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PubMed2006

Reduction of postoperative adhesions with an auto-crosslinked hyaluronan gel in gynaecological laparoscopic surgery: a blinded, controlled, randomized, multicentre study.

BACKGROUND: Following myomectomy, postoperative adhesions occur in many patients with adverse effects on fertility. This study investigated the applicability, safety and efficacy of an auto-crosslinked hyaluronan gel in preventing adhesion formation after laparoscopic myomectomy. METHODS: Fifty-two patients aged 22-42 years, undergoing surgery at four centres, were randomly allocated to receive either the gel or no adhesion prevention. The incidence and severity of postoperative adhesions were assessed laparoscopically after 12-14 weeks in a blinded, scored fashion. The primary efficacy variable was the presence/absence of postoperative adhesions at second-look. RESULTS: A nonsignificantly higher proportion of patients receiving the gel were free from adhesions (13 of 21; 62%) compared with control patients (9 of 22; 41%), with a statistically significant difference between the severity of uterine adhesions at baseline and at second-look (0.3 +/- 0.9 versus 0.8 +/- 1.0, P < 0.05). In subjects undergoing myomectomy without concomitant surgery, the proportion of adhesion-free patients was 8 of 12 (67%) and 4 of 11 (36%) (not significant) in the gel and control groups, respectively, with a significant difference in the mean severity scores (P < 0.05). In subjects without uterine adhesions before myomectomy, 12 of 18 (67%) and 8 of 20 (40%) patients in the gel and control groups, respectively were adhesion-free (not significant), with a significant difference in the severity of uterine adhesions (P = 0.05). CONCLUSIONS: Our results suggest that the auto-crosslinked hyaluronan gel may have a favourable safety profile and efficacious antiadhesive action following laparoscopic myomectomy.

Adult↗
PubMed1997

Diminished adhesion of CD4+ T cells from dialysis patients to extracellular matrix and its components fibronectin and laminin.

BACKGROUND: Cell-mediated immunity is impaired in uraemia. The recognition and ensuing interactions of immune cells, such as CD4+ T lymphocytes, with adhesive glycoproteins of the extra-cellular matrix (ECM) are mediated by integrins of the beta 1 subfamily. We have previously demonstrated that uraemic sera inhibit the proliferation and adhesion of normal CD4+ T cells to ECM components. In the present study, the adhesive capacity of CD4+ T lymphocytes of dialyzed patients (both haemodialysis [HD] and continuous ambulatory peritoneal dialysis [CAPD] was evaluated. METHODS: Adhesion of CD4+ T cells from dialysis patients to intact ECM and its immobilized moieties, fibronectin (FN) and laminin (LN) was measured following phorbol-12-myristate-13-acetate (PMA) stimulation. In addition, cell surface expression of beta 1 integrins (VLA 4-6) was determined by FACScan analysis. RESULTS: Compared to normal cells, CD4+ T cells of dialysis patients demonstrated a significantly reduced adhesion to ECM, FN and LN (27-28 vs 52-55%, P < 0.001). This decreased adhesive capacity was not normalized upon incubation of the cells with normal sera. Cell surface expression of beta 1 integrins was not modified. The inhibition of cell adhesion was more pronounced in CAPD patients (23-24% vs 29-30% in HD, P < 0.02). Serum albumin correlated directly with cell adhesion. Aged HD patients' T cells demonstrated increased adhesion to ECM and its ligands, whereas a reverse trend was demonstrated in the CAPD group. CONCLUSIONS: T cells of dialysis patients exhibit abnormal adhesive activity, which may be due to an acquired cellular defect induced by uraemic milieu. CAPD patients show a greater degree of adhesion impairment, possibly due to their lower concentrations of serum albumin.

Adult↗
PubMed1999

Inhibition of neutrophil activation by volatile anesthetics decreases adhesion to cultured human endothelial cells.

