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PubMed1992

Localization of two binding domains for thrombospondin within fibronectin.

Thrombospondin is a major glycoprotein of the platelet alpha-granule and is secreted during platelet activation. Several protease-resistant domains of thrombospondin mediate its interactions with components of the extracellular matrix including fibronectin, collagen, heparin, laminin, and fibrinogen. Thrombospondin, as well as fibronectin, is composed of several discretely located biologically active domains. We have characterized the thrombospondin binding domains of plasma fibronectin and determined the binding affinities of the purified domains; fibronectin has at least two binding sites for thrombospondin. Thrombospondin bound specifically to the 29-kDa amino-terminal heparin binding domain of fibronectin as well as to the 31-kDa non-heparin binding domain located within the larger 40-kDa carboxy-terminal fibronectin domain generated by chymotrypsin proteolysis. Platelet thrombospondin interacted with plasma fibronectin in a specific and saturable manner in blot binding as well as solid-phase binding assays. These interactions were independent of divalent cations. Thrombospondin bound to the 29-kDa fibronectin heparin binding domain with a Kd of 1.35 x 10(-9) M. The Kd for the 31-kDa domain of fibronectin was 2.28 x 10(-8) M. The 40-kDa carboxy-terminal fragment bound with a Kd of 1.65 x 10(-8) M. Heparin, which binds to both proteins, inhibited thrombospondin binding to the amino-terminal domain of fibronectin by more than 70%. The heparin effect was less pronounced with the non-heparin binding carboxy-terminal domain of fibronectin. By contrast, the binding affinity of the thrombospondin 150-kDa domain, which itself lacked heparin binding, was not affected by the presence of heparin. Based on these data, we conclude that thrombospondin binds with different affinities to two distinct domains in the fibronectin molecule.

Animals↗
PubMed1985

Effects of different fragments of the fibronectin molecule on latex bead translocation along neural crest migratory pathways.

Previous studies from this laboratory have utilized latex beads as probes of embryonic migratory pathways. After microinjection into embryos at the time of neural crest migration, uncoated latex polystyrene beads were found to translocate to ventral sites and to settle in the vicinity of endogenous neural crest derivatives. However, latex beads coated with fibronectin did not translocate ventrally, but remained associated with cells surrounding the implantation site. Fibronectin is a large glycoprotein with a variety of biological activities and multiple binding domains. Here, the binding activities which might be responsible for immobilization of the fibronectin-coated beads are examined. Latex beads were coated with three types of fragments of the fibronectin molecule representing different functional domains: (i) a 66-kDa fragment containing collagen-binding activity; (ii) a mixture of 45- and 32-kDa fragments containing heparin-binding activity; and (iii) a 120-kDa fragment containing cell-binding activity. The beads coated with fibronectin fragments were injected into the newly formed trunk somites of avian embryos. After injection, beads coated with either the heparin- or the collagen-binding domain translocated ventrally and distributed analogously to uncoated latex beads. In contrast, the majority of beads coated with the fibronectin cell-binding domain did not translocate but remained associated with dermamyotomal cells surrounding the injection site. The cell-binding fragment, however, was not as effective as the intact fibronectin molecule in preventing translocation of the beads. The results suggest that the cell-binding domain is primarily responsible for restriction of fibronectin beads from the ventral neural crest pathway. Because intact fibronectin is more effective at immobilizing beads than is the cell-binding fragment, other binding domains of fibronectin, more efficient coating with intact fibronectin, or crosslinking of intact fibronectin molecules may also play some role in immobilization of the beads at the implantation site.

Animals↗
PubMed1995

Immunochemical analyses of human plasma fibronectin-cytosolic transglutaminase interactions.

