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PubMed2000

VLA-4 (alpha(4)beta(1)) engagement defines a novel activation pathway for beta(2) integrin-dependent leukocyte adhesion involving the urokinase receptor.

During acute inflammatory processes, beta(2) and beta(1) integrins sequentially mediate leukocyte recruitment into extravascular tissues. We studied the influence of VLA-4 (very late antigen-4) (alpha(4)beta(1)) engagement on beta(2) integrin activation-dependent cell-to-cell adhesion. Ligation of VLA-4 by the soluble chimera fusion product vascular cell adhesion molecule-1 (VCAM-1)-Fc or by 2 anti-CD29 (beta(1) chain) monoclonal antibodies (mAb) rapidly induced adhesion of myelomonocytic cells (HL60, U937) to human umbilical vein endothelial cells (HUVECs). Cell adhesion was mediated via beta(2) integrin (LFA-1 and Mac-1) activation: induced adhesion to HUVECs was inhibited by blocking mAbs anti-CD18 (70%-90%), anti-CD11a (50%-60%), or anti-CD11b (60%-70%). Adhesion to immobilized ligands of beta(2) integrins (intercellular adhesion molecule-1 [ICAM-1], fibrinogen, keyhole limpet hemocyanin) as well as to ICAM-1-transfected Chinese hamster ovary cells, but not to ligands of beta(1) integrins (VCAM-1, fibronectin, laminin, and collagen), was augmented. VCAM-1-Fc binding provoked the expression of the activation-dependent epitope CBRM1/5 of Mac-1 on leukocytes. Clustering of VLA-4 through dimeric VCAM-1-Fc was required for beta(2) integrin activation and induction of cell adhesion, whereas monovalent VCAM-1 or Fab fragments of anti-beta(1) integrin mAb were ineffective. Activation of beta(2) integrins by alpha(4)beta(1) integrin ligation (VCAM-1-Fc or anti-beta(1) mAb) required the presence of urokinase receptor (uPAR) on leukocytic cells, because the removal of uPAR from the cell surface by phosphatidylinositol-specific phospholipase C reduced cell adhesion to less than 40%. Adhesion was reconstituted when soluble recombinant uPAR was allowed to reassociate with the cells. Finally, VLA-4 engagement by VCAM-1-Fc or anti-beta(1) integrin mAb induced uPAR-dependent adhesion to immobilized vitronectin as well. These results elucidate a novel activation pathway of beta(2) integrin-dependent cell-to-cell adhesion that requires alpha(4)beta(1) integrin ligation for initiation and uPAR as activation transducer. (Blood. 2000;96:506-513)

Antibodies, Monoclonal↗
PubMed1994

An endothelial cell adhesion protein for monocytes recognized by monoclonal antibody IG9. Expression in vivo in inflamed human vessels and atherosclerotic human and Watanabe rabbit vessels.

BACKGROUND: Monocyte adhesion to the vascular endothelium, an important component of an inflammatory response, is one of the earliest detected events in the pathogenesis of atherosclerosis. We have identified a monocyte adhesion molecule, recognized by monoclonal antibody (mAb) IG9, on the cell surface of human umbilical vein endothelial cells (HUVEC) treated with tumor necrosis factor-alpha (TNF-alpha), interleukin-1, or lipopolysaccharide. Endothelial cell expression in vitro and in vivo of the protein recognized by mAb IG9 (IG9 protein) was further characterized. EXPERIMENTAL DESIGN: The kinetics of cytokine-induced IG9 protein expression on HUVEC were evaluated by enzyme-linked immunosorbent assay. TNF-alpha-treated HUVEC surface proteins, labeled with [125I]Na, were solubilized in NP-40 detergent and immunoprecipitated with mAb IG9 to determine the molecular weight of the IG9 protein. The functional role of the IG9 protein in monocyte binding in vitro to cytokine-activated endothelial cells was established in adhesion assays utilizing U937 cells (human promyelomonocytic cell line) and human peripheral blood monocytes. Minimally oxidized or modified low density lipoproteins (MM-LDL) have previously been shown to induce monocyte adhesion to endothelial cells for up to 48 hours after exposure. In order to characterize the adhesion molecule(s) contributing to this increase in monocyte binding, MM-LDL-treated HUVEC and human aortic endothelial cells were assayed for monocyte adhesion molecule expression by enzyme-linked immunosorbent assay. In addition, mAb IG9-mediated alterations in MM-LDL-induced monocyte binding were studied in endothelial-monocyte adhesion assays. To assess IG9 protein expression in vivo, formalin-fixed, paraffin-embedded sections of inflamed human tissues obtained from lung and healing myocardial infarctions, in addition to sections of human atherosclerotic coronary arteries, were analyzed by immunohistochemistry. Tissue sections from atherosclerotic Watanabe heritable hyperlipidemic rabbit aortas were also included in these studies. RESULTS: The IG9 protein, undetected on untreated HUVEC, was expressed on their cell surface within 3 hours of treatment with TNF-alpha, peaked at 4 to 9 hours, and persisted for up to 48 hours as determined by enzyme-linked immunosorbent assay. A similar kinetic profile was elicited by interleukin-1 and lipopolysaccharide, whereas interferon-gamma (IFN-gamma) had minimal effect on IG9 expression. The IG9 protein has a molecular weight of 105,000 as determined by immunoprecipitation studies with TNF-alpha-treated HUVEC protein lysates. mAb IG9 significantly inhibited the binding of U937 cells and human peripheral blood monocytes to TNF-alpha-treated HUVEC and had no effect on peripheral blood lymphocyte or granulocyte adhesion. Treatment of human aortic endothelial cells or HUVEC with MM-LDL for 24 hours induced IG9 protein expression 3-fold above background with no concomitant increase in binding of antibodies to intercellular adhesion molecule-1 (ICAM-1), E-selectin, or vascular cell adhesion molecule-1 (VCAM-1), endothelial cell adhesion proteins involved in monocyte binding. mAb IG9 F(ab')2 inhibited MM-LDL-induced monocyte adhesion to HAEC by 23%. Immunohistochemical analysis demonstrated that the endothelial cell lining of vessels in human lung and heart with evidence of inflammation characterized by an extensive mononuclear cell infiltration exhibited reactivity with mAb IG9, whereas vessels with no evidence of inflammation in the same sections as well as in sections from normal lung and heart were nonreactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Adhesion molecules in tumor metastasis.