BACKGROUND: Polymorphonuclear leukocytes (neutrophils, PMNs) have been shown to mediate vascular and tissue injury, leading to so-called systemic inflammatory response syndrome. The authors evaluated the effect of volatile anesthetics on neutrophil adhesion to human endothelial cells, focusing on whether the inhibitory effect observed is linked to an alteration in the function of endothelial cells or neutrophils. METHODS: The adhesion of human PMNs was quantified using cultured human umbilical vein endothelial cells (HUVECs). The increase in the number of adhering PMNs was assessed when HUVECs (with 1 mM hydrogen peroxide), PMNs (with 10 nM N-formyl-methionyl-leucyl-phenylalanine), or both were prestimulated. To determine the influence of volatile anesthetics on the adhesion of PMNs, the experiments were performed in the absence or presence of 0.5, 1, and 2 minimum alveolar concentration halothane, isoflurane, or sevoflurane, whereby HUVECs, PMNs, or both were pretreated with gas. RESULTS: Activation of HUVECs with hydrogen peroxide or stimulation of PMNs with N-formyl-methionyl-leucyl-phenylalanine resulted in a 2.5-fold increase in PMN adhesion. Preincubation of PMNs, separately, with halothane, isoflurane, or sevoflurane, respectively, abolished enhanced neutrophil adhesion to hydrogen peroxide-activated HUVECs and adhesion of PMNs prestimulated with N-formyl-methionyl-leucyl-phenylalanine to unstimulated HUVECs (maximal effect at 1 minimum alveolar concentration). No decrease in adhesion was detected when only HUVECs were pretreated with volatile anesthetics. Additional exposure of HUVECs and PMNs to volatile anesthetics had no inhibitory effect on adhesion greater than that seen when only PMNs were treated. Appropriately, the volatile anesthetics abolished the upward regulation of the adhesion molecule CD11b on PMNs (as evaluated at 1 minimum alveolar concentration each), whereas 1 minimum alveolar concentration halothane failed to affect the expression of P-selectin, an adhesion molecule on endothelial cells. CONCLUSIONS: This study indicates that halothane, isoflurane, and sevoflurane inhibit neutrophil adhesion to human endothelial cells at concentrations relevant to anesthesia in a static system. The effects appear to be mediated by inhibition of PMN activation; that is, by attenuating the upward regulation of neutrophil CD11b.

Anesthetics, Inhalation↗
PubMed2000

Nitric oxide synthase inhibition increases venular leukocyte rolling and adhesion in septic rats.

OBJECTIVE: Excess production of nitric oxide (NO) has been implicated in hypotension and blood flow abnormalities in sepsis, but NO is also an important inhibitor of leukocyte rolling and adhesion. Leukocyte adhesion is increased in sepsis despite elevated NO production. We hypothesized that inhibition of NO synthase (NOS) could increase leukocyte adhesion in sepsis. DESIGN: Prospective animal study. SETTING: Experimental animal laboratory. SUBJECTS: Twenty-five male rats, anesthetized with ketamine and acepromazine. INTERVENTIONS: Topical superfusion of the nonselective NOS inhibitor N(G)-monomethyl-L-arginine (NMA) on skeletal muscle postcapillary venules. MEASUREMENTS AND MAIN RESULTS: Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Leukocyte rolling and adhesion were measured in cremasteric postcapillary venules of septic and control rats using in vivo videomicroscopy. The effects of NOS inhibition on leukocyte rolling and adhesion were also measured. After a stable baseline was reached, 1 microM of the nonselective NOS inhibitor NMA was suffused topically followed by physiologic buffer. The effects of L-arginine on leukocyte rolling and adhesion were also measured, both before and after suffusion of NMA. Leukocyte rolling and adhesion was increased in septic rats as compared with controls (control 5.5+/-0.9 rolling cells/min, 1.0+/-0.3 adherent cells/min; septic 13.7+/-2.0 rolling cells/min, 3.1+/-0.6 adherent cells/min; p < .001), and NOS inhibition further increased leukocyte rolling and adhesion in both septic and control rats (control 14.0+/-1.7 rolling cells/min, 2.8+/-0.5 adherent cells/min; septic 25+/-2.1 rolling cells/min, 5.4+/-0.5 adherent cells/min; both p < .001 vs. baseline). Prior suffusion of excess L-arginine prevented the increase in leukocyte adhesion with NMA in septic rats (2.6+/-0.4 adherent cells/min vs. 3.0+/-0.6 adherent cells/min; n = 3; p > .05). When administered after NMA, excess L-arginine partially reversed leukocyte adhesion in septic rats (5.4+/-0.7 adherent cells/min, with NMA vs. 4.3+/-0.7 adherent cells/min, after L-arginine; n = 5; p < .05). Venular shear did not differ between septic and control rats (600+/-109 (sec(-1)) vs. 620+/-37 (sec(-1)); p > .05). CONCLUSIONS: Although NOS inhibition may ameliorate hypotension in sepsis, such therapy may be deleterious by increasing leukocyte adhesion.