Fibronectin is a glycoprotein involved in cell adhesion, tissue organization and wound healing. Transglutaminase binding and covalent cross-linking of fibronectin are physiologically important reactions. We describe microtiter plate-based immunochemical methods to analyze cytosolic transglutaminase-human plasma fibronectin interactions. The method was sensitive, specific, species-independent and capable of simultaneously analyzing 96 samples for binding. Binding was time-, temperature- and concentration-dependent and demonstrable with either protein immobilized to the plastic. The assay detected 1-5 ng transglutaminase or 50 pg fibronectin and was comparable in sensitivity to enzyme-linked immunosorbent assays. CaCl2 (8 mM) enhanced transglutaminase binding by two-fold. Molar concentrations of NaCl or millimolar concentrations of chloride salts of barium, copper or zinc inhibited binding by 50-60%. The binding was also competitively blocked by soluble fibronectin (IC50 = 2.3 nM) or by anti-fibronectin IgG (IC50 = 0.5 microM). Inclusion of dithiothreitol or 2-mercaptoethanol during binding resulted in a concentration-dependent inhibition of transglutaminase-fibronectin interactions (IC50 = 1.5 mM and 20 mM, respectively). A complex of [anti-transglutaminase IgG-transglutaminase-fibronectin-anti- fibronectin IgG] suggested that the binding sites and antibody epitopes could overlap, but are distinct and surface-exposed in the two proteins. Liver transglutaminase bound fibronectin 30-50% less compared to erythrocyte transglutaminase. Fibronectin-transglutaminase affinity was adequate for quantitating either antigen in lysates of lung fibroblasts, breast carcinomas or Escherichia coli. These immunochemical analyses will be useful for determining the affinity and mapping the domains involved in antibody recognition or protein-protein interactions using recombinant molecules of transglutaminase and fibronectin.

Animals↗
PubMed1985

Plasma fibronectin metabolism during hemorrhagic shock and starvation.

In this report we characterize the response of the plasma protein fibronectin to hemorrhagic shock and starvation, conditions associated with decreased function of mononuclear phagocyte system (MPS). Rats were starved for 3 days, then half of the animals were subjected to fixed-volume hemorrhagic shock by removing an estimated 35% of their blood volumes for 20 min. After volume replacement, animals were injected iv with [14C]valine. At time points up to 10 hr after hemorrhage, plasma fibronectin concentrations and fibronectin synthesis were quantitated. In additional rats treated identically, fibronectin clearance was assessed by measuring the disappearance of 125I-fibronectin from the plasma. When compared to control animals, either starvation or hemorrhagic shock produced similar perturbations in plasma fibronectin metabolism; fibronectin concentrations were reduced from 241.3 +/- 34.6 micrograms/ml (mean +/- SEM) (controls) to 123 +/- 32.6 micrograms/ml (starvation) or 150.0 +/- 13.0 micrograms/ml (hemorrhage). Plasma [14C]fibronectin specific radioactivities, indicative of fibronectin synthesis, were also significantly reduced. Hemorrhagic shock in rats that previously had been starved did not depress fibronectin concentrations or synthesis to a greater extent than starvation alone. The rates of 125I-fibronectin clearance were increased in starvation and hemorrhagic shock (t1/2 = 233.0 +/- 13.0 min, controls; 174.6 +/- 10.7 min, starvation; 167.4 +/- 13.6 min, hemorrhage). In contrast to changes observed in fibronectin metabolism, total plasma protein concentrations were not significantly altered in any experimental groups. Furthermore, total plasma protein synthesis increased in rats subjected to either starvation or hemorrhagic shock, but decreased in starved rats that were subsequently shocked.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Fibronectin coating of an experimental PTFE vascular prosthesis.

Because of the known inefficiency of endothelial cell seeding of vascular prostheses, some investigators have pretreated their grafts with fibronectin in an effort to increase endothelial cell adhesion. However, the most efficient method of coating vascular prostheses with fibronectin has not yet been determined and more importantly, the durability of this coating following restoration of pulsatile perfusion has not yet been established. This experiment measured the adsorption of fibronectin which was perfused at three different concentrations through an experimental, highly porous PTFE vascular graft. Most efficient coating of the prosthetic appeared to occur with a 250 mg/ml concentration of fibronectin perfused through the graft for 60 min. Grafts so prepared were subsequently studied in a pulsatile perfusion system which mimicked the canine circulation. Fifteen additional fibronectin-coated grafts were also interposed in the canine carotid artery. Flow was restored, grafts were removed at varying intervals, and fibronectin disappearance was measured. In both the in vitro and in vivo models, three distinct phases of fibronectin dissociation were seen: an initial rapid loss which resulted in an average 30.5% retention of the initial concentration of fibronectin following 30 min of perfusion; a second phase, which occurred from 30 to 120 min, demonstrated an average 2.5% loss of fibronectin per hour; and a final phase, from 2 to 24 hr, during which no significant additional loss of fibronectin was seen. This study describes a new method by which PTFE vascular prostheses can be effectively coated by perfusing them with physiologic concentrations of fibronectin and demonstrates that the resulting bond between fibronectin and prosthetic is stable following restoration of pulsatile flow.