It is now clear that adhesive interactions play a critical role in the process of metastatic tumor dissemination. Adhesion molecules act as both positive and negative modulators of the metastatic process. Molecules such as E-cadherin that promote homotypic tumor cell adhesion function to maintain intercellular contacts that confine cells to the primary tumor site and are negatively correlated with metastatic potential. Because tumor cells are rapidly eliminated from the circulation, those cells that can quickly arrest in the vasculature at a secondary site and pass through the vessel wall into the surrounding tissue will have a selective advantage toward establishing new metastatic colonies. The first step in this process is specific adhesion to venular endothelial cells in selected organs, a process mediated by tumor cell surface molecules such as Sialyl LewisX or the VLA-4 (alpha 4 beta 1) integrin that mediate binding to endothelial adhesion molecules such as the E-selectin or the vascular cell adhesion molecule, VCAM-1. Site-specific endothelial determinants such as the lung endothelial cell adhesion molecule, LuECAM, may additionally specify particular sites for preferential adhesion and subsequent site-specific metastasis of particular tumor types. After adherence to endothelial cells and subsequent endothelial retraction, metastatic tumor cells must adhere to elements of the subendothelial basement membrane such as laminin and types IV and V collagen, interactions frequently mediated by members of the beta 1 and beta 4 integrin families. Finally, metastatic tumor cell adhesion to connective tissue elements such as fibronectin, type I collagen and hyaluronan, mediated by molecules such as the beta 1 integrins and by the CD44 cell surface adhesion molecule, are required for movement of tumor cells into the subendothelial stroma and subsequent growth at these new sites. Thus, metastatic potential can be influenced both positively and negatively by a variety of cell surface adhesive molecules that act both independently and in concert to direct tumor cells to particular tissues, allowing them to arrest in those tissues, migrate across the vessel wall and grow at the secondary site. In the current review, I discuss the nature of the adhesion molecules that have been implicated in the metastatic process, emphasizing those molecules that have been shown to correlate with metastasis in clinical human tumors or that have been shown to influence metastatic potential in in vivo experimental assays.

Animals↗
PubMed1996

Platelet-dependent primary hemostasis promotes selectin- and integrin-mediated neutrophil adhesion to damaged endothelium under flow conditions.