Animals↗
PubMed2004

A quantitative method for determining polarization of neutrophil adhesion molecules associated with ischemia reperfusion.

Ischemia-reperfusion-induced neutrophil adhesion to endothelium is CD18-dependent, but information regarding polarity of CD18 adhesion molecules remains speculative. This study evaluated neutrophil adhesion using an in vitro cell adhesion assay and introduces a quantitative method of measuring CD18 membrane distribution using confocal microscopy. Neutrophils from normal animals were isolated from whole blood and incubated with plasma from rat gracilis muscle flaps with no ischemia and reperfusion (nonischemic control, n = 10) or 4 hours of ischemia and 90 minutes of reperfusion (ischemia/reperfusion, n = 10), on coverslips pretreated with and without (phosphate-buffered saline) soluble intercellular adhesion molecules. Coverslips without intercellular adhesion molecules represented a negative control (intercellular adhesion molecules were required for adhesion). Percent adherence to intercellular adhesion molecules was expressed as a ratio of adherent cells/total cells. CD18 polarization was assessed by staining neutrophils with fluorescein isothiocyanate-labeled anti-CD11b, followed by confocal microscopy and Z-stack analysis. Membrane-associated CD18 was expressed as fluorescence intensity units in three equal areas of the cell membrane. Capping was defined as twice as much fluorescence in 33 percent of the cell membrane as in the remaining 67 percent. Neutrophils exposed to ischemia and reperfusion plasma showed a significant increase in adhesion (0.8 +/- 0.1 percent versus 16.7 +/- 2.2 percent, p < 0.001) and CD18 polarization (6.2 +/- 1.7 percent versus 43.9 +/- 12.2 percent, p = 0.0206) compared with controls. This article describes an in vitro assay that reliably reproduces the neutrophil adhesion phenomenon associated with ischemia-reperfusion injury. Results from confocal microscopy allowed for quantitative estimation of membrane-associated receptor polarization.

Animals↗
PubMed2005

Prevention of intra-abdominal adhesions using the antiangiogenic COX-2 inhibitor celecoxib.

OBJECTIVE: To determine the effects of COX-2 specific inhibitors on postoperative adhesion formation. SUMMARY AND BACKGROUND DATA: Intra-abdominal adhesions are the major cause of intestinal obstruction and secondary infertility after surgical procedures. Because adhesion synthesis requires angiogenesis, and cyclooxygenase-2 enzyme (COX-2) inhibitors have antiendothelial activity, we tested COX-2 inhibitors in a murine model of intra-abdominal adhesion formation. METHODS: A silicone patch was secured to the lateral abdominal wall of groups of C57BL/6 mice, followed by cecal abrasion to promote adhesion formation. Beginning on the day of surgery, mice were treated with the selective COX-2 agents, celecoxib or rofecoxib, and the nonspecific COX inhibitors, aspirin, naproxen, ibuprofen, or indomethacin. Animals were treated for 10 days and killed. A second group (celecoxib, rofecoxib, aspirin) was treated for 10 days and observed for an additional 25 days. After treatment, intra-abdominal adhesions were scored using a standard method. The patch was subjected to immunohistochemistry with the endothelial-specific marker, CD31. RESULTS: Animals treated with selective and nonselective COX-2 inhibitors, except aspirin, had significantly fewer adhesions than control animals. Celecoxib produced a maximal reduction in adhesion formation compared with rofecoxib and the nonselective COX-2 inhibitors at 10 days. After 25 days, celecoxib and rofecoxib, but not aspirin, had fewer adhesions than control mice. Adhesions from mice treated with celecoxib had reduced microvessel density compared with rofecoxib, the nonselective COX inhibitors, and control animals. CONCLUSIONS: Selective COX-2 inhibitors, in particular celecoxib, provide durable inhibition of intra-abdominal adhesions through an antiangiogenic mechanism.

