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PubMed1998

Binding of latent matrix metalloproteinase 9 to fibrin: activation via a plasmin-dependent pathway.

The binding of two matrix metalloproteinases (MMP) to fibrin was evaluated. MMP-2 (72-kDa) and MMP-9 (92-, 130-, and 225-kDa) were selected since both contain a fibronectin-like region and fibronectin binds fibrin. Gelatin zymography indicated selective and dose dependent binding of MMP-9 to fibrin. No MMP-2 binding to fibrin occurred. Densitometry revealed that the 130- and 225-kDa forms demonstrated similar sigmoidal binding profiles whereas 92-kDa uptake was hyperbolic. Fibronectin and TIMP-1 competition studies indicated that the fibronectin and C-terminal MMP-9 domains, respectively, were not involved with fibrin binding. The MMP-9 collagen-like region may be of regulatory significance since type I and II fibrillar and type IV basement membrane collagens demonstrated fibrin binding. During fibrinolysis, latent fibrin-bound MMP-9 was processed to lower molecular weight forms consistent with proteolytic activation. This process was inhibited by epsilon-aminocaproic acid, indicating a plasmin-dependent pathway. The significance of these findings to procoagulant activity and MMP-mediated extracellular matrix destruction during inflammation and tumor invasion and metastasis is discussed.

Collagenases↗
PubMed1988

Kinetic studies on the effect of heparin and fibrin on plasminogen activators.

1. Possible interactions between fibrin(ogen) and heparin in the control of plasminogen activation were studied in model systems using the thrombolytic agents tissue-type plasminogen activator (t-PA), urokinase and streptokinase.plasminogen activator complex and the substrates Glu- and Lys-plasminogen. 2. Both t-PA and urokinase activities were promoted by heparin and by pentosan polysulphate, but not by chondroitin sulphate or hyaluronic acid. The effect was on Km. 3. In the presence of soluble fibrin (and its mimic, CNBr-digested fibrinogen) the effect of heparin on t-PA was attenuated, although not abolished. In studies using a monoclonal antibody and 6-aminohexanoic acid, it was found that heparin and fibrin did not seem to share a binding site on t-PA. 4. The activity of t-PA B-chain was unaffected by heparin, so the binding site is located on the A-chain of t-PA (and urokinase). 5. Fibrin potentiated the activity of heparin on urokinase. The activity of streptokinase.plasminogen was unaffected by heparin whether or not fibrin was present. 6. If these influences of heparin and fibrin also occur in vivo, then, in the presence of heparin, the relative fibrin enhancement of t-PA will be diminished and the likelihood of systemic activation by t-PA is increased.

Aminocaproic Acid↗
PubMed1975

Soluble high-molecular-weight E fragments in the plasmin-induced degradation products of cross-linked human fibrin.

1. The factor XIII-mediated cross-linked alpha chains in fibrin have no effect on the nature of the fragments released during the solubilization of fibrin by plasmin. 2. Besides the known D dimer and E fragments solubilized during the lysis of cross-linked fibrin, other fragments have been observed on sodium dodecyl sulphate-polyacrylamide gel electrophoresis which have a molecular weight of about 135 000. After prolonged plasmin digestion, these fragments (U fragments) were no longer evident on the gels and the high-molecular-weight E antigen was absent. It is assumed that the E antigen was associated with the U fragments. These fragments also cross-reacted with an anti-D serum. 3. The U fragments have been tentatively presumed to be a factor XIII-mediated cross-linked D-E complex since they degrade only after prolonged degradation with plasmin. Whereas it is known that the fibrin D dimer fragment contains the cross-linked gamma chain residues of the originating fibrin, the presumed covalent cross-linking of the D-E fragments has not been proved. 4. The presence of these high-molecular-weight fragments, containing the E antigen, in cross-linked human fibrin digests should be taken into account in the development of D dimer assays to monitor fibrin lysis in vivo.

Animals↗
PubMed2003

Increased plasma fibrin gel porosity in patients with Type I diabetes during continuous subcutaneous insulin infusion.