Co-localization of blood platelets and granulocytes at sites of hemostasis and inflammation has triggered an intense interest in possible interactions between these cellular processes and induction of vessel wall injury. Leukocyte adhesion to endothelial cells decreases with increasing shear and is dependent on an initial rolling phase mediated by selectins. We hypothesized that flow-dependent platelet adhesion at an injured vessel wall will lead to P-selectin expression by platelets, thus mediating leukocyte co-localization. A perfusion chamber was used in which flowing whole blood induced platelet adhesion to a subendothelial matrix (ECM) of cultured human umbilical vein endothelial cells (HUVEC). We compared neutrophil (polymorphonuclear leukocyte [PMN]) interactions with HUVEC and their ECM with and without adhered platelets. PMNs adhered predominantly to ECM-adhered platelets and not to endothelial cells. ECM alone did not support PMN adhesion under flow conditions. PMN adhesion to unstimulated HUVEC was only substantial at low shear (up to 200 cells/mm2 at shear stress 80 mPa). In marked contrast, PMN adhesion to ECM-adhered platelets was dramatically increased, and adhesion was demonstrated at much higher shear stress (up to 640 mPa). Studies with specific antibodies showed that the platelet-dependent neutrophil adhesion was selectin-mediated. Inhibition of P-selectin caused a marked inhibition of adhesion at high shear stress, whereas the role of leukocyte L-selectin was less pronounced. beta2-Integrin-blocking antibodies inhibited static neutrophil adhesion. fMLP induced L-selectin shedding from leukocytes, resulting in decreased leukocyte adhesion. In conclusion, platelet-dependent hemostasis at the ECM appears to be a powerful intermediate in neutrophil-vessel wall interactions at shear stresses that normally do not allow neutrophil adhesion to intact endothelium.

Antibodies, Monoclonal↗
PubMed1998

Impaired integrin-mediated adhesion and signaling in fibroblasts expressing a dominant-negative mutant PTP1B.

To investigate the role of nonreceptor protein tyrosine phosphatase 1B (PTP1B) in beta1-integrin- mediated adhesion and signaling, we transfected mouse L cells with normal and catalytically inactive forms of the phosphatase. Parental cells and cells expressing the wild-type or mutant PTP1B were assayed for (a) adhesion, (b) spreading, (c) presence of focal adhesions and stress fibers, and (d) tyrosine phosphorylation. Parental cells and cells expressing wild-type PTP1B show similar morphology, are able to attach and spread on fibronectin, and form focal adhesions and stress fibers. In contrast, cells expressing the inactive PTP1B have a spindle-shaped morphology, reduced adhesion and spreading on fibronectin, and almost a complete absence of focal adhesions and stress fibers. Attachment to fibronectin induces tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin in parental cells and cells transfected with the wild-type PTP1B, while in cells transfected with the mutant PTP1B, such induction is not observed. Additionally, in cells expressing the mutant PTP1B, tyrosine phosphorylation of Src is enhanced and activity is reduced. Lysophosphatidic acid temporarily reverses the effects of the mutant PTP1B, suggesting the existence of a signaling pathway triggering focal adhesion assembly that bypasses the need for active PTP1B. PTP1B coimmunoprecipitates with beta1-integrin from nonionic detergent extracts and colocalizes with vinculin and the ends of actin stress fibers in focal adhesions. Our data suggest that PTP1B is a critical regulatory component of integrin signaling pathways, which is essential for adhesion, spreading, and formation of focal adhesions.

Animals↗
PubMed2000

The small GTPase, Rap1, mediates CD31-induced integrin adhesion.

Integrin-mediated leukocyte adhesion is a critical aspect of leukocyte function that is tightly regulated by diverse stimuli, including chemokines, antigen receptors, and adhesion receptors. How cellular signals from CD31 and other adhesion amplifiers are integrated with those from classical mitogenic stimuli to regulate leukocyte function remains poorly understood. Here, we show that the cytoplasmic tail of CD31, an important integrin adhesion amplifier, propagates signals that induce T cell adhesion via beta1 (VLA-4) and beta2 (LFA-1) integrins. We identify the small GTPase, Rap1, as a critical mediator of this effect. Importantly, CD31 selectively activated the small Ras-related GTPase, Rap1, but not Ras, R-Ras, or Rap2. An activated Rap1 mutant stimulated T lymphocyte adhesion to intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as did the Rap1 guanine nucleotide exchange factor C3G and a catalytically inactive mutant of RapGAP. Conversely, negative regulators of Rap1 signaling blocked CD31-dependent adhesion. These findings identify a novel important role for Rap1 in regulating ligand-induced cell adhesion and suggest that Rap1 may play a more general role in coordinating adhesion-dependent signals during leukocyte migration and extravasation. Our findings also suggest an alternative mechanism, distinct from interference with Ras-proximal signaling, by which Rap1 might mediate transformation reversion.

Antigens, CD↗
PubMed2005

Pathophysiological levels of the obesity related peptides resistin and ghrelin increase adhesion molecule expression on human vascular endothelial cells.

