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PubMed1991

Altered renal fibronectin excretion in early adriamycin nephrosis of rats.

The anticancer drug adriamycin (ADR) induces severe nonselective glomerular proteinuria in rats. The proliferation of the glomerular mesangium in chronic ADR nephrosis suggests a disturbed metabolism of extracellular matrix proteins. In the present study the structural protein fibronectin was analyzed by immunological methods in urine and plasma in two rat strains after a single injection of 5 mg of ADR/kg b.wt. After ADR administration the excretion of 220 kd-plasma fibronectin, identified by its electrophoretic mobility and Western blotting, increased. This was confirmed by quantitative measurement (ELISA) of total urinary fibronectin (ADR-treated Munich Wistar Frömter rats: 85.4 +/- 49.5 ng/hr, N = 31; controls: 1.7 +/- 0.7 ng/hr, N = 26; day 7 after ADR injection). Control urines contained distinct fragments of fibronectin with a molecular weight range of 40 to 60 kd. It is suggested that these fragments did not originate from plasma inasmuch as only little correspondence between the fibronectin patterns of urine and plasma was found, and also because in ADR-treated rats the excretion of the fibronectin fragments decreased from day 4 of ADR administration. The data suggest that the urinary fibronectin fragments are released from cellular fibronectin during the normal catabolism of the glomerular extracellular matrices, and that ADR interferes in the metabolism of matrix components. Only as a consequence of an enhanced glomerular permeability is plasma fibronectin excreted in ADR-treated rats.

Animals↗
PubMed1990

[Fibronectin binding to Staphylococcus aureus in experimental staphylococcal skin infection in mice].

Staphylococcus aureus infection of skin was produced in cyclophosphamide-treated mice by intracutaneous inoculation of a strain in this organism clinically isolated from a carbuncle. Deposition and binding of fibronectin in initial stage of the infection were followed by immunohistochemistry and immunoelectron microscopy. Fibronectin began to deposit in a fine granular pattern in the dermis and musculocutaneous layer at 2 minutes after the inoculation and gradually increased with time. Fibronectin binding on the surface of staphylococcal cells was seen after 12 hours of inoculation. At 24 hours two patterns of binding were seen. In one pattern, fibronectin was bound to a part of the cell surface of the microorganisms. The fibronectin binding parts were seen very close or attached to the fibrin-like-structure and dermal connective tissues. This suggests that fibronectin helped staphylococcus cells to attach to fibrin or connective tissues. The other pattern of fibronectin binding was the binding of fibronectin all around the cells. This pattern could be interpreted as inhibition by fibronectin of staphylococcus attachment to the fibrins and the tissues.

Animals↗
PubMed1990

Effect of hypertension on fibronectin expression in the rat aorta.

Interactions between extracellular fibronectin and vascular cells are thought to influence the phenotype of those cells. To determine if changes in fibronectin expression accompany the phenotypic changes of vascular tissue characteristic of experimental hypertension, steady state mRNA levels for fibronectin were determined in aortae of normotensive and hypertensive rats. A 3-6-fold increase in fibronectin mRNA was observed in aortic tissue of hypertensive rats following 3 weeks of treatment with deoxycorticosterone and salt, whereas if rats were treated only with deoxycorticosterone or salt alone, no changes occurred. The changes were reversed by normalization of blood pressure. The increases observed were localized to aorta and not to the periaortic tissue. Angiotensin II infusion using osmotic minipumps also caused an increase in fibronectin expression. Age-dependent increases in aortic fibronectin mRNA occurred in several rat strains, and the combined effects of hypertension and aging were greater than either variable alone. A clear distinction between the expression of fibronectin mRNA and that for collagen or tropoelastin were found in hypertensive and aging models. Aortic fibronectin was also increased in the hypertensive rats as determined by Western blot analysis. The findings indicate that elevation in blood pressure increases fibronectin expression in rat aorta and suggest that such changes may influence the aortic cellular responses to hypertension.