BACKGROUND: Patients with Type 1 diabetes have a tighter plasma fibrin gel structure, to which impaired glycemic control might contribute. Improved glycemic control can be achieved with continuous subcutaneous insulin infusion (CSII). OBJECTIVES: The aim of the present study was to investigate the effect of CSII on plasma fibrin gel properties and circulating markers of inflammatory activity in patients with Type 1 diabetes. PATIENTS AND METHODS: Twenty-eight patients were investigated before and after 4-6 months' treatment with CSII. Fibrin gel structure formed in vitro from plasma samples was investigated by liquid permeation of hydrated fibrin gel networks. P-fibrinogen was analyzed by a syneresis method. Comparisons were made between patients with improved (> 0.5%) and unchanged (< 0.5%) glucosylated hemoglobin (HbA1c) during CSII. RESULTS: Eighteen patients showed improved and 10 patients unchanged HbA1c during CSII. P-fibrinogen, high sensitive C-reactive protein and serum amyloid A-antigen were not significantly changed, while fibrin gel permeability (Ks) and fiber mass-length ratio ( micro ) increased in both groups (P < 0.02). P-insulin and triglycerides decreased (P < 0.05) in both groups, while reductions of total cholesterol and intercellular adhesion molecule-1 were seen only in patients with improved HbA(1c) (P < 0.05). Absolute changes in Ks were inversely correlated to changes in plasma fibrinogen (r = 0.50; P < 0.01) and in LDL-cholesterol (r = 0.46; P < 0.05). CONCLUSIONS: Treatment with CSII in patients with Type 1 diabetes is associated with increased plasma fibrin gel porosity. Slight attenuation of the inflammatory activity was also observed. The changes in fibrin gel porosity seem to be mainly mediated by changes in plasma fibrinogen and blood lipids, and are probably secondary to improved insulin sensitivity.

Adolescent↗
PubMed2003

Endogenous alpha2-antiplasmin does not enhance glomerular fibrin deposition or injury in glomerulonephritis.

BACKGROUND: Fibrin deposition is an important mechanism of glomerular injury in crescentic glomerulonephritis (GN), a severe form of immune renal injury. Both coagulation and fibrinolysis (via the plasminogen-plasmin system) are important in net glomerular fibrin accumulation in GN. alpha2-Antiplasmin (alpha2-AP) is the major circulating inhibitor of plasmin and is expressed in the renal tubulointerstitium. OBJECTIVE: To determine whether endogenous alpha2-AP contributes to glomerular fibrin accumulation in GN. METHODS: Crescentic autologous phase antiglomerular basement membrane GN was induced in mice with intact and deficient endogenous alpha2-AP (alpha2-AP+/+ and alpha2-AP-/- mice). RESULTS: In mice with crescentic GN, alpha2-AP was detected in the tubulointerstitium and in segmental deposits within some glomeruli. alpha2-AP+/+ mice developed crescentic GN (38 +/- 9% glomeruli affected) with glomerular fibrin deposition and renal impairment (serum creatinine 30 +/- 1 micro mol L-1, normal without GN 11 +/- 1 micro mol L-1). Genetic deficiency of alpha2-AP did not result in attenuated glomerular fibrin deposition, crescent formation (39 +/- 8% glomeruli affected), glomerular leukocyte infiltration or renal impairment (serum creatinine 33 +/- 7 micro mol L-1). alpha2-AP was unmeasurable in kidneys from alpha2-AP-/- mice, which did not develop compensatory changes in plasminogen, tissue type plasminogen activator (tPA), urokinase type PA (uPA) or plasminogen activator inhibitor-1 proteins, or changes in tPA or uPA activity. alpha2-AP-/- mice did have enhanced total renal fibrinolytic capacity as assessed by in situ fibrin overlay (alpha2-AP+/+ 0.19 +/- 0.01, alpha2-AP-/- 0.36 +/- 0.03 lyzed area/total area). CONCLUSIONS: alpha2-AP is not important to net glomerular fibrin deposition, crescent formation or renal impairment in crescentic GN.

Animals↗
PubMed1999

The effect of a low molecular mass thrombin inhibitor, inogatran, and heparin on thrombin generation and fibrin turnover in patients with unstable coronary artery disease.