1. In the present study, we sought to determine whether physiological or pathophysiological concentrations of obesity related peptides influence the key early atherogenic events of monocyte adhesion to endothelial cells and adhesion molecule expression using primary human cells. 2. Human umbilical vein endothelial cells were grown to confluence and human monocytes were obtained by elutriation. Adhesion was assessed by automated cell counting and cell adhesion molecule expression (E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)) was assayed by ELISA. 3. Experimental conditions included untreated control, ghrelin (100, 150, 450 and 1350 pmol/L), resistin (15, 40 and 100 ng/mL) and combined leptin and insulin (combinations of 30 and 120 pmol/L insulin and 5, 50 and 500 ng/mL leptin). 4. Both resistin and ghrelin produced modest but significant increases in VCAM-1 expression (110 +/- 4 and 117 +/- 13% compared with controls, respectively; both P <or= 0.01). Ghrelin also increased ICAM-1 expression (119 +/- 17% of control; P <or= 0.01). 5. However, despite these increases in adhesion molecule expression, neither ghrelin nor resistin altered monocyte adhesion values. 6. Neither leptin nor insulin altered monocyte adhesion to endothelial cells or cell adhesion molecule expression. 7. Pathophysiologically relevant concentrations of ghrelin and resistin, within the range of concentrations exhibited by patients with anorexia nervosa or the Prader-Willi syndrome and type 2 diabetes, respectively, increase endothelial cell adhesion molecule expression, possibly contributing to increased atherosclerosis risk in such subjects.

Cell Adhesion↗
PubMed2003

SETA/CIN85/Ruk and its binding partner AIP1 associate with diverse cytoskeletal elements, including FAKs, and modulate cell adhesion.

The adaptor protein SETA/CIN85/Ruk is involved in regulating diverse signal transduction pathways, including the internalization of tyrosine kinase receptors via the Cbl ubiquitin ligases, and attenuating PI3K activity by interaction with its regulatory subunit. Here we present evidence for a new aspect of SETA function, based on the initial observation that it co-localizes with actin in microfilaments and at focal adhesions, and with microtubules. Although there was no evidence for direct molecular interactions between SETA and cytoskeletal proteins, the SETA-interacting protein AIP1, which is a rat ortholog of the Xenopus src substrate Xp95, strongly interacted with structural proteins of the cytoskeleton, including actin and tubulins. Both SETA and AIP1 interacted with focal adhesion kinase (FAK) and proline rich tyrosine kinase 2 (PYK-2), and c-Cbl interacted with PYK-2. AIP1, which interacted more strongly than either SETA or c-Cbl, required an intact consensus tyrosine kinase phosphorylation sequence at Y319 to bind to focal adhesion kinases, which suggests that phosphorylation is an important mediator of this complex. SETA, which interacted as a dimer with focal adhesion kinases, promoted the interaction between PYK-2 and AIP1. Direct analysis of the impact of these proteins on cell adhesion, by use of an electrical cell-substrate impedance sensor (ECIS), showed that SETA promoted cell adhesion while AIP1 and c-Cbl reduced it. Furthermore, the ability of AIP1 and AIP1 mutants to decrease cell adhesion in ECIS analysis correlated with their presence in PYK-2 complexes, providing a direct link between AIP1-mediated molecular interactions and cellular behavior. Transfection of AIP1 also reduced the level of phosphorylation of endogenous PYK-2 and FAK, suggesting that this protein may directly regulate focal adhesion kinases, and thereby cell adhesion. These data are the first to implicate the adaptor protein SETA and its binding partner AIP1 as being involved with the cytoskeleton and in the regulation of cell adhesion, and suggest that they may be part of the focal adhesion kinase regulatory complex.

Actins↗
PubMed1998

Microinjection of protein tyrosine phosphatases into fibroblasts disrupts focal adhesions and stress fibers.

Microinjection and scrape-loading have been used to load cells in culture with soluble protein tyrosine phosphatases (PTPs). The introduction of protein tyrosine phosphatases into cells caused a rapid (within 5 minutes) decrease in tyrosine phosphorylation of major tyrosine phosphorylated substrates, including the focal adhesion kinase and paxillin. This decrease was detected both by blotting whole cell lysates with anti-phosphotyrosine antibodies and visualizing the phosphotyrosine in focal adhesions by immunofluorescence microscopy. After 30 minutes, many of the cells injected with tyrosine phosphatases revealed disruption of focal adhesions and stress fibers. To determine whether this disruption was due to the dephosphorylation of FAK and its substrates in focal adhesions, we have compared the effects of protein tyrosine phosphatase microinjection with the effects of displacing FAK from focal adhesions by microinjection of a dominant negative FAK construct. Although both procedures resulted in a marked decrease in the level of phosphotyrosine in focal adhesions, disruption of focal adhesions and stress fibers only occurred in cells loaded with exogenous protein tyrosine phosphatases. These results lead us to conclude that although tyrosine phosphorylation regulates focal adhesion and stress fiber stability, this does not involve FAK nor does it appear to involve tyrosine-phosphorylated proteins within focal adhesions. The critical tyrosine phosphorylation event is upstream of focal adhesions, a likely target being in the Rho pathway that regulates the formation of stress fibers and focal adhesions.