Adsorption↗
PubMed1996

The preterm prediction study: fetal fibronectin, bacterial vaginosis, and peripartum infection. NICHD Maternal Fetal Medicine Units Network.

OBJECTIVE: To determine the relation between vaginal and upper genital tract infection and cervical-vaginal fetal fibronectin levels. METHODS: We screened 2899 women at ten centers every 2 weeks from 23-24 to 30 weeks' gestation for cervical and vaginal fetal fibronectin. A positive test was defined as a level of at least 50 ng/mL. The relation between a positive test and bacterial vaginosis at 23-24 weeks and clinical or histologic chorioamnionitis at delivery plus neonatal sepsis was determined. RESULTS: Fetal fibronectin was present in 4.0% of cervical and/or vaginal samples at 23-24 weeks and was nearly twice as common in women with bacterial vaginosis. Adjusting for the presence of bacterial vaginosis, race, and parity, women positive for fetal fibronectin were much more likely to have clinical chorioamnionitis (mean +/- standard deviation gestational age 30.6 +/- 4.1 weeks), with an odds ratio of 16.4 and 95% confidence interval of 7.1-37.8, and neonatal sepsis (6.3 and 2.0-20.0, respectively), than those who were fetal fibronectin-negative. A positive cervical fetal fibronectin test was a better predictor of clinical chorioamnionitis and neonatal sepsis than was a vaginal test or a combination of vaginal and cervical tests. Among 40 women who delivered before 32 weeks and had placental histology available for evaluation, ten had a positive cervical and/or vaginal fetal fibronectin test before delivery; all ten had histologic evidence of chorioamnionitis, compared with only 13 of 30 women (43%) who were fetal fibronectin-negative (P = .02). CONCLUSION: Women with bacterial vaginosis were more likely to have a positive fetal fibronectin test than uninfected women. Women with a positive fetal fibronectin test who delivered before 32 weeks' gestation all had evidence of histologic chorioamnionitis. Women positive for fetal fibronectin also had a 16-fold increase in clinical chorioamnionitis and a sixfold increase in neonatal sepsis. There is strong evidence that upper genital tract infection and cervical and/or vaginal fetal fibronectin are closely linked.

Adult↗
PubMed1996

The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network.

OBJECTIVE: To evaluate the presence of fetal fibronectin in the cervix and vagina as a screening test for spontaneous preterm birth. METHODS: Two thousand nine hundred twenty-nine women at ten centers were routinely screened every 2 weeks from 22-24 to 30 weeks for cervical and vaginal fetal fibronectin. A positive test was defined as a value equal to or greater than 50 ng/mL. The relation between a positive test at four gestational ages and spontaneous preterm birth at various intervals after the test was determined. RESULTS: In each testing period, 3-4% of the fetal fibronectin tests were positive. The correlation between cervical and vaginal fetal fibronectin at the same visit was always approximately 0.7 (P < .001), and that between cervical or vaginal fetal fibronectin in consecutive visits was between 0.17 and 0.25 (P < .001). The sensitivity of fetal fibronectin at 22-24 weeks to predict spontaneous preterm birth at less than 28 weeks was 0.63, and the relative risk for a positive versus negative test was 59. The specificity was always 96-98%, whereas the positive predictive value rose from 13% to 36% as the upper limit of the definition of preterm birth was increased from less than 28 to less than 37 weeks. The relative risk for spontaneous preterm birth after a positive fetal fibronectin test compared with a negative fetal fibronectin test varied substantially by testing period and by the definition of spontaneous preterm birth, but always remained greater than 4 and statistically significant. CONCLUSION: A positive cervical or vaginal fetal fibronectin test at 22-24 weeks predicted more than half of the spontaneous preterm births at less than 28 weeks (sensitivity 0.63). As the definition of spontaneous preterm birth was extended to include later gestational ages or when the fetal fibronectin test was performed later in pregnancy, the level of association between a positive fetal fibronectin test and spontaneous preterm birth, while remaining highly significant, tended to decrease. Although fetal fibronectin is an excellent test for predicting spontaneous preterm birth, we present no evidence that the use of this test will result in a reduction in spontaneous preterm birth.