Adipose Tissue, Brown↗
PubMed1989

Variation of plasma fibronectin levels in leukemia patients.

In the present study plasma fibronectin levels were determined in patients with hematopoietic malignancy, particularly leukemias, in an effort to clarify their clinical implications. Among leukemia patients, those with AML, ALL, ATL or CLL had various plasma fibronectin levels that were higher in some cases, while lower in others, as compared to normal control values. An elevation of the fibronectin level was noted often in APL, while lower fibronectin values were observed in many instances of CML. In these types of leukemia, acute exacerbation as well as supervention of infection tended to be associated with lower than normal levels of fibronectin. An especially marked depression of fibronectin occurred, when leukemia was complicated by sepsis or DIC, in which a good parallel was noted between the progress of disease and the fibronectin level. In lymphoproliferative diseases, the fibronectin value varied widely, but low fibronectin levels were frequently associated with intercurrent infection or an extreme deterioration of the general physical conditions.

Fibronectins↗
PubMed1989

[The regulation of DNA synthesis by fibronectin and its proteolytic products in the skin fibroblasts of healthy donors and patients with systemic scleroderma and rheumatoid arthritis].

To study the effect of fibronectin isolated from plasma and culture media and the effect of its tryptic hydrolyzates on DNA synthesis, cultured skin fibroblasts of healthy donors and these of patients with systemic scleroderma (SSD) and rheumatoid arthritis (RA) were employed. It was shown that both fibronectin and total products of its proteolysis markedly stimulated DNA synthesis only in skin fibroblasts of patients with SSD. Fibronectin fragments inhibited DNA synthesis in all fibroblast strains studied. The effect of fibronectin and all its Gel fragments on the DNA synthesis in skin fibroblasts of patients with SSD was dose-dependent. The activity of total fibronectin tryptate, Gel-fragment-free tryptate, and Gel fragments themselves depended on the duration of fibronectin proteolysis, i. e. on the size of the fragments obtained. Culture media collected after treatment of fibroblast monolayer with trypsin and subsequent removal of fibronectin Gel fragments had mitogenic effect on skin fibroblasts, especially on those of patients with SSD and RA. It is supposed that fibronectin Gel fragments are inhibitors of growth factors produced by fibroblasts. The results suggest that fibronectin and its fragments have an important regulatory role in fibroblast proliferation.

Arthritis, Rheumatoid↗
PubMed1989

Elevated plasma levels of ED1+ ("cellular") fibronectin in patients with vascular injury.

Using an enzyme-linked immunosorbent assay, we measured the concentration of fibronectin containing an extra type III domain (ED1) in the circulation of humans. Plasma levels of ED1 + fibronectin averaged 2.8 +/- 1.0 micrograms/ml in healthy individuals and did not differ substantially according to age or sex. In comparison with those from normal subjects, plasma samples obtained from patients with collagen vascular disorders contained increased average levels of ED1 + fibronectin. Among this group, levels of ED1 + fibronectin were significantly greater in samples taken from individuals with clinical evidence of vasculitis. Although levels of total (ED1 + plus ED1 -) fibronectin were also elevated in plasma samples from patients with vasculitis, only the concentration of the ED1 + variant correlated with severity of disease in two patients examined serially. Elevations in plasma content of ED1 + fibronectin, but not total fibronectin, were also noted in patients with acute vascular tissue injury associated with major trauma or sepsis syndrome. Western blot examination revealed the presence of intact dimeric ED1 + fibronectin in the circulation of all patients studied, although fragments bearing the ED1 were also detected. Human plasma normally contains small quantities of soluble ED1 + ("cellular") fibronectin, and these levels are increased in disorders involving vascular injury.

Adolescent↗
PubMed1987

Influence of factor XIII and fibronectin on fiber size and density in thrombin-induced fibrin gels.