Animals↗
PubMed2001

The effects of surface chemistry and adsorbed proteins on monocyte/macrophage adhesion to chemically modified polystyrene surfaces.

Monocytes and macrophages play critical roles in inflammatory responses to implanted biomaterials. Monocyte adhesion may lead to macrophage activation and the foreign body response. We report that surface chemistry, preadsorbed proteins, and adhesion time all play important roles during monocyte adhesion in vitro. The surface chemistry of tissue culture polystyrene (TCPS), polystyrene, Primaria, and ultra low attachment (ULA) used for adhesion studies was characterized by electron spectroscopy for chemical analysis. Fibrinogen adsorption measured by (125)I-labeled fibrinogen was the lowest on ULA, higher on TCPS, and the highest on polystyrene or Primaria. Monocyte adhesion on protein preadsorbed surfaces for 2 h or 1 day was measured with a lactate-dehydrogenase method. Monocyte adhesion decreased over time. The ability of preadsorbed proteins to modulate monocyte adhesion was surface dependent. Adhesion was the lowest on ULA, higher and similar on TCPS or polystyrene, and the highest on Primaria. Monocyte adhesion on plasma or fibrinogen adsorbed surfaces correlated positively and linearly to the amount of adsorbed fibrinogen. Preadsorbed fibronectin, immunoglobulin G, plasma, or serum also promoted adhesion compared with albumin preadsorbed or uncoated surfaces. Overall, biomaterial surface chemistry, the type and amount of adsorbed proteins, and adhesion time all affected monocyte adhesion in vitro.

Adsorption↗
PubMed2000

Barrier agents for preventing adhesions after surgery for subfertility.

BACKGROUND: Pelvic adhesions can be the result of inflamation, endometriosis or surgical trauma. Prevention of postoperative adhesions (either new or reoccurance) has been postulated by using barriers to prevent two surfaces being in contact. When pelvic surgery is being undertaken strategies to reduce pelvic adhesions occurring may be undertaken and these include barrier agents which are placed between the pelvic structures. Two synthetic barriers with differential characteristics are commercially available: oxidised regenerated cellulose (Interceed) and polytetrafluoroethylene (PTFC) (GoreTex). OBJECTIVES: The objective of this review was to assess the effect of mechanical barriers (materials interposed between pelvic structures to prevent adherence of serosal surfaces) used during pelvic surgery in women of reproductive age on pregnancy rates, pelvic pain, or postoperative adhesion reformation. SEARCH STRATEGY: The Cochrane Menstrual Disorders and Subfertility Group specialised register of controlled clinical trials was undertaken. In addition, companies were contacted for unpublished trials. SELECTION CRITERIA: Randomised controlled trials or controlled clinical trials of barriers versus no treatment or other barriers in women undergoing fertility preserving pelvic surgery. DATA COLLECTION AND ANALYSIS: Reviewers assessed eligibility and trial quality. MAIN RESULTS: 15 randomised controlled trials were included. Five trials randomised patients while the remainder randomised pelvic organs. Laparoscopy was the primary surgical technique in six trials while the remaining trials were laparotomy. Indications for surgery included myomectomy (five trials), ovarian surgery (four trials), pelvic adhesions (six trials), endometriosis (two trials) and mixed (one trial). Thirteen trials assessed Interceed versus no treatment, two assessed Interceed versus Gore-Tex, one trial assessed Gore-Tex versus no treatment, and one trial assessed Seprafilm versus no treatment. No study reported pregnancy or reduction in pain as an outcome. The use of Interceed in women was associated with reduced incidence of pelvic adhesion formation, both new formation and re-formation following laparoscopic surgery and after laparotomy. Gore-Tex was more effective than no barrier or Interceed in preventing adhesion formation. There was limited evidence that Seprafilm was effective in preventing adhesion formation in women following myomectomy. REVIEWER'S CONCLUSIONS: The absorbable adhesion barrier Interceed reduces the incidence of adhesion formation, both new formation and re-formation, at laparoscopy and laparotomy, but there are insufficient data to support its use to improve pregnancy rates. Gore-Tex may be superior to Interceed in preventing adhesion formation but its usefulness is limited by the need for suturing and later removal. There was no evidence of effectiveness of Seprafilm in preventing adhesion formation.

Cellulose, Oxidized↗
PubMed1996

Identification of a novel surface molecule, RM3/1, that contributes to the adhesion of glucocorticoid-induced human monocytes to endothelial cells.