Adult↗
PubMed1983

Importance of plasma fibronectin in determining PFP and PRP clot mechanical properties.

Plasma fibronectin has been shown to be incorporated into fibrin clots. The serum concentration of fibronectin is 20-50% lower than the plasma concentration (1). Grinnell and Feld, using an indirect immunofluorescence analysis on blood clots prepared on plastic strata, demonstrated that the fibrin-platelet meshwork was covered with a uniform coating of fibronectin (2). Fibronectin binds to fibrin by either non-covalent attachment or covalent crosslinking. The covalent crosslinking of fibronectin to the fibrin alpha-chain is via an epsilon-(gamma-glutamyl)lysine linkage, mediated by Factor XIIIa (3). Each fibronectin molecule has two such binding sites. Thus it appears that fibronectin may play a role in blood coagulation. It has been suggested that the mechanical properties of fibrin clots may be enhanced by the presence of fibronectin crosslinking (2). Kamykowski, et al. (4) have shown that the shear modulus of a ligated clot formed from purified fibrinogen can be either increased or decreased if fibronectin is present, depending on the ionic strength and the pH during network formation. Although fibronectin is associated with the network structure in plasma clots, the mechanical role of this fibronectin has not been established. In this study we examine quantitatively the effect of plasma fibronectin on the dynamic rigidity moduli of fibrin clots formed from platelet free plasma (PFP), as well as from platelet rich plasma (PRP).

Biophysical Phenomena↗
PubMed1981

A transmembrane relationship between fibronectin and vinculin (130 kd protein): serum modulation in normal and transformed hamster fibroblasts.

Using electron microscopy, we had previously demonstrated a very close transmembrane relationship between actin microfilaments and fibronectin fibrils, termed the fibronexus. Since vinculin, a recently discovered intracellular protein, is localized at the membrane-insertion regions of actin fibers, we studied its possible relationship to fibronectin and the fibronexus. Using double-label immunofluorescence microscopy, we have observed that the distributions of vinculin and fibronectin are strikingly coincident in normal Nil 8 hamster fibroblasts arrested in the G1 phase of the cell cycle, and in HSV-transformed Nil hamster cells treated with purified fibronectin after culturing in 0.3% serum. Extensively spread Nil 8 cells have numerous vinculin-positive focal patches, which are localized either directly over or in tandem with fibronectin fibers at the ventral surface. However, fibronectin and vinculin do not exhibit this relationship in Nil 8 cells grown in 5% serum. These vinculin patches closely resemble the vinculin plaques that Geiger found to be dark under interference-reflection microscopy, suggesting that fibronectin is associated with substrate-adhesion plaques in arrested cells. Fibronectin treatment of the HSV-transformed Nil cells cultured in a low concentration of serum results in the formation of ventral microprocesses, exhibiting an extraordinary congruence of vinculin and fibronectin staining. In addition, these cells bind matrix-like arrangements of fibronectin on their dorsal surface at sites of cell-cell interaction that are vinculin-negative. These results imply that two distinct types of fibronexuses may exist: a ventral substrate-adhesive nexus consisting of fibronectin, vinculin and actin, and a dorsal association matrix fibers. Transmembrane vinculin-fibronectin associations are evidently sensitive to the growth state of the cell.

Animals↗
PubMed1994

Heparin binding to monodisperse plasma fibronectin induces aggregation without large-scale changes in conformation in solution.