Animals↗
PubMed2005

Erythrocyte adhesion is modified by alterations in cellular tonicity and volume.

We tested the hypothesis that dehydration-induced alterations in red blood cell (RBC) membrane organisation or composition contribute to sickle cell adhesion in sickle cell disease (SCD). To examine the role of RBC hydration in adhesion to the subendothelial matrix protein thrombospondin-1 (TSP), normal and sickle RBCs were incubated in buffers of varying tonicity and tested for adhesion to immobilised TSP under flow conditions. Sickle RBCs exhibited a decrease in TSP binding with increasing cell hydration (P<0.005), suggesting that cellular dehydration may contribute to TSP adhesion. Consistent with this hypothesis, normal RBCs showed an increase in TSP adhesion with increasing dehydration (P<0.01). Furthermore, increased TSP adhesion of normal RBCs could also be induced by isotonic dehydration using nystatin-sucrose buffers. Finally, TSP adhesion of both sickle RBCs and dehydrated normal RBCs was inhibited by the anionic polysaccharides, chondroitin sulphate A and high molecular weight dextran sulphate, but not by competitors of CD47-, band 3-, or RBC phosphatidylserine-mediated adhesion. More importantly, we found increased adhesion of nystatin-sucrose dehydrated normal mouse RBCs to kidney capillaries following re-infusion in vivo. In summary, these findings demonstrate that changes in hydration can significantly impact adhesion, causing normal erythrocytes to display adhesive properties similar to those of sickle cells and vice versa.

Adolescent↗
PubMedDate not supplied

Evaluation of a sheep laparoscopic uterine trauma model and repeat laparoscopy for evaluation of adhesion formation and prevention with sodium carboxymethylcellulose.

OBJECTIVE: To evaluate topical application of 1% sodium carboxymethyl cellulose (SCMC) for prevention of postoperative adhesions in a laparoscopic model of uterine trauma in sheep. STUDY DESIGN: Experimental study. ANIMALS: Fourteen non-pregnant ewes. METHODS: Ewes were randomly assigned to 1 of 2 groups: control (saline solution) or 1% SCMC treatment. By left flank laparoscopy, traumatic forceps were used to create serosal trauma (1.5 x 5 cm) and hemorrhage on the left uterine horn. Either 30 mL saline solution or 30 mL 1% SCMC was applied topically to the traumatized uterine horn. Adhesion formation was evaluated by repeat laparoscopy at days 14 and 21. Sheep were euthanatized on day 28 for necropsy evaluation of adhesions. RESULTS: Five control sheep had adhesions of the uterine horn by day 14, but only 4 had adhesions at day 21, and 2 at day 28. Adhesions did not occur in SCMC-treated sheep. No adhesions occurred elsewhere in the abdomen. CONCLUSIONS: Laparoscopically created uterine trauma is an effective method for induction of uterine adhesions, and laparoscopy is an excellent method for serial evaluation of adhesion formation. SCMC (1%) was effective at preventing adhesion formation in sheep and no inflammatory response was noted. CLINICAL RELEVANCE: SCMC (1%) should be considered for prevention of adhesions in abdominal surgery in sheep.

Animals↗
PubMed2001

Adhesion of bifidobacteria to granular starch and its implications in probiotic technologies.

Adhesion of 19 Bifidobacterium strains to native maize, potato, oat, and barley starch granules was examined to investigate links between adhesion and substrate utilization and to determine if adhesion to starch could be exploited in probiotic food technologies. Starch adhesion was not characteristic of all the bifidobacteria tested. Adherent bacteria bound similarly to the different types of starch, and the binding capacity of the starch (number of bacteria per gram) correlated to the surface area of the granules. Highly adherent strains were able to hydrolyze the granular starches, but not all amylolytic strains were adherent, indicating that starch adhesion is not a prerequisite for efficient substrate utilization for all bifidobacteria. Adhesion was mediated by a cell surface protein(s). For the model organisms tested (Bifidobacterium adolescentis VTT E-001561 and Bifidobacterium pseudolongum ATCC 25526), adhesion appeared to be specific for alpha-1,4-linked glucose sugars, since adhesion was inhibited by maltose, maltodextrin, amylose, and soluble starch but not by trehalose, cellobiose, or lactose. In an in vitro gastric model, adhesion was inhibited both by the action of protease and at pH values of < or =3. Adhesion was not affected by bile, but the binding capacity of the starch was reduced by exposure to pancreatin. It may be possible to exploit adhesion of probiotic bifidobacteria to starch granules in microencapsulation technology and for synbiotic food applications.