The functions of different populations of peripheral blood monocytes in the course of an inflammatory reaction are presently not fully understood. In particular, the mechanisms for their specific recruitment to an inflammatory site are not yet known. We investigated a dexamethasone (Dex)-inducible monocyte subtype and its adhesion to either unstimulated or lipopolysaccharide (LPS)- or interferon (IFN)-gamma-stimulated human umbilical vein endothelial cells (HUVEC). The Dex-induced monocytes were characterized by the expression of the surface glycoprotein RM3/1. It was found that pretreatment of monocytes with Dex increased their adhesion to unstimulated and stimulated HUVEC. This increase in adhesion was paralleled by the expression of the RM3/1 surface molecule. Treatment with cyclosporin A (CsA) caused a down-regulation of the RM3/1 density per cell by 67% and also decreased adhesion to HUVEC. In contrast, the expression of other adhesion molecules remained unaffected by Dex or CsA treatment. Treatment of Dex-induced monocytes with antibodies against RM3/1, CD11a, CD11b, CD11c, CD14 and CD18 resulted in suppression of adhesion to stimulated HUVEC by 46%, 18%, 17%, 12%, 25% and 15%, respectively. Antibodies to the known adhesion molecules on endothelial cells (vascular cell adhesion molecule-1, E-selectin) did not block adhesion of Dex-induced monocytes. However, the combination of antibodies to RM3/1 and CD14 inhibited adhesion to LPS-stimulated HUVEC by 74%. These effects were also seen on IFN-gamma-stimulated HUVEC, where adhesion of Dex-induced monocytes was blocked with antibodies to RM3/1 + CD14 by 63%. From this, it is concluded that the RM3/1-molecule is a novel surface molecule that contributes to the adhesion of cortisone-induced monocytes to LPS or cytokine-stimulated endothelial cells.

Antigens, CD↗
PubMed1994

Involvement of CD11b/CD18 in enhanced neutrophil adhesion by Fc gamma receptor stimulation.

Neutrophils showed a rapid and transient adhesion to immunoglobulin G (IgG)-coated plates compared with their adhesion to bovine serum albumin (BSA)-coated plates: the adhesion reached a peak after 15 min of incubation and then gradually returned to almost the basal state in 60 min. The addition of monomeric IgG or anti-Fc gamma RII monoclonal antibody (mAb) (IV.3) suppressed the increase in adhesion, whereas anti-Fc gamma RIII mAb (3G8) was hardly effective, indicating that the interaction of Fc gamma R, especially Fc gamma RII, with coated IgG is involved in the process. Adhesion was also blocked by cytochalasin B, suggesting that functional actin filament structures are crucial. Protein kinase inhibitors, erbstatin and genistein, inhibited the adhesion in a dose-dependent manner. The adhesion was inhibited by anti-CD11b (M1/70) and anti-CD18 (MHM23, TS1/18) mAbs. Moreover, neutrophils from a patient with complete leukocyte adhesion deficiency syndrome did not show increased adhesion to IgG-coated plates. The adhesion of neutrophils to fibrinogen- and BSA-coated plates was also increased when Fc gamma R was stimulated in the fluid phase with soluble aggregated IgG, which was also inhibited by anti-CD11b mAb. Stimulation of neutrophil Fc gamma R with soluble aggregated IgG enhanced the expression of CD11b in concert with the enhanced adhesion. These data collectively suggest that stimulation via Fc gamma R evokes a tyrosine kinase-dependent and actin filament-dependent intracellular signal that enhances the specific and nonspecific adhesive activity of neutrophils, presumably through the activation of CD11b/CD18.

Adult↗
PubMed1996

Platelet-activating factor is involved in the regulation of pathological leukocyte adhesion after liver transplantation.