Plasma fibronectin was purified by gelatin affinity chromatography in the absence of urea and studied by photon correlation spectroscopy. Polydispersity in the observed translational diffusion coefficient (D20,w) was minimized by subsequent gel permeation fast protein liquid chromatography (FPLC) on Superose 6, which separated fibronectin monomers (D20,w = 2.15 +/- 0.03 x 10(-7) cm2 sec-1; polydispersity 5.2%) from aggregates. Addition of heparin to FPLC-purified fibronectin, at physiological pH, ionic strength and temperature, induced fibronectin aggregation, as shown by an increase of up to 60% in the static light-scattering intensity. Additional changes induced by heparin were an approximate 40% decrease in D20,w and an increase in polydispersity to 33%. After removal of aggregates by FPLC, the translational diffusion coefficient for fibronectin monomers was unaffected by the presence of heparin, in conditions where fluorescence polarization with fluoresceinamine-labelled heparin showed that 80% of the available heparin binding sites on fibronectin were occupied. Small differences in the circular dichroism spectrum of gelatin affinity-purified fibronectin were observed before and after removal of aggregates by gel permeation FPLC, and similar changes were seen when heparin was added to FLPC-purified fibronectin, without subsequent removal of aggregates. The results demonstrate the importance of minimizing polydispersity in the biophysical analysis of fibronectin in solution. We conclude that heparin binding to monomeric fibronectin occurs without large-scale changes in the conformation of the fibronectin molecule, although the possibility of more extended conformations in aggregated forms of fibronectin cannot be excluded.

Amino Acid Sequence↗
PubMed1989

Cellular localization of fibronectin gene expression in the seminiferous tubule.

The cellular location of fibronectin expression within the seminiferous tubule was investigated in order to better understand testicular cell functions and cell-cell interactions. Peritubular cells were shown to actively synthesize and secrete fibronectin in culture by the detection of a radiolabeled 220 kDa secreted protein that is immunologically similar to fibronectin and by the quantitation of fibronectin in peritubular cell conditioned medium with a fibronectin enzyme-linked immunosorbent assay. Sertoli cells did not produce detectable levels of fibronectin when assayed by either of these procedures. A 6.5 kb fibronectin messenger RNA was detected in freshly isolated or cultured peritubular cells, but no fibronectin gene expression was detected in Sertoli cells or developing germinal cells. Combined results imply that the peritubular cells are the only apparent site of fibronectin expression within the seminiferous tubule. During the development of the testis the levels of fibronectin expression increased to a maximum at early puberty (15-day-old rats) and then slowly declined. The results demonstrate that fibronectin can be utilized as a unique functional and biochemical marker for peritubular cells when compared to other cell types in the seminiferous tubule. Production of fibronectin by peritubular cells provides an example of the ability of peritubular cells and Sertoli cells to cooperate in the production of individual components of the basement membrane of the seminiferous tubule. This cellular interaction is an example of a mesenchymal/stromal-epithelial interaction which is postulated to be important for the physiology of many tissues.

Animals↗
PubMed1995

Role of progesterone in luteinizing hormone-induced fibronectin production and deposition by chicken granulosa cells in vitro.

The role of progesterone in luteinizing hormone- (LH) induced fibronectin production and deposition by chicken ovarian granulosa cells was examined in vitro. Granulosa cells isolated from pre-ovulatory follicles of the domestic hen ovary were incubated in serum-free Medium 199, and the total amount of fibronectin (deposited, secreted into the medium and associated with cells) produced was measured by ELISA. LH increased the amount of fibronectin deposited by granulosa cells. Similarly, it increased the quantity of fibronectin secreted into the medium or associated with cells. Cyanoketone (an inhibitor of progesterone synthesis) suppressed dose dependently basal and LH-induced fibronectin deposition. Cyanketone also attenuated the total amount of fibronectin produced by control or LH-stimulated granulosa cells. Exogenous progesterone reversed the inhibitory effects of cyanoketone on basal and LH-induced fibronectin production and deposition. The non-degradable synthetic progestin R5020 stimulated fibronectin production in a dose-dependent manner. R5020 also reversed the inhibitory effects of cyanoketone on LH-induced fibronectin production and deposition. The antiprogestin, ZK 98.299, inhibited basal and LH-stimulated fibronectin production. The data demonstrate that endogenous progesterone regulates fibronectin production and deposition perhaps in an intracrine/autocrine manner. They indicate that LH-stimulated fibronectin production and deposition by chicken granulosa cells is mediated (at least in part) by progesterone.