The possible role of fibronectin as a molecular anchor for fibrin to ground substance, the ability of factor XIII to cross-link fibronectin to fibrin, and the demonstrated differences between purified fibrin and fibrin formed in plasma prompted this study of the effect of both proteins on fibrin assembly and structure. The influences of activated factor XIII (FXIIIa) and fibronectin were studied by use of turbidity techniques. Fibronectin over a concentration range of 0 to 800 micrograms/ml produced no change in either the mass-length ratio or density of fibrin fibers in 1 mg/ml fibrin gels. FXIIIa at concentrations as high as 6.5 mumol/L, although not altering fiber mass-length ratio, caused a 30% increase in fiber density. Gels formed in the presence of fibronectin plus FXIIIa demonstrated increasing fiber mass-length ratios and increasing fiber density with increasing fibronectin concentration. Mass-length ratios for gels formed in the presence of 3.24 mumol/L FXIIIa increased from 3.25 to 5.20 x 10(13) daltons/cm as the fibronectin concentration increased from 0 to 800 micrograms/ml. Fiber density increased from 13.6 to 19.1 x 10(22) daltons/cm3 over the same fibronectin range. These results imply that FXIIIa-induced structural changes such as increased elastic modulus may be mediated in part by increased fiber density. Fibronectin alone has virtually no impact on fibrin assembly, but in the presence of FXIIIa becomes incorporated into fibrin and results in increased fiber size and density.

Chemical Phenomena↗
PubMed1988

A peptide from fibronectin cell-binding domain inhibits attachment of epithelial cells.

Fibronectin is thought to contribute to the adhesion of corneal epithelium during epithelial repair, presumably by mediating epithelial attachment to stroma during epithelial migration. To understand the mechanism of the interaction of fibronectin with corneal epithelial cells, the effects of intact plasma fibronectin and of the synthetic peptide GRGDS from the cell binding domain of fibronectin on the attachment of rabbit corneal epithelial cells have been examined. When dissociated epithelial cells were plated on fibronectin-coated culture dishes, the number of cells that attached increased in proportion to the concentration of fibronectin used for coating. Attachment of the cells was inhibited in a dose-dependent manner by the addition of GRGDS to the medium. When the structurally similar control peptide GRGES was added to the medium, no inhibition of epithelial attachment was observed. Our results demonstrate that corneal epithelial cells use an adhesive recognition system for fibronectin related to that characterized in fibroblastic cells. GRGDS thus presumably competes for receptors for fibronectin on epithelial cells of the cornea, resulting in the observed inhibition of attachment. These results identify a mechanism for corneal epithelial cell adhesion, compatible with that identified in other fibronectin-dependent systems.

Amino Acid Sequence↗
PubMed1988

Human hepatocytes in culture synthesize and secrete fibronectin.

Hepatocytes were isolated by application of the two-step collagenase perfusion technique to pieces of human liver. Hepatocytes were cultivated in serum-free medium or 10% fetal calf serum medium supplemented with insulin, glucagon and dexamethasone. The cells were kept in culture for up to 16 days and 75% of the medium was regularly changed. Fibronectin in culture medium was detected by means of an ELISA with an assay range of 2.2-560 micrograms/l. The interassay imprecision was 6.3% at 500 micrograms/l and 14.3% at 10 micrograms/l. Significant amounts of fibronectin were detected in all cultures. During culture, fibronectin accumulated in the medium and the quantity secreted by hepatocytes by far exceeded the amounts of fibronectin associated with hepatocytes prior to cultivation. Maximum secretion rate by 10(6) hepatocytes was 167.5 +/- 73.3 ng fibronectin (mean +/- SEM, n = 3) in 24 h. When analysed by means of SDS-PAGE and immunoblotting the fibronectin isolated from hepatocyte culture medium and cell lysate co-migrated with fibronectin obtained from plasma. Our data show, for the first time, that human hepatocytes synthesize and secrete fibronectin, and it is suggested that the human liver is an important source of plasma fibronectin.