An increased leukocyte adhesion and loss of integrity of endothelial cells is known to be a critical step in the reperfusion period after cold ischemia of transplanted livers. Platelet-activating factor (PAF) is discussed as one of the inflammatory mediators involved in mediating reperfusion injury, e.g., by regulation of leukocyte adhesion. In this study we investigated the effect of a synthetic PAF receptor antagonist, WEB 2086 (Boehringer Ingelheim, FRG), on microcirculation and adhesion of leukocytes to sinusoidal endothelium after liver transplantation in the rat. Livers from SPRD rats (n = 6 per group) were stored for 5 hr in ice-cold UW solution and orthotopically transplanted using the cuff technique. In a randomized and blinded fashion WEB 2086 (1 mg/kg body wt) or placebo was given twice intravenously, at the beginning of the recipient operation and 1 min prior to reperfusion of the liver graft. After in vivo staining of leukocytes with acridine orange, microcirculation and leukocyte-endothelium interaction of transplanted livers and livers from sham-operated animals were investigated 90 min and 5 hr after surgery by means of intravital microscopy. After 90 min of reperfusion, temporary leukocyte adhesion in periportal regions was increased after liver transplantation (22.0 +/- 2.5%; mean +/- SEM) in contrast to the sham group (14.2 +/- 1.8%). Administration of WEB 2086 reduced temporary leukocyte adhesion significantly (11.5 +/- 2.5%; P < 0.05), whereas no significant differences were observed with respect to permanent leukocyte adhesion. Five hours after recipient operation, a significant increase of permanent leukocyte adhesion was observed after transplantation (21.0 +/- 2.6%; P < 0.05) compared to sham-operated animals (12.1 +/- 1.7%). Application of WEB 2086 diminished permanent leukocyte adhesion significantly (12.2 +/- 1.3%; P < 0.05), whereas no differences were noticed between the different groups with respect to temporary leukocyte adhesion at this time. The results indicate that reduction of temporary leukocyte adhesion in the early reperfusion period by administration of PAF receptor antagonist WEB 2086 was followed by a reduction of permanent leukocyte adhesion in the late reperfusion period, e.g., at 5 hr. Thus, it is concluded that PAF is one of the mediators which is involved in the regulation of leukocyte adhesion after liver transplantation.

Animals↗
PubMed1990

Tumor cell adhesion to frozen lymph node sections--a correlate of lymphatic metastasis in breast carcinoma models of human and rat origin.

The role of tumor cell adhesion in lymphatic metastasis of breast cancer was investigated in vitro using a rat mammary carcinoma model of four cell lines with different metastatic phenotypes, two human breast cancer cell lines, and cryostast sections of normal rat or human lymph nodes, respectively. A positive correlation was found between the adhesion levels obtained with three metastatic rat mammary cell lines (TMT-081 greater than MT-100M & TMT-50) and a non-metastatic line MT-W9B, the latter being 3-4 fold less adhesive to the lymph node sections than the metastatic tumors. This selective adhesion was specific, as it was not found with cryostat sections of rat liver and brain. Enzyme assays indicated that cell surface glycoproteins bearing terminal beta-galactoside residues were involved in the adhesion of the rat tumors. Adhesion of the human breast carcinoma cells Hs578T to sections of human lymph nodes was significantly higher than that of the normal breast epithelial cell line Hs578Bst, and comparable to adhesion of a second breast carcinoma line, MCF-7. Moreover, Hs578T cells isolated from regional lymph nodes of tumor-bearing nude mice were significantly more adhesive to human lymph node sections than the parental line. Adhesion of both human and rat tumors could be partially blocked by the addition of the synthetic peptide GRGDSPK and by antibodies directed to the beta 1 chain of integrin, suggesting that an integrin receptor may played a role in the adhesion. The results suggest that tumor cell adhesion to cryostat sections of lymph nodes is a correlate of the malignant phenotype in mammary tumors of diverse origins, and could be used to delineate the adhesion factors mediating lymphatic metastasis.

Animals↗
PubMed2001

Postoperative adhesions: ten-year follow-up of 12,584 patients undergoing lower abdominal surgery.

PURPOSE: Postoperative adhesions are a significant problem after colorectal surgery. However, the basic epidemiology and clinical burden are unknown. The Surgical and Clinical Adhesions Research Study has investigated the scale of the problem in a population of 5 million. METHODS: Validated data from the Scottish National Health Service Medical Record Linkage Database were used to define a cohort of 12,584 patients undergoing open lower abdominal surgery in 1986. Readmissions for potential adhesion-related disease in the subsequent ten years were analyzed. The methodology was conservative in interpreting adhesion-related disease. RESULTS: In the study cohort 32.6 percent of patients were readmitted a mean of 2.2 times in the subsequent ten years for a potential adhesion-related problem. Although 25.4 percent of readmissions were in the first postoperative year, they continued steadily throughout the study period. After open lower abdominal surgery 7.3 percent (643) of readmissions (8,861) were directly related to adhesions. This varied according to operation site: colon (7.1 percent), rectum (8.8 percent), and small intestine (7.6 percent). The readmission rate was assessed to provide an indicator of relative risk of adhesion-related problems after initial surgery. The overall average rate of readmissions was 70.4 per 100 initial operations, with 5.1 directly related to adhesions. This rose to 116.4 and 116.5, respectively, after colonic or rectal surgery-with 8.2 and 10.3 directly related to adhesions. CONCLUSIONS: There is a high relative risk of adhesion-related problems after open lower abdominal surgery and a correspondingly high workload associated with these readmissions. This is influenced by the initial site of surgery, colon and rectum having both the greatest impact on workload and highest relative risk of directly adhesion-related problems. The study provides sound justification for improved adhesion prevention strategies.