Animals↗
PubMed2004

The potential and limitations of cartilage-specific (V+C)(-) fibronectin and cartilage oligomeric matrix protein as osteoarthritis biomarkers in canine synovial fluid.

OBJECTIVE: To determine if levels of the cartilage-specific (V+C)(-) fibronectin isoform in the synovial fluid is associated with cartilage change during osteoarthritis. DESIGN: Synovial fluid was collected from 26 healthy dogs presenting to the Orthopedic Surgery Clinic with unilateral cranial cruciate rupture, 22 control dogs, and 13 dogs from a colony maintained for the study of canine hip dysplasia. Total fibronectin, (V+C)(-) fibronectin, and cartilage oligomeric matrix protein (COMP) were quantitated by ELISA assays. Statistical analysis used Wilcoxon's signed-rank and rank-sum tests and Spearman's rank correlation. RESULTS: The concentration of total fibronectin was increased in affected (P<0.0001) and contralateral (P=0.0005) knees of the clinic population (compared to unaffected knees in colony controls). Both (V+C)(-) fibronectin and COMP concentrations were elevated in the contralateral knees in clinical patients relative to unaffected knees in the colony controls (P=0.03 and P=0.04, respectively), and relative to the affected knees (P=0.003); however, corrections for joint effusions suggest elevated totals in the affected knees. (V+C)(-) fibronectin and COMP concentrations were correlated (r(sp)=0.74; P<0.0001) in 30 unaffected knees of patients and colony controls. Total fibronectin was correlated negatively with months since the initial injury (r(sp)=-0.44; P=0.03) in the affected joints. The intraoperative lesion severity score did not correlate with total fibronectin or (V+C)(-) fibronectin (P>or=0.35). CONCLUSIONS: Concentration of total fibronectin in synovial fluid might be a useful biomarker for cross-sectional studies in osteoarthritis, but only (V+C)(-) fibronectin provides information specifically about cartilage damage. Elevated concentrations of (V+C)(-) fibronectin and COMP seen in the contralateral knees of patients with cranial cruciate rupture might indicate cartilage changes early in the disease process (pre-clinical). However, the wide range of values obtained limits the diagnostic value for any one individual. Joint effusions obscure the total amount of biomarkers in affected synovial joints.

Animals↗
PubMed1996

The presence of fetal fibronectin in the cervicovaginal secretions of women at term--its role in the assessment of women before labor induction and in the investigation of the physiologic mechanisms of labor.

OBJECTIVE: Our purpose was to determine whether the presence of fetal fibronectin in cervicovaginal secretions of patients undergoing induction of labor reflected the cervical state and ultimately the ease of induction of labor. STUDY DESIGN: A prospective observational study of 103 patients undergoing induction of labor at term was conducted at Liverpool Maternity Hospital, a large university teaching hospital. We studied the women after 37 completed weeks of pregnancy. A Dacron (Adeza Biomedical, Sunnyvale, Calif.) polyester swab specimen was first taken from the endocervix for assessment of the presence of the fetal fibronectin. The cervix was then assessed by digital vaginal examination and scored with a modified Bishop's score. The fetal fibronectin swab was processed at the bedside with a membrane immunoassay kit specific for fetal fibronectin. A score was ascribed depending on the strength of the fibronectin reaction determined by the intensity of the color change on the plate, the presence of fetal fibronectin resulting in a score of 1 to 4. The patient was subsequently managed according to the standard induction protocol of the unit. The clinicians involved in the patient's care were blind to the result of the fetal fibronectin swab. RESULTS: There was a good correlation between the modified Bishop's score and the fetal fibronectin score (r = 0.58, p < 0.001). To predict a latent phase of < 8 hours, a fetal fibronectin score of 3 or 4 has a sensitivity of 73% with a specificity of 83% and a modified Bishop score of > or = 4 has a sensitivity of 75% and a specificity of 73%. For delivery within 12 hours of induction of labor a fetal fibronectin score of > or = 3 has a sensitivity of 61% and specificity of 83% compared with the modified Bishop score of > or = 4, which has a sensitivity of 76% and a specificity of 72.5%. CONCLUSIONS: The fetal fibronectin score is as good as the modified Bishop score as an index of the ease with which induction of labor may be performed. This would imply that it also reflects the proximity of the onset of labor. The presence of fetal fibronectin cervicovaginal secretions is therefore a marker of the changes in the cervix and membranes that precede labor regardless of the gestational age.