Bacterial Adhesion↗
PubMed1993

Effects of multiplicity of infection, bacterial protein synthesis, and growth phase on adhesion to and invasion of human cell lines by Salmonella typhimurium.

Monolayers of intestine 407 (Int-407) cells were infected with the virulent Salmonella typhimurium strain C52, and the adhesion to and invasion of these cells were studied. The effects of the multiplicity of infection and growth phase of the bacteria (logarithmic versus stationary) on the interaction with eukaryotic cells were investigated. In contrast to other reports, we found no differences in the adhesive and invasive capacities of bacteria derived from logarithmic- or stationary-phase cultures. Invasion by S. typhimurium required bacterial protein synthesis and live Int-407 cells. Bacteria adhered equally well to dead or live Int-407 cells, which indicates that adhesion does not require metabolically active cells. Adhesion of S. typhimurium followed saturation kinetics, with a maximum of 10 adhesive bacteria per cell. This indicates that there is a limited number of bacterial adhesion sites (receptors) available on the surface of the host cell. Killed and live bacteria adhered equally well and competed with each other for cellular adhesion sites. This and adhesion experiments performed in the presence of chloramphenicol showed that bacterial protein synthesis is not required for adhesion. The general validity of the results obtained with S. typhimurium C52 was confirmed by comparing the invasion and adhesion data with those of the frequently used SL1344 and SR11 strains. In addition, we assayed the adhesion and invasion of S. typhimurium C52, SL1344, and SR11 and 27 S. typhimurium field isolates with Int-407, HeLa, and HEp-2 cells.

Bacterial Adhesion↗
PubMed1995

Quantitative differences in adhesiveness of type 1 fimbriated Escherichia coli due to structural differences in fimH genes.

Type 1 fimbriae are heteropolymeric surface organelles responsible for the D-mannose-sensitive (MS) adhesion of Escherichia coli. We recently reported that variation of receptor specificity of type 1 fimbriae can result solely from minor alterations in the structure of the gene for the FimH adhesin subunit. To further study the relationship between allelic variation of the fimH gene and adhesive properties of type 1 fimbriae, the fimH genes from five additional strains were cloned and used to complement the FimH deletion in E. coli KB18. When the parental and recombinant strains were tested for adhesion to immobilized mannan, a wide quantitative range in the ability of bacteria to adhere was noted. The differences in adhesion do not appear to be due to differences in the levels of fimbriation or relative levels of incorporation of FimH, because these parameters were similar in low-adhesion and high-adhesion strains. The nucleotide sequence for each of the fimH genes was determined. Analysis of deduced FimH sequences allowed identification of two sequence homology groups, based on the presence of Asn-70 and Ser-78 or Ser-70 and Asn-78 residues. The consensus sequences for each group conferred very low adhesion activity, and this low-adhesion phenotype predominated among a group of 43 fecal isolates. Strains isolated from a different host niche, the urinary tract, expressed type 1 fimbriae that conferred an increased level of adhesion. The results presented here strongly suggest that the quantitative variations in MS adhesion are due primarily to structural differences in the FimH adhesin. The observed differences in MS adhesion among populations of E. coli isolated from different host niches call attention to the possibility that phenotypic variants of FimH may play a functional role in populations dynamics.

Adhesins, Bacterial↗
PubMed1993

Involvement of membrane-bound viral glycoproteins in adhesion of pseudorabies virus-infected cells.