Abdomen↗
PubMed2002

Expression of connective tissue growth factor in intra-abdominal adhesions.

PURPOSE: Connective tissue growth factor stimulates fibroblast proliferation and extracellular matrix deposition in many fibrotic disorders. The aim of our study was to determine the expression pattern of connective tissue growth factor in postoperative intra-abdominal adhesions. METHODS: Adhesions were created in 46 Sprague-Dawley rats by complete dissection and resuturing of a peritoneal patch 2 cm in diameter, lateral from the midline incision. Animals were killed at postoperative Days 3, 6, 9, 12, 15, 18, and 21 and the adhesions scored on a scale of 0 to 5. Tissue samples from adhesion areas and from uninvolved peritoneum were evaluated by Northern and Western blotting for temporal connective tissue growth factor mRNA and protein expression, respectively. Immunohistochemical analysis was performed for connective tissue growth factor localization. RESULTS: Adhesions formed in all animals after surgery and were confined to the peritoneal patches. Adhesion formation increased across time, with significant correlation between adhesion scores and postoperative days (r = 0.329, P = 0.026). Connective tissue growth factor mRNA concentrations were significantly elevated in adhesion tissue throughout the three-week period when compared with normal peritoneum (P = 0.012); peak levels occurred between Days 6 and 15. Western blots demonstrated connective tissue growth factor protein expression in adhesions from Days 6 to 21, in contrast to negligible bands in normal peritoneum. Fibroblasts within the adhesive tissue, but not in uninjured peritoneum, stained positive for connective tissue growth factor by immunohistochemistry. CONCLUSIONS: We have demonstrated a specific temporal and spatial expression pattern for connective tissue growth factor in intra-abdominal adhesions during a three-week postoperative time course. According to what is known about the functional role of connective tissue growth factor in fibrogenesis, our findings warrant further investigations addressing a causal relationship between this growth factor and fibrous adhesion formation.

Animals↗
PubMed1984

Ibuprofen inhibition of postsurgical adhesion formation: a time and dose response biochemical evaluation in rabbits.

Recently, a reduction in postoperative adhesion formation in rabbits which received high-dose ibuprofen (280 mg/kg/day) treatment in the perioperative interval was reported. Because these results could have resulted from a nonspecific effect of ibuprofen, the effects of ibuprofen on peritoneal injury in a time and dose response fashion was evaluated. Seventy rabbits were assigned to seven groups. All rabbits received a dose of ibuprofen 1 hr prior to surgery. The time of the second dose was either 8 or 12 hr after the surgical procedure; 8 hr for groups A, C, and E; 12 hr for groups B, D, and F (A, B: 70 mg/kg; C, D: 35 mg/kg; E, F: 17.5 mg/kg, respectively). Thereafter, rabbits received further dosing every 6 hr to complete a total 10-dose regimen. Group G served as a nontreatment control. Surgical injury was induced by either abrasion or ischemia of the right uterine horn. Immediately after closing the incision, 10 muCi of 14C-labeled glucosamine and 10 muCi of 14C-labeled proline were injected into each rabbit. All rabbits underwent a second laparotomy on the fifth postoperative day for evaluation of adhesion formation. Uterine tissue adjacent to the site of uterine healing was excised for determination of glycosaminoglycan and collagen concentration. In the nontreatment control group G, 5 of the 10 rabbits had severe grade 2 adhesions at the time of second laparotomy, 3 had grade 1 filmy adhesions, and 2 had no adhesions. This is in marked contrast (P less than 0.025) to the group that received ibuprofen at 70 mg/kg/day with the first postoperative dose 8 hr after surgery (group A). In this group, no rabbits had severe grade 2 adhesions, 3 rabbits had filmy grade 1 adhesions, and 7 rabbits were free of pelvic adhesions. A gradual tendency towards more adhesions and more severe adhesions was apparent in groups B-F as the dose of ibuprofen was decreased and the time of first postoperative injection was prolonged. The recovery of 14C-labeled glucosamine from the glycosaminoglycan extraction demonstrated a positive correlation between the cpm recovered and the severity of adhesions formed. Groups A and B had, overall, the lowest ratios of glucosamine (1.47 +/- 0.08 and 1.56 +/- 0.09, respectively) which were statistically different from the nontreatment control group G (1.76 +/- 0.11, P less than 0.05). There was also a positive correlation between the formation of severe adhesions and the ratio of 14C-labeled proline recovered by collagen extraction.(ABSTRACT TRUNCATED AT 400 WORDS)

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