Cells, Cultured↗
PubMed1987

Vitamin A deficiency alters genomic expression for fibronectin in liver and hepatocytes.

Earlier work from our laboratory had shown that vitamin A-deficient rats had increased levels of fibronectin in their serum. To explain this result, we investigated the mechanism whereby vitamin A deficiency affects the production of fibronectin by liver and hepatocytes, since liver is the known source of plasma fibronectin. By use of cDNA specific for rat liver fibronectin, we showed that livers of vitamin A-deficient rats had a 2-4-fold increase in the level of fibronectin mRNA and also a higher transcription rate. Rate of synthesis and secretion of fibronectin was found to be increased 2-fold in primary cultures of hepatocytes of deficient animals. Exogenous addition of retinyl acetate or retinoic acid to the media reversed this increase to control levels. The increase was paralleled by an increase in fibronectin mRNA, also reversed by exogenous retinoic acid. At least 12 h were needed for this reversal to take place. Thus, vitamin A appears to regulate the synthesis of fibronectin through its action on fibronectin mRNA transcription. This represents the first reported observation of an action of vitamin A at the genomic level on the synthesis of a specific protein in liver.

Animals↗
PubMed1985

Fibronectin in artery subendothelium is important for platelet adhesion.

The role of subendothelial fibronectin in platelet interaction with subendothelium was studied. Human umbilical artery subendothelium was exposed to flowing blood containing 111In-labeled platelets in an annular perfusion chamber. Platelet adhesion was determined from the 111In radioactivity on the vessel wall. When perfusions were performed for five minutes at a wall shear rate of 1,800 s-1, platelet adhesion was the same whether normal plasma or fibronectin-free plasma was used. Preincubation of subendothelium with rabbit anti-human fibronectin serum, however, resulted in a marked inhibition of platelet adhesion. Preincubation with normal rabbit serum had no effect. Platelet adhesion was also diminished when the vessel wall was preincubated with anti-fibronectin IgG fraction or F(ab')2 fragment. After the latter preincubations, frozen sections of 4 micron were incubated with fluorescein isothiocyanate-conjugated goat anti-rabbit IgG, F(ab')2 fragment specific. Fluorescence was seen throughout the subendothelium both before and after perfusion. No fluorescence was seen when subendothelium was preincubated with normal rabbit IgG or F(ab')2 or with anti-fibronectin IgG that had been absorbed with purified fibronectin. After absorption of anti-fibronectin IgG with purified fibronectin, the inhibiting effect on platelet adhesion was also no longer present. Preincubation of the vessel wall with anti-fibronectin IgG reduced platelet adhesion significantly at a wall shear rate of 800 s-1. This effect was even greater at 1,800 s-1. At low shear rate (400 s-1), there was no inhibition.

Animals↗
PubMedDate not supplied

Cell surface fibronectin on peripheral blood lymphocytes in normal individuals and in patients with acute and chronic lymphocytic leukemia and non Hodgkin's lymphoma.

Fibronectin was detected by immunofluorescence on the surface of one fraction of separated normal peripheral blood lymphocytes using FITC-conjugated anti-human fibronectin antibodies. Approximately one fifth of isolated B cells and 7% of O cells contained surface bound fibronectin but T cells failed to stain. There were no detectable free receptors for fibronectin on the surfaces of the lymphocytes in the different subsets isolated from healthy controls as studied using FITC-labelled purified fibronectin. The per cent of B and O cells bearing surface bound fibronectin was markedly decreased in patients with acute and chronic lymphocytic leukemias and non Hodgkin's lymphoma, only 1-4% of B and 1-2% of O cells stained with FITC-labelled antifibronectin immunoglobulins. FITC-conjugated fibronectin was not bound to the different lymphoblasts isolated from patients with leukemia and lymphoma. Treatment of cells with trypsin and EDTA removed fibronectin bound to the cell surfaces. Fibronectin attached to the surfaces of lymphocytes may have an immunoregulatory function.