Cell-associated spread of pseudorabies virus (PrV) plays an important role in the pathogenesis of the disease. Besides the already known direct cell-to-cell spread of the virus in monolayers, adhesion and subsequent fusion of suspended PrV infected cells to monolayers of uninfected cells are thought to occur. To study the adhesion of PrV-infected cells, an in vitro model was developed in SK-6 cells. Specific adhesion of PrV-infected cells to an uninfected monolayer started 5 h after infection of the cells and reached a maximum 6 h later. A correlation was found between the surface expression of PrV glycoproteins on the infected cells and the adhesion of these cells. PrV hyperimmune serum completely inhibited binding of the infected cells. To investigate which PrV envelope glycoproteins were responsible for the cell adhesion, the infected cells were incubated with antisera against glycoproteins gII, gIII, and gp50. Antiserum against either gII or gIII inhibited cell adhesion, and antisera against gII and gIII together had a cooperative effect. Antiserum against gp50 had no effect on binding when used alone but enhanced the inhibition induced by gII and gIII antisera. Heparin and neomycin inhibited adhesion, showing that the receptor for adhesion was a heparinlike substance. SK-6 cells infected with a gIII deletion mutant of PrV exhibited a much lower adhesion. This binding was heparin and neomycin independent and was not blocked by anti-gII serum. Nevertheless, it was completely inhibited with PrV hyperimmune serum and with anti-gp50 serum. This finding demonstrates that the ligand for adhesion of gIII(-)-infected cells is glycoprotein gp50. These results strongly suggest that the mechanism for adhesion of a PrV-infected cell to an uninfected monolayer is similar to the mechanism of adsorption and penetration of a PrV virion to a host cell.

Animals↗
PubMed2004

Histamine selectively interrupts VE-cadherin adhesion independently of capacitive calcium entry.

Histamine is an important agent of innate immunity, transiently increasing the flux of immune-competent molecules from the vascular space to the tissues and then allowing rapid restoration of the integrity of the endothelial barrier. In previous work we found that histamine alters the endothelial barrier by disrupting cell-cell adhesion and identified VE-cadherin as an essential participant in this process. The previous work did not determine whether histamine directly interrupted VE-cadherin adhesion, whether the effects of histamine were selective for cadherin adhesion, or whether capacitive calcium flux across the cell membrane was necessary for the effects of histamine on cell-cell adhesion. In the current work we found that histamine directly interrupts adhesion of L cells expressing the type 1 histamine (H1) receptor and VE-cadherin to a VE-cadherin-Fc fusion protein. In contrast, integrin-mediated adhesion to fibronectin of the same L cells expressing the H1 receptor was not affected by histamine, demonstrating that the effects of histamine are selective for cadherin adhesion. Some of the effects of many edemagenic agonists on endothelium are dependent on the capacitive flux of calcium across the endothelial cell membrane. Blocking capacitive calcium flux with LaCl3 did not prevent histamine from interrupting VE-cadherin adhesion of transfected L cells, nor did it prevent histamine from interrupting cell-cell adhesion of human umbilical vein endothelial cells. These data support the contentions that histamine directly and selectively interrupts cadherin adhesion and this effect on cadherin adhesion is independent of capacitive calcium flux.

Animals↗
PubMed2001

Characterization of alpha 5-integrin-dependent mast cell adhesion following Fc epsilon RI aggregation.

BACKGROUND: Integrin receptors are engaged in the upregulation of mast cell adhesion to extracellular matrix components upon stimulation with cytokines and antigen. Fibronectin receptor containing the alpha 5-integrin subunit is critical for mast cell interaction with the extracellular matrix protein fibronectin (FN). METHODS: The murine MCP5/L mast cell line was employed to investigate the process of Fc epsilon RI-mediated mast cell adhesion to FN. RT-PCR and cytofluorimetric analysis were used to assess the expression of alpha 5 integrin in MCP5/L mast cells. Radiolabelled mast cells were sensitized with monoclonal IgE and used in adhesion assays. Anti-alpha 5-integrin antibody (Ab), monovalent hapten and metabolic inhibitors were used to characterize antigen-mediated mast cell adhesion to FN. RESULTS: Addition of antigen to IgE-sensitized cells resulted in transient upregulation of mast cell adhesion to FN with a maximum adhesion following 30 min of incubation. Mast cell adhesion was inhibited with anti-alpha 5-integrin monoclonal antibodies blocking FN receptor or with excess monovalent hapten preventing antigen-mediated IgE cross-linking. The presence of the protein kinase C (PKC) inhibitor staurosporine also inhibited mast cell adhesion in a dose-dependent fashion. The process of Fc epsilon RI-mediated upregulation of mast cell adhesion to FN was not associated with an increase in surface expression of mast cell FN receptors. CONCLUSION: The major FN receptor on MCP5/L mast cell surface, an integrin containing the alpha 5 subunit mediates a transient change in mast cell adhesiveness following IgE cross-linking. Fc epsilon RI-derived signals engage PKC and upregulate mast cell adhesion in a process which might involve changes in integrin avidity rather than integrin expression.