AIM: This study evaluated a novel specific thrombin inhibitor, inogatran, in comparison with unfractionated heparin, with regard to markers for coagulation activity in patients with unstable coronary artery disease. METHODS AND RESULTS: In the Thrombin Inhibition In Myocardial Ischaemia (TRIM) study patients were randomized to one of three different doses of inogatran or to unfractionated heparin, given intravenously over 72 h. In a subpopulation of 320 patients, markers for coagulation activity were measured at baseline, during and after the study infusion. Prothrombin fragment 1 + 2, indicating thrombin generation, decreased in the low, medium and high dose inogatran groups and in the heparin group during the first 6 h of treatment by 12%, 15%, 21% and 26%, respectively. From 6 h to 72 h after the start of infusion the levels changed by -7%, -6%, -4% and +34%, respectively. The increase in the heparin group continued after the infusion was stopped. Thrombin-antithrombin complex, also indicating thrombin generation, decreased by 0%, 2%, 18% and 22%, respectively, during the first 6 h of treatment. During the same period soluble fibrin, an intermediate in fibrin formation, increased both in the low and medium inogatran group by 9%, while a decrease by 4% and 18%, respectively, was seen in the high dose inogatran group and in the heparin group. Fibrin dissolution, as measured by fibrin D-dimer, decreased during the first 24 h of treatment by 20%, 18%, 18% and 20%, respectively. The first 24 h after discontinuation of infusion, fibrin D-dimer increased by 6%, 23%, 25% and 44%, respectively. After 72 h, at the end of infusion, patients treated with inogatran, to a larger extent than those given heparin, had suffered from death, myocardial infarction or refractory angina pectoris. After 7 days this trend was less marked. CONCLUSION: The more pronounced decrease in thrombin generation and fibrin turnover during the first 6 h of infusion, and the later increase in thrombin generation and fibrin turnover, in the heparin group, as compared to the inogatran groups, may be related to the lower clinical event rate during infusion with heparin compared with inogatran and the recurrence of ischaemic events, early after cessation of heparin infusion.

Aged↗
PubMed2006

Fibrin glue: an alternative technique for nerve coaptation--Part II. Nerve regeneration and histomorphometric assessment.

The results of nerve repair with fibrin glue and microsuture were evaluated in rat nerve transection models. Ninety Wistar-Furth rat median nerves were exposed, transected, and repaired in an end-to-end fashion with one of four substances/techniques: 1) human fibrin sealant (Quixil); 2) autologous graft and human fibrin sealant (Quixil); 3) bovine fibrin sealant (Tissucol); and 4) nylon microsuture, epineurial technique. Histologic analyses were performed at 3-, 6-, and 9-month postoperative intervals, and factors evaluated included: presence of inflammatory cells (i.e., macrophages and T cells); number of Schwann cells at the repair site; number of blood vessels; fibrosis; axonal regeneration; and fiber alignment. An additional group underwent histologic analysis at 3 weeks following repair with Quixil. Surgical time of repair was also measured. Nerve repairs performed with fibrin sealants produced less inflammatory response and fibrosis, and better axonal regeneration and fiber alignment than nerve repairs performed with microsuture. In addition, the fibrin sealant techniques were quicker and easier to use. The authors conclude that fibrin sealant represents a good alternative technique to microsuture for peripheral-nerve repair.

Animals↗
PubMed1982

Evaluation of fibrin seal in animal experiments.

This paper presents experimental investigations to evaluate fibrin seal for bleeding control under systemic heparinization as well as some of the benefits and limits of fibrin-presealing vascular prostheses. Local hemostasis using fibrin seal plus collagen fleece was achieved in 3 standardized sources of bleeding produced in mongrel dogs under full heparinization. Water porosity was measured in 3 standard prosthetic materials of different porosity. It could be shown that all graft types investigated were sufficiently sealed up to a pressure of 600 mmHg. The influence of fibrinolysis on the stability of the fibrin network in vascular grafts was tested by in vitro experiments using urokinase incubation. While water permeability increased in fibrin-sealed fabric without aprotinin added, no fibrinolysis-induced leakage was observed in those exposed to aprotinin. Surface thrombogenicity of the fibrin-sealed grafts was higher than in blood-preclotted prostheses, if not rinsed with isotonic saline. After rinsing, thrombogenicity decreased below values obtained in grafts preclotted conventionally. Survival studies in animals show no difference between blood-preclotted and fibrin-presealed prostheses both 3 and 7 days after implantation.

Animals↗
PubMed2004

Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis.

In multiple sclerosis, in which brain tissue becomes permeable to blood proteins, extravascular fibrin deposition correlates with sites of inflammatory demyelination and axonal damage. To examine the role of fibrin in neuroinflammatory demyelination, we depleted fibrin in two tumor necrosis factor transgenic mouse models of multiple sclerosis, transgenic lines TgK21 and Tg6074. In a genetic analysis, we crossed TgK21 mice into a fibrin-deficient background. TgK21fib(-/-) mice had decreased inflammation and expression of major histocompatibility complex class I antigens, reduced demyelination, and a lengthened lifespan compared with TgK21 mice. In a pharmacologic analysis, fibrin depletion, by using the snake venom ancrod, in Tg6074 mice also delayed the onset of inflammatory demyelination. Overall, these results indicate that fibrin regulates the inflammatory response in neuroinflammatory diseases. Design of therapeutic strategies based on fibrin depletion could potentially benefit the clinical course of demyelinating diseases such as multiple sclerosis.