Adolescent↗
PubMed1998

Fetal fibronectin detection in preterm labor: evaluation of a prototype bedside dipstick technique and cervical assessment.

OBJECTIVE: The aims of this study were to evaluate a prototype bedside test for fetal fibronectin detection in women with symptoms of preterm labor, to compare the efficacy of obtaining fetal fibronectin swabs with and without a speculum, and to assess the value of combining the fetal fibronectin test with cervical dilatation for predicting delivery within 10 days. STUDY DESIGN: This investigation prospectively studied a cohort of women with symptoms of preterm labor (n = 121), gestational age between 24 and 33 6/7 weeks, and cervical dilatation </=3 cm. Vaginal swabs for fibronectin testing with the bedside dipstick Fetal Fibronectin Membrane Immunoassay test (Adeza Biomedical, Sunnyvale, Calif) were obtained with and without a speculum. Results were not available to the clinicians. RESULTS: Twenty-two percent of the fetal fibronectin samples collected with a speculum (27/121) yielded positive results. The incidence of delivery within 10 days of testing was 14% (17/121). Fetal fibronectin detection predicted delivery within 10 days with sensitivity, specificity, and positive and negative predictive values of 65%, 85%, 41%, and 94%, respectively. The positive and negative likelihood ratios were 4.3 and 0.41, respectively. There was substantial association between samples obtained with and without a speculum (Cohen kappa statistic 0.65, 95% confidence interval 0.44-0.87). Cervical dilatation >/=1 cm predicted delivery within 10 days with sensitivity, specificity, and positive and negative predictive values of 71%, 87%, 46%, and 95%, respectively, with positive and negative likelihood ratios of 5.5 and 0.33, respectively. Combination of fetal fibronectin testing with cervical dilatation >/=1 cm did not significantly improve the fetal fibronectin test characteristics. After exclusion of women with slight vaginal bleeding, cervical dilatation >/=1 cm and fetal fibronectin status remained the only independent variables associated with delivery within 10 days. CONCLUSION: Fetal fibronectin testing according to this prototype may have a limited role in clinical decision analysis. In this study a cervical dilatation >/=1 cm had predictive values equivalent to those of the fetal fibronectin test, and it should be evaluated further in a clinical setting.

Adult↗
PubMed1997

Cartilage fibronectin isoforms: in search of functions for a special population of matrix glycoproteins.

Fibronectins are a part of the repertoire of matrix molecules produced by the chondrocyte in order to assemble a functional cartilage matrix. They are encoded by a single gene, but significant protein heterogeneity results from alternative RNA splicing. The population of fibronectin isofroms in adult cartilage is significantly different from fibronectins in other tissues and includes relatively high levels (20-30%) of ED-B(+) fibronectins and high levels (50-80%) of the cartilage specific (V + C)- isoform which lacks the V, III-15 and I-10 segments. Less than 4% of the fibronectins in cartilage are ED-A(+). The synthesis and accumulation of cartilage fibronectins are modulated in response to matrix pathology and to biochemical and mechanical mediators. In addition, alternative splicing patterns are altered when chondrocytes are allowed to dedifferentiate in monolayer culture such that the (V + C)- isoform is lost but the ED-A(+) isoform is reexpressed at high levels. Cartilage fibronectins have the potential to participate in cell signalling via integrin mediated pathways and to interact with other cartilage matrix macromolecules. The tissue-specific splicing pattern gives rise to a unique population of fibronectins within the cartilage. Together, this points to a critical role for cartilage fibronectins in chondrocyte cell biology and the organization of a biomechanically sound matrix. However, the precise function (or functions) of the cartilage fibronectins has (or have) not been defined. This minireview examines current information about the structure, synthesis and interactions of cartilage fibronectins. When possible, potential consequences of the inclusion of the ED-B segment or the exclusion of the V, III-15 and I-10 segments are discussed. The goal is to stimulate critical thought and discussion in the field about cartilage fibronectin isoforms, their function(s) in normal cartilage, and their role(s) in the pathogenesis of cartilage diseases.