Adolescent↗
PubMed1985

Astrocytes in culture synthesize and secrete a variant form of fibronectin.

Astrocytes in culture have very little cell surface fibronectin as detected by iodination or immunocytochemistry. Nonetheless, they synthesize and secrete this glycoprotein in amounts comparable with the production by fibroblasts. Astrocyte fibronectin has properties in common with other forms of the protein. It binds to gelatin- and heparin-coupled Sepharose and it is recognized by specific anti-fibronectin sera. It also exists as a dimer under non-reducing conditions. However, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), astrocyte fibronectin appears larger, under both reduced and non-reduced conditions, than other cellular fibronectins. This apparent size difference is not the result of post-translational modifications. If the cultures are treated with tunicamycin, the astrocytes produce fibronectin that is unglycosylated, as shown by [3H]glucosamine labeling, and is neither sulfated nor phosphorylated as indicated by [35S]O4 and [32P]O4 labeling studies. This astrocyte-derived, carbohydrate-free fibronectin resolves on SDS-PAGE as four bands, of which the heavier ones predominate. Fibroblasts produce a similar set of four bands, but in this form of fibronectin the less heavy bands predominate. Thus, we conclude that fibronectin is a major secreted protein of astrocytes in vitro and that these cells produce a variant form of the protein which is enriched in the higher molecular weight subunits.

Animals↗
PubMed1985

Intraglomerular distribution of fibronectin in primary glomerular diseases.

The intraglomerular distribution of fibronectin was examined in 152 renal biopsy specimens with the direct immunofluorescence technique. Fibronectin was detected only in the mesangial area in normal glomeruli, while in proliferative glomerulonephritis, it extended from the mesangium to the pericapillary regions proportionately with the proliferative changes. In membranoproliferative glomerulonephritis, fibronectin globally extended in the glomeruli. Also in membranous nephropathy, fibronectin was observed in the capillary walls despite an absence of proliferation. Electron microscopic examinations revealed that the glomeruli with the pericapillary distribution of fibronectin were mostly found in stage II or III, as determined by WHO criteria. The double immunofluorescence technique demonstrated that in membranous nephropathy fibronectin was on the inner side of the glomerular basement membrane, and that in membranoproliferative glomerulonephritis fibronectin extended concomitantly with the expansion of mesangial matrix. These findings suggest that intraglomerular fibronectin is localized only in the mesangial area in normal glomeruli, and that the pericapillary distribution of fibronectin occurs not only by mesangial proliferation but also by additional unknown mechanisms.

Animals↗
PubMed1985

Fibronectin. A new nutritional parameter.

Acute and chronic malnutrition is associated with increased morbidity and mortality in surgical patients. Plasma fibronectin levels have been shown to correlate with reticuloendothelial function and are reduced in burns, shock, trauma, and sepsis. Patients failing to show an increase in fibronectin levels after stress have been shown to do poorly. Starvation studies in human volunteers have demonstrated decreasing plasma fibronectin levels until feeding was resumed. The purpose of this study is to examine the usefulness of fibronectin as an assessment parameter in nutritionally depleted hospitalized patients. Eight patients initiated on parenteral nutrition were studied. Plasma fibronectin, albumin, and transferrin levels were drawn before TPN and repeated at various intervals after total parenteral nutrition (TPN) was begun. Mean pre-TPN transferrin was 198.1 +/- 16.1 gm/dl (nl 220-400). Transferrin levels remained statistically unchanged after 8 to 11 days of TPN. Mean pre-TPN albumin was 3.0 +/- 0.2 gm/dl (nl 3.6-4.8) and also remained statistically unchanged after 8 to 11 days of TPN. The mean fibronectin level pre-TPN was 236.4 +/- 24.4 microgram/ml (nl 370-410). Fibronectin rose statistically (P less than 0.005) after 1 to 4 days of TPN to a mean of 341.9 +/- 30.1 microgram/ml and remained elevated and statistically unchanged after 8 to 11 days of TPN. Six of the eight patients studied survived and had demonstrated at least a 30 per cent increase in fibronectin after 1 to 4 days of TPN. Both patients who died demonstrated minimal increase in fibronectin levels after 1 to 4 days of TPN.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Changes in lung tissue and lavage fibronectin after paraquat injury in rats.