Animals↗
PubMed1972

Isolation and characterization of the S-carboxymethyl derivatives of crosslinked and noncrosslinked human fibrin.

The S-carboxymethyl derivative chains of crosslinked and noncrosslinked fibrins were prepared from purified human fibrinogen. For crosslinked fibrin, fibrinogen was clotted with thrombin in the presence of calcium and purified human factor XIII. For noncrosslinked fibrin, ethylenediaminetetraacetate was substituted for factor XIII and calcium. After reduction with dithiothrcitol and alkylation with tritiated iodoacetic acid, the derivative chains were separated on carboxymethyl cellulose in a sodium acetate-pH gradient that contained 8 M urea. Purity of the separated chains was determined by polyacrylamide gel electrophoresis at acid and at neutral pH. The derivative chains of noncrosslinked fibrin were eluted from carboxymethyl cellulose in the order: gamma-chain, beta-chain, and alpha-chain. Each of the purified derivative chains was characterized and identified by amino-terminal aminoacid analysis, aminoacid composition, tryptic peptide mapping, and molecular weight estimation by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. In like manner, the derivative components of crosslinked fibrin were eluted from carboxymethyl cellulose in the order: gamma-gamma-dimer, beta-chain, and alpha-polymer. Application of the same analytical criteria and comparision with the derivatives of noncrosslinked fibrin confirmed the identity of these components. These data provide conclusive evidence that crosslinking of human fibrin involves formation of peptide bonds between two gamma-chains to form gamma-gamma-dimer and between multiple alpha-chains to form high molecular weight polymers of alpha-chains.

Amino Acids↗
PubMed1973

Discriminating neoantigenic differences between fibrinogen and fibrin derivatives.

Discrimination between the physiological cleavage fragments of fibrinogen and fibrin offers an approach to differentiation between fibrinogenolytic processes and fibrinolysis after coagulation. By use of the cleavage-associated neoantigen of fibrinogen (fg-D(neo)) as a molecular marker, characteristic differences between the D regions of fibrinogen derivatives and fibrin derivatives can be demonstrated. The expression of fg-D(neo) by X, Y, D:E complex, and D-fragments of fibrinogen or fibrin is shown to be quantitative and unitary. Characteristic differences between fg-D(neo) sites present on fibrinogen cleavage fragments, as contrasted to fibrin cleavage fragments, are indicated by different competitive inhibition slopes, and appear to reflect differential binding affinity of selected anti-fg-D(neo) antibodies for the specific molecular site. There is a linear relationship between the slope of quantitative competitive inhibition and the relative molar ratio of fibrinogen and fibrin derivatives. Identical immunochemical expressions are observed in vitro and in vivo, and support the thesis that cleavage in vivo is produced by plasmin. The differential immunochemical features of fg-D(neo) expression may be the result of stable conformational and/or subtle structural differences between the D region of fibrinogen and fibrin cleavage fragments and suggest that precise changes in the D region are associated with the fibrin transition. These molecular features not only provide additional insight into the molecular immunology and structure of fibrinogen, but also appear to offer a new molecular approach to discrimination between fibrinogenolytic mechanisms as contrasted to fibrinolysis secondary to coagulation.

Abruptio Placentae↗
PubMed1985

Discrimination between fibrin and fibrinogen by a monoclonal antibody against a synthetic peptide.

Circulating soluble fibrin, observed in the blood of patients with ongoing intravascular coagulation, is generated from the plasma protein fibrinogen by the limited proteolytic action of thrombin. We report the production of a monoclonal antibody that discriminates between fibrin and fibrinogen in blood. The synthetic hexapeptide Gly-Pro-Arg-Val-Val-Glu, representing the amino terminus of the alpha chain of human fibrin, was used as immunogen. This hexapeptide is located within the A alpha chain of fibrinogen but becomes the amino terminus of the fibrin alpha chain, after fibrinopeptide A is removed by the action of thrombin, and thus becomes accessible for antibody binding. The monoclonal antibody we have prepared can discriminate between fibrin and fibrinogen and thus can be used in assay systems to quantitate soluble fibrin or, potentially, to image fibrin-rich thrombi.

