by altering kinetics associated with the clearance of fibronectin from the blood.

Plasma fibronectin depletion after cardiac surgery in children with or without cardiopulmonary bypass.

Plasma fibronectin depletion decreases resistance to sepsis. After cardiac surgery, septic complications occur more frequently when the surgical procedure is managed with a cardio-pulmonary bypass than when it is not. To determine whether cardio-pulmonary bypass produces a greater decrease in plasma fibronectin than surgery without cardio-pulmonary bypass, we studied plasma fibronectin concentrations in two groups of children operated for congenital heart diseases. Group I: 10 children undergoing surgery with cardio-pulmonary bypass. Group II: 11 children undergoing surgery without cardio-pulmonary bypass. Plasma fibronectin was monitored pre-operatively (t 1) and post-operatively at the 6th hour (t 2), 1st (t 3) and 7th (t 4) days. In both groups, plasma fibronectin concentration dropped at (t 2) and (t 3) and rose again at (t 4). There was no significant difference in plasma fibronectin levels between the two groups at any time. We conclude that the plasma fibronectin decline alone cannot explain why septic complications after surgery are more frequent with cardio-pulmonary bypass than without.

Changes in plasma fibronectin during donor apheresis and therapeutic plasma exchange.

Changes in plasma levels of the opsonic glycoprotein fibronectin were studied during machine apheresis in 32 healthy plasma donors and 18 patients undergoing a total of 86 therapeutic plasma exchanges. Donation of 500 ml of plasma at 3-monthly intervals produced a 10% immediate decrease in plasma fibronectin with no evidence of a long-term affect on levels of this protein. One plasma volume exchange with fibronectin-poor plasma protein fraction produced subnormal plasma fibronectin levels in 98% of post-exchange samples. Efficiency of exchange was significantly lower in patients with paraproteinaemia, probably reflecting increased plasma volume in such patients. Daily plasma exchange produced progressive depletion of plasma fibronectin (index of recovery 0.68) whereas levels were maintained close to the initial value with longer exchange intervals, except in the more severely ill patients. Reduction of plasma fibronectin by plasma exchange may increase susceptibility to infection and reduce the efficacy of this procedure when the object of exchange is to reverse reticuloendothelial blockade.

Circulating fibronectin depletion in burned patients: relationship to development of infection and prognostic value.

The time course of the level of plasma fibronectin (PFN) and its relationship to severity of injury, infection, and prognosis were studied in 27 burn patients with body surface area (BSA) burn greater than 20%. PFN was measured daily or every two days using a laser nephelometer. During the first four postburn days, a decrease in PFN was observed that was significant on days 2 and 3. On postburn day 2, a positive correlation was found between PFN decrease and extent of injury. The decrease was of high prognostic value. Between postburn days 4 and 16, PFN levels of infected patients were significantly lower than those of noninfected ones, but the onset of infection was not preceded by any significant decrease in PFN levels. This study offers arguments in favor of a close relationship between PFN deficiency and sepsis in burn patients, but it is impossible to assert that this deficiency plays a major role in the occurrence of infection.

Lung vascular injury with protease infusion. Relationship to plasma fibronectin.

Fibronectin exists in a soluble form in plasma and in an insoluble form in tissues. Plasma fibronectin can modulate phagocytic function as well as incorporate into the tissue matrix where it is believed to influence microvascular integrity and tissue repair. The temporal alterations in plasma and lung lymph fibronectin were studied in relation to increased pulmonary vascular permeability induced by protease infusion. The acute sheep lung lymph fistula model was used. A 39% decrease in plasma fibronectin (control = 421 +/- 67 micrograms/ml) was observed 2.5 hours (255 +/- 43 micrograms/ml) after protease infusion. There was an elevation of lymph fibronectin early after protease infusion, followed by a progressive decline. Concomitant with the decrease in plasma fibronectin, an increase in lymph flow (QL) of greater than 200% (from a control of 6.7 +/- 1.0 ml/hr to 13.9 +/- 1.4 ml/hr) was observed within 2.5 hours. Also, there was a sustained elevation in the total protein lymph/plasma concentration (L/P) ratio, which was maximal at 2.5 hours. The transvascular protein clearance (TVPC = QL X L/P) was 4.5 +/- 0.7 ml/hr at the control period and 13.1 +/- 2.0 ml/hr by 2.5 hours. This was indicative of increased flux of protein-rich fluid across the pulmonary endothelial barrier. Lung vascular permeability stabilized after 2.5 hours as manifested by a slowly declining L/P ratio. Thus, plasma fibronectin deficiency may contribute to the etiology of increased lung vascular permeability with protease infusion. Since the progressive decline in plasma fibronectin was not reflected in a proportional increase in lymph fibronectin, plasma fibronectin may have sequestered in tissues such as the lung, or perhaps in reticuloendothelial cells during the injury phase. Whether the progressive decrease in plasma fibronectin reflects its incorporation into the endothelial barrier matrix where it may mediate stabilization of the pulmonary microvascular barrier remains to be determined.

Plasma fibronectin is initially decreased during septicemia.

Plasma fibronectin (PFN) levels were measured by radioimmunoassay in 24 normals and serially in 24 septic patients without underlying major trauma. All patients responded promptly to antibiotic therapy and none developed signs of shock or disseminated intravascular coagulation (DIC). After an initial decrease in PFN registered in most of the septic patients, the levels were normalized within 2 weeks of antibiotic treatment. The mean nadir levels of PFN were decreased (p less than 0.001) both in patients with gram-negative and gram-positive etiologies compared to the control group. Furthermore, the mean PFN value of the gram-positive group was lower (p less than 0.05) than that of the gram-negative group. It is concluded that a transient depletion of PFN is a constant finding in septic patients with a favourable outcome and that a single low PFN level alone does not justify fibronectin replacement therapy nor does it indicate a poor prognosis.