Lung lavage fibronectin is known to be elevated after experimental lung injury; however, changes in lung tissue fibronectin content probably more directly reflect tissue injury and repair. We injured rat lungs with a single injection of paraquat and serially measured the fibronectin content of both lung lavage fluid and lung tissue. Changes in lung ultrastructural morphology and collagen content were also assessed. Although both lavage and tissue content of fibronectin increased, the temporal patterns of increase were very different. Lavage fibronectin peaked at 1 day post-injury, was normal by 7 days, and paralleled changes in lavage albumin. Tissue fibronectin was normal at 1 day post-injury, peaked at 4 days and was still high at 7 and 14 days. The period of increased tissue fibronectin coincided with electron microscopic evidence of cell injury and repair at 7 days. By 14 days post-injury the lungs appeared virtually normal. Lung collagen content remained normal throughout the period of injury and repair. We conclude that increases in lung lavage fibronectin do not necessarily correlate with changes in lung tissue fibronectin and that the latter may more accurately reflect lung tissue repair. In addition, even large increases in both measurements do not necessarily predict the development of post-injury fibrosis.

Albumins↗
PubMed1985

Fibronectin in chronic inflammation: studies using the rat air pouch model of chronic allergic inflammation.

Fibronectin is a large glycoprotein of plasma, tissue fluids and tissues. The rat air pouch model of mesenchymal inflammation was used to examine changes in fibronectin levels during inflammation within a mesenchymal cavity. Rat plasma fibronectin levels showed a rapid and significant rise in relation to the induction of an air pouch. In contrast pouch fluid fibronectin levels were initially low and gradually increased with chronicity. They were unrelated to plasma levels. Pouch fluid fibronectin showed no relationship to cell content of the fluid, its volume, nor the weight of granulation tissue. Two-dimensional immuno-electrophoresis showed pouch fluid fibronectin was partially complexed but plasma fibronectin was not. These results show plasma and tissue fluid fibronectin have different patterns of response to inflammation. In rats plasma fibronectin is an acute-phase reactant, although this is not the case in humans.

Air↗
PubMed1985

Fibronectin and F-actin redistribution in cultured endothelial cells exposed to shear stress.

Cultured endothelial cells exposed to shear stresses in vitro undergo a reorganization of their F-actin-containing cytoskeletons which culminates in realignment with flow direction. Since a close transmembrane association exists between actin microfilaments and extracellular fibronectin, this study was undertaken to examine whether the actin reorganization induced by shear stress is accompanied by perturbations in the underlying fibronectin matrix. In a closed circulatory loop, bovine endothelial monolayers were exposed to steady, laminar flows corresponding to shear stress levels of 6 and 26 dynes/cm2 for 2, 6, 12, and 24 hours. The co-distribution of fibronectin and F-actin was determined in specimens which were double-labeled with antiserum to fibronectin and rhodamine phalloidin, respectively. Under the influence of shear stress, cells underwent coordinate shape changes resulting in varying degrees of alignment with flow direction. Reorientation at these shear stress levels was dependent on both the time of exposure and the magnitude of shear stress and was accompanied by a reorganization in cellular fibronectin and F-actin. In controls (no flow) correspondence between the two proteins was limited to similarly arranged, radial foci of fibronectin and F-actin filaments at the basal cell surfaces. In flow specimens, coincidence was detected only between occasional fibronectin fibrils and F-actin stress fibers. As a consequence of shear stress, fibronectin became more uniformly distributed beneath monolayers and frequently was organized into bands of densely packed fibrils. Despite this extensive reorganization, rearrangement of fibronectin did not result in the formation of identical, linear structures with F-.

Actins↗