Amino Acid Sequence↗
PubMed1992

Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism.

We have previously shown that lipoprotein(a) [Lp(a)], an atherogenic lipoprotein that contains apolipoprotein(a), which shares partial structural homology to plasminogen, binds to a plasmin-modified fibrin surface, and we have postulated that this interaction may be atherogenic. Moderate elevations in blood homocysteine, a relatively common condition, predispose to premature atherosclerosis. The reasons for this are not established. We now report that homocysteine, at concentrations as low as 8 microM, significantly increases the affinity of Lp(a) for fibrin. Homocysteine induces a 20-fold increase in the affinity between Lp(a) and plasmin-treated fibrin and a 4-fold increase with unmodified fibrin. Lp(a) binding is inhibited by epsilon-aminocaproic acid, indicating lysine binding site specificity. Homocysteine does not enhance the binding of Lp(a) to other surface-bound proteins. Cysteine, glutathione, and N-acetylcysteine also increase the affinity between Lp(a) and fibrin. Homocysteine does not affect the binding of low density lipoprotein or plasminogen to fibrin, nor does it alter the gel-filtration elution pattern of Lp(a). Immunoblot analysis documents the fact that homocysteine partially reduces Lp(a). These results suggest that homocysteine alters the intact Lp(a) particle so as to increase the reactivity of the plasminogen-like apolipoprotein(a) portion of the molecule. The observation that sulfhydryl amino acids increase Lp(a) binding to fibrin suggests a biochemical relationship between sulfhydryl compound metabolism, thrombosis, and atherogenesis.

Blotting, Western↗
PubMed1997

The primary fibrin polymerization pocket: three-dimensional structure of a 30-kDa C-terminal gamma chain fragment complexed with the peptide Gly-Pro-Arg-Pro.

After vascular injury, a cascade of serine protease activations leads to the conversion of the soluble fibrinogen molecule into fibrin. The fibrin monomers then polymerize spontaneously and noncovalently to form a fibrin gel. The primary interaction of this polymerization reaction is between the newly exposed N-terminal Gly-Pro-Arg sequence of the alpha chain of one fibrin molecule and the C-terminal region of a gamma chain of an adjacent fibrin(ogen) molecule. In this report, the polymerization pocket has been identified by determining the crystal structure of a 30-kDa C-terminal fragment of the fibrin(ogen) gamma chain complexed with the peptide Gly-Pro-Arg-Pro. This peptide mimics the N terminus of the alpha chain of fibrin. The conformational change in the protein upon binding the peptide is subtle, with electrostatic interactions primarily mediating the association. This is consistent with biophysical experiments carried out over the last 50 years on this fundamental polymerization reaction.

Dimerization↗
PubMed1996

Rearrangements of the fibrin network and spatial distribution of fibrinolytic components during plasma clot lysis. Study with confocal microscopy.

Binding of components of the fibrinolytic system to fibrin is important for the regulation of fibrinolysis. In this study, decomposition of the fibrin network and binding of plasminogen and plasminogen activators (PAs) to fibrin during lysis of a plasma clot were investigated with confocal microscopy using fluorescein-labeled preparations of fibrinogen, plasminogen, tissue-type PA (t-PA), and two-chain urokinase-type PA (tcu-PA). Lysis induced by PAs present throughout the plasma clot was accompanied by a gradual loss of fibrin content of fibers and by accumulation of plasminogen onto the fibers. Two sequential phases could be distinguished: a phase of prelysis, during which the fibrin network remained immobile, and a phase of final lysis, during which fibers moved with a tendency to shrink and eventually disappeared. The two phases occurred simultaneously but in different locations when lysis was induced by PAs present in the plasma surrounding the clot. The zone of final lysis was located within a 5-8 microns superficial layer, where fibers were mobile, a surface-associated fibrin agglomerates appeared. Plasminogen accumulated in these agglomerates up to 30-fold as compared with its concentration in the outer plasma. t-PA was also highly concentrated in the agglomerates, and tcu-PA bound to them slightly. The zone of prelysis, where plasminogen was moderately accumulated on the immobile fibers, was located deeper in the clot. This zone was much thinner in the case of t-PA-induced lysis than in the case of tcu-PA-induced lysis, reflecting the difference in penetration of the two PAs into the clot. We conclude that under conditions of diffusional transport of fibrinolytic enzymes from outside a plasma clot, extensive lysis is spatially restricted to a zone not exceeding 5-8 microns from the clot surface. In this zone the structure of the fibrin network undergoes significant changes, and strikingly high accumulation of fibrinolytic components takes place.