Alternative Splicing↗
PubMed1992

Effects of high glucose on cellular proliferation and fibronectin production by cultured human mesangial cells.

Diabetic glomerulosclerosis is characterized by the accumulation of the matrix protein fibronectin in the glomerular mesangium and could result from increased mesangial cell fibronectin synthesis induced by hyperglycemia. To test this hypothesis, we cultured human mesangial cells for up to 14 days in media containing normal (5 mM) or high glucose (20 to 115 mM) concentrations and assessed cellular proliferation and fibronectin synthesis. When compared to 5 mM glucose, high glucose levels significantly inhibited cellular proliferation in a dose dependent fashion, as assessed by direct cell counting and thymidine incorporation. After eight days in culture, tissue culture supernatant fibronectin levels, as assessed by ELISA, were significantly higher from cells cultured under high glucose conditions than cells exposed to normal glucose levels. After 14 days and when compared to 5 mM glucose, matrix fibronectin levels and fibronectin mRNA expression (by Northern analysis) were also increased by 20 mM glucose. To control for the osmotic effects of high glucose, mesangial cells were also cultured in the presence of 20 mM or 50 mM mannitol. Mannitol had no effect on cellular proliferation but significantly increased tissue culture supernatant fibronectin levels and fibronectin gene expression. These studies demonstrate that, in vitro, high glucose suppresses human mesangial cell proliferation and stimulates fibronectin synthesis. The increase in fibronectin synthesis may in part result from changes in osmolality induced by high glucose. These data suggest that increased mesangial cell fibronectin synthesis may play a role in the accumulation of glomerular fibronectin common to diabetic glomerulosclerosis.

Cell Division↗
PubMed2001

The frequency and clinical significance of intra-amniotic inflammation in patients with a positive cervical fetal fibronectin.

OBJECTIVE: A positive fetal fibronectin result in cervicovaginal fluid is a powerful predictor of preterm delivery and is considered a marker for upper genital tract infection (ie, intrauterine infection). Treatment with antimicrobial agents is being considered in patients with a positive fetal fibronectin test of cervico/vaginal fluid. This study was undertaken to determine the frequency and clinical significance of intra-amniotic infection/inflammation in patients with a positive fetal fibronectin. STUDY DESIGN: A total of 1709 pregnant women (gestational age, 23-31 weeks) were screened for cervical fetal fibronectin. Patients with a positive fibronectin were offered amniocentesis for the diagnosis of intra-amniotic infection and treatment with antibiotics. Amniocentesis was performed in 58 patients with a positive fibronectin test (>50 ng/mL). Amniotic fluid was cultured for aerobic/anaerobic bacteria and mycoplasmas. Polymerase chain reaction assay for Ureaplasma urealyticum was performed. Interleukin-6 concentrations were measured by a specific immunoassay. Nonparametric statistics were used for analysis. RESULTS: None of the patients with a positive fibronectin had a positive amniotic fluid culture. U urealyticum was detected in 1 case (1.8%) with the polymerase chain reaction assay. Amniotic fluid IL-6 was elevated (>2.5 ng/mL) in 5.3% of patients (3/57 patients); all of these patients delivered preterm neonates. There was no relationship between amniotic fluid IL-6 and cervical fibronectin concentration (r = 0.14;P: >.1). Patients who delivered preterm (<34 weeks) had higher median amniotic fluid IL-6 and cervical fetal fibronectin concentrations than those patients who delivered after 34 weeks (IL-6: median, 2.1 ng/mL [range, 0.1-25.3 ng/mL] vs median, 0.3 ng/mL [0.03-2.4 ng/mL]; P <.05; fibronectin: median, 509 ng/mL [260->1000 ng/mL] vs median, 155 ng/mL [50-889 ng/mL]; P <.01). CONCLUSION: Intra-amniotic infection was detected in 1.8% of cases with a positive fibronectin in the cervical fluid; intra-amniotic inflammation was present in 5.3% of cases. All patients with a positive fetal fibronectin and intra-amniotic inflammation delivered preterm neonates.

Adult↗