Animals↗
PubMed1996

Adhesion of blood platelets is inhibited by VCL, a recombinant fragment (leucine504 to lysine728) of von Willebrand factor.

VCL, fragment Leu504 to Lys728 of von Willebrand factor (vWF) expressed in Escherichia coli, contains the glycoprotein (GP) Ib-binding domain of vWF. This fragment inhibited ristocetin-induced platelet aggregation with an IC50 of 0.2 mumol/L and botrocetin-induced platelet aggregation with an IC50 of 0.08 mumol/L. We studied the antiadhesive profile of VCL by adding it to blood that was circulated over various adhesive surfaces. VCL inhibited adhesion to endothelial cell matrix, which served as a model of the vessel wall. Maximal inhibition at a high shear rate of 1600 s-1 was stronger (60%) than at a low shear rate of 300 s-1 (40%). Half maximal inhibition was found to be 1.5 mumol/L at both shear rates. The role of various adhesive molecules was investigated in more detail by coating glass coverslips with collagen type I, laminin, fibronectin, or vWF. Fibrinogen was studied as well. Platelet adhesion to laminin and vWF was not inhibited by VCL. Adhesion to collagen, fibronectin, and fibrinogen was particularly inhibited at a high shear rate. VCL coated to a coverslip caused a concentration-dependent adhesion that was blocked by antibodies against GPIb, which block interaction with vWF. Binding studies showed a nonsaturable ristocetin binding of VCL to platelets that was blocked by vWF or inhibitory antibodies against GPIb. Binding to collagen was weak, and VCL did not inhibit binding of vWF at a 5000-fold excess. From these data, we conclude that VCL inhibits adhesion in all cases in which adhesion is vWF dependent by competing for vWF binding to activated GPIb. The lack of inhibition of adhesion to vWF as a single molecule may be explained by assuming that this adhesion is determined by interaction of nonactivated GPIb with vWF that has been changed in conformation by adsorption. Studies investigating thrombus formation on the connective tissue of an atherosclerotic plaque in a human coronary artery showed that VCL was able to partially prevent this thrombus formation. VCL may be of value in preventing adhesion and thrombus formation under conditions in which these processes are dependent on vWF.

Animals↗
PubMed1996

Platelet adhesion to multimeric and dimeric von Willebrand factor and to collagen type III preincubated with von Willebrand factor.

As part of a systematic study of platelet interaction with adhesive proteins under flow conditions, we studied platelet adhesion to multimeric and dimeric von Willebrand factor (vWF) coated to glass. vWF-dependent adhesion to collagen type III was studied for comparison. Adhesion to glass-coated vWF and vWF-mediated adhesion to collagen type III were in many respects similar. Both showed no decrease at increasing shear rates and a decline to 50% of maximum with a low-molecular-weight multimeric fraction. Adhesion to glass-coated vWF was partially inhibited by heparin and completely inhibited by prostaglandin I(2) and anti-glycoprotein (GP) Ib and anti-GPIIb-IIIa antibodies. vWF-dependent adhesion to collagen was not inhibited by heparin, was partially inhibited by anti-GPIIb-IIIa, and was completely inhibited by prostaglandin I(2) and anti-GPIb. Recombinant dimeric vWF was made by deletion of the propeptide and expression in Chinese hamster ovary cells. Adhesion was 50% of that with plasma vWF, and larger concentrations of dimeric vWF were required. Adhesion to dimeric vWF was optimal at 1500 s(-1), with a gradual decrease at higher shear rates. We conclude that adhesion to collagen type III is strongly but not completely determined by the adhesive properties of vWF.

Animals↗
PubMed1997

Adhesiveness of mononuclear cells in hypercholesterolemic humans is normalized by dietary L-arginine.