Blood Coagulation↗
PubMed1996

Binding of fibrin monomer and heparin to thrombin in a ternary complex alters the environment of the thrombin catalytic site, reduces affinity for hirudin, and inhibits cleavage of fibrinogen.

Interaction of the blood clotting proteinase, thrombin, with fibrin monomer and heparin to form a thrombin.fibrin monomer.heparin ternary complex is accompanied by a change in thrombin catalytic specificity. Equilibrium binding interactions in the assembly of the ternary complex were characterized quantitatively using thrombin labeled at the active site with a fluorescent probe and related to changes in thrombin specificity toward exosite I-dependent binding of hirudin and cleavage of fibrinogen. Changes in the active site environment accompanying binding of heparin or fibrin to thrombin in binary complexes were reported by fluorescence enhancements which contributed additively to the perturbation accompanying formation of the ternary complex. Quantitative analysis of the interactions supports a preferentially ordered path of ternary complex assembly, in which initial binding of heparin to thrombin facilitates binding of fibrin monomer with an approximately 40-fold increased affinity. Binding of fibrin monomer in the ternary complex decreased the affinity of native thrombin for hirudin by >100-fold and inhibited cleavage of fibrinogen, but this inhibition was overcome when fibrin(ogen)-fibrin interactions occurred. These results support a ternary complex model in which heparin binding through exosite II of thrombin facilitates fibrin monomer binding via exosite I, with accompanying changes in thrombin catalytic specificity resulting from perturbations in the active site and reduced accessibility of exosite I to hirudin and fibrinogen.

Anilino Naphthalenesulfonates↗
PubMed2006

Decorin modulates fibrin assembly and structure.

Emerging evidence indicates that fibrin clotting is regulated by different external factors. We demonstrated recently that decorin, a regulator of collagen fibrillogenesis and transforming growth factor-beta activity, binds to the D regions of fibrinogen (Dugan, T.A., Yang, V. W.-C., McQuillan, D.J., and Höök, M. (2003) J. Biol. Chem. 278, 13655-13662). We now report that the decorin-fibrinogen interaction alters the assembly, structure, and clearance of fibrin fibers. Relative to fibrinogen, substoichiometric amounts of decorin core protein modulated clotting, whereas an excess of an active decorin peptide was necessary for similar activity. These concentration-dependent effects suggest that decorin bound to the D regions sterically modulates fibrin assembly. Scanning electron microscopy images of fibrin clotted in the presence of increasing concentrations of decorin core protein showed progressively decreasing fiber diameter. The sequestration of Zn(2+) ions from the N-terminal fibrinogen-binding region abrogated decorin incorporation into the fibrin network. Compared with linear thicker fibrin fibers, the curving thin fibers formed with decorin underwent accelerated tissue-type plasminogen activator-dependent fibrinolysis. Collectively, these data demonstrate that decorin can regulate fibrin organization and reveal a novel mechanism by which extracellular matrix components can participate in hemostasis, thrombosis, and wound repair.

Binding Sites↗
PubMed2004

Biological in vitro effects of fibrin glue: fibroblast proliferation, expression and binding of growth factors.

BACKGROUND: Fibrin glue is used in the endoscopic therapy of bleeding ulcerations. Accelerated closure of ulcers has been documented for this treatment in comparison with other injection techniques; the biological reason, however, remains unclear. METHODS: In an in vitro model the effects of fibrin glue on the expression and secretion of growth factors by gastric epithelial (AGS, KATO III) and mesenchymal cells (fibroblasts) as well as their proliferative response and their interaction were compared with those of other matrices. RESULTS: Native fibrin glue does not release vascular endothelial growth factor (VEGF) but is able to bind this growth factor in biologically relevant concentrations of 152.6 pg/mL. The addition of fibrin glue to a collagen type I matrix led to an increased proliferation rate of gastric wall fibroblasts. The transcription of VEGF and platelet-derived growth factor (PDGF) mRNA was significantly increased in epithelial cells. Co-culture of fibroblasts grown on fibrin glue containing matrix and epithelial cells resulted in an increased secretion of VEGF by both cell lines. CONCLUSIONS: Fibrin glue leads to increased proliferation of fibroblasts and local accumulation of VEGF. These findings might at least partly explain the accelerated closure of bleeding ulcers treated by fibrin glue injection.

Base Sequence↗