Hypercholesterolemia reduces vascular nitric oxide (NO) activity. This dysfunction may promote endothelial monocyte interaction, as NO is a potent inhibitor of cell adhesion. We have previously shown that in hypercholesterolemic (HC) rabbits, chronic oral supplementation of L-arginine (Arg) restores NO activity and inhibits monocyte-endothelial cell interaction, in association with a reduction in atherogenesis. We hypothesized that enhancement of endothelial NO activity in HC humans would reduce monocyte adhesiveness. We used a functional binding assay to assess the adhesiveness of human mononuclear cells (MNCs) ex vivo to determine the effects of hypercholesterolemia and L-arginine administration. MNCs from HC subjects adhered in greater numbers (50% more cells per high-power field; P < .0001) than cells derived from normocholesterolemic (NC) subjects. To determine whether enhancement of endogenous NO activity could inhibit mononuclear cell adhesiveness, in a double-blinded placebo-controlled study, oral arginine HCl (8.4 g/d) was administered to HC subjects. Over a course of 2 weeks, this treatment abolished the increased adhesiveness of HC MNCs (160 +/- 11% versus 104 +/- 5%; before and after 2 weeks of Arg treatment; results expressed as a percentage of the binding values obtained using cells derived from paired NC individuals). By contrast, MNC adhesion remained significantly elevated in placebo-treated HC subjects. To examine whether endothelium-derived NO could act as a paracrine modulator of monocyte behavior, monocytes were exposed to NO donors or cocultered in the presence of endothelial cells exposed to antagonists of NO synthase in the presence or absence of L-arginine. NO donors inhibited monocyte adhesiveness. Furthermore, the adhesiveness of monocytes cocultured with endothelial cells was increased by antagonists of NO synthase; this effect was reversed by L-arginine. This study shows that the adhesiveness of human MNCs is increased by hypercholesterolemia. The increase in adhesiveness was reversed in vivo by administration of the NO precursor L-arginine. NO donors or endothelium-derived NO inhibits the adhesiveness of monocytes in vitro, supporting the hypothesis that the effects of L-arginine are mediated by NO.

Adult↗
PubMed1998

Urokinase receptor-dependent upregulation of smooth muscle cell adhesion to vitronectin by urokinase.

The plasminogen activator system has been implicated in the modulation of the response to vascular injury. Although urokinase-type plasminogen activator (uPA) and its receptor (uPAR) may enhance matrix degradation as well as migration and invasion by smooth muscle cells (SMCs), their roles in cell adhesion are uncertain. Therefore, we examined the ability of uPA and uPAR to modulate adhesion of cultured human vascular SMCs to various matrices. We demonstrated a dose-dependent stimulation of adhesion by single-chain uPA (scuPA) to vitronectin (maximum 1.55-fold [+/-0. 04-fold] increase, 10 nmol/L, P<0.002) but not to laminin, collagen I, or collagen IV. Baseline adhesion to vitronectin was completely inhibited by both EDTA and RGD peptide but was restored to >40% of control in the presence of scuPA (P=0.001 and 0.046, respectively). Adhesion to vitronectin was also significantly enhanced by the amino-terminal fragment of uPA (P=0.007) and two-chain, high-molecular-weight uPA (P<0.01) but not by the low-molecular-weight fragment of uPA, which lacks the receptor-binding domain. Aprotinin, a plasmin inhibitor, had no effect on baseline or scuPA-stimulated adhesion, suggesting a plasmin-independent process. Preincubation of scuPA with soluble uPAR inhibited scuPA stimulation of adhesion by 88+/-14% (P=0.01), as did pretreatment of SMCs with phosphatidylinositol-specific phospholipase C, which removes glycophosphatidylinositol-anchored proteins, including uPAR. Antibodies to both alphavbeta3 and alphavbeta5 integrin inhibited baseline adhesion but not scuPA stimulation. Finally, coating plates with scuPA alone enabled cell adhesion, which could be inhibited by both soluble uPAR and anti-uPAR antibodies. These data suggest that uPA stimulates adhesion of SMCs specifically to vitronectin and that it is mediated by an interaction with uPAR. Upregulation of both proteins after vascular injury may facilitate migration through stimulation of both matrix degradation and cell adhesion.

Adult↗