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PubMed1992

Thrombin-induced expression of endothelial P-selectin and intercellular adhesion molecule-1: a mechanism for stabilizing neutrophil adhesion.

Thrombin-induced expression of endothelial adhesivity toward neutrophils (PMN) was studied using human umbilical vein endothelial cells (HUVEC). HUVEC were challenged with human alpha-thrombin for varying durations up to 120 min, after which the cells were fixed with 1% paraformaldehyde and 51Cr-labeled human PMN were added to determine PMN adhesion. Endothelial adhesivity increased within 15 min after alpha-thrombin exposure, and the response persisted up to 120 min. Expression of endothelial adhesion proteins, P-selectin (GMP-140, PADGEM, CD62), and intercellular adhesion molecule-1 (ICAM-1; CD54) on the endothelial surface was quantitated by increase in the specific binding of anti-P-selectin mAb G1 and anti-ICAM-1 mAb RR1/1 labeled with 125I. P-selectin expression was maximal at 5-15 min alpha-thrombin exposure and decayed to basal levels within 90 min. In contrast, ICAM-1 activity increased at 30 min and remained elevated for 120 min after alpha-thrombin challenge. The initial endothelial adhesivity was dependent on P-selectin expression since PMN adhesion occurring within the first 30 min after alpha-thrombin challenge was inhibited by mAb G1. The later prolonged PMN adhesion was ICAM-1 dependent since this response was inhibited by mAb RR1/1 and to the same degree by the anti-CD18 mAb IB4. Anti-ELAM-1 mAb BB11 had no effect on adhesion of PMN to the alpha-thrombin-challenged cells. The initial P-selectin expression and PMN adhesion responses were reproduced by the 14-amino peptide (SFLLRNPNDKYEPF) (thrombin-receptor activity peptide; TRP-14) which comprised the NH2 terminus created by thrombin's proteolytic action on its receptors. However, TRP-14-induced PMN adhesion was transient, and TRP-14 did not cause ICAM-1 expression. The ICAM-1-dependent PMN adhesion mediated by alpha-thrombin was protein synthesis independent since ICAM-1 expression and PMN adhesion were not inhibited by cycloheximide pretreatment of HUVEC. Moreover, Northern blot analysis indicated absence of ICAM-1 mRNA signal up to 180 min after alpha-thrombin challenge. In conclusion, thrombin-induced endothelial adhesivity involves early- and late-phase responses. The initial reversible PMN adhesion is mediated by rapid P-selectin expression via TRP-14 generation. Thrombin-induced PMN adhesion is stabilized by a protein synthesis-independent upregulation of the constitutive ICAM-1 activity which enables the interaction of ICAM-1 with the CD18 beta 2 integrin on PMN.

Amino Acid Sequence↗
PubMed2005

Adhesion formation after laparoscopic excision of endometriosis and lysis of adhesions.

OBJECTIVE: To evaluate adhesion reformation after laparoscopic excision of endometriosis and adhesiolysis in women with chronic pelvic pain. DESIGN: Prospective clinical trial. SETTING: University hospital. PATIENT(S): Thirty-eight women with endometriosis and chronic pelvic pain. INTERVENTION(S): A primary and second-look laparoscopy with adhesiolysis and excision of endometriotic lesions with a neodymium-yttrium argon garnet surgical laser technologies (SLT) contact laser. MAIN OUTCOME MEASURE(S): Adhesion formation and character (thin, thin and thick, or thick). Location of adhesions at a first laparoscopy was compared with de novo or reformation of adhesions and the location of adhesions at a second surgery. RESULT(S): Adhesions or adhesions combined with endometriotic lesions were significantly more likely to reform at second surgery compared with sites having only an endometriosis lesion. Thick adhesions were associated with a significantly increased likelihood of an adhesion reforming, compared with thin adhesions or thin and thick adhesions. Lesions or adhesions involving the ovary were more likely to be associated with adhesions at a subsequent surgery, compared with lesions in the adjacent ovarian fossa or fallopian tube. CONCLUSION(S): Most patients developed adhesions after radical surgical excision of endometriosis for pelvic pain. The high incidence of adhesion formation after surgery for endometriosis underscores the importance of optimizing surgical techniques to potentially reduce adhesion formation.

Adult↗
PubMed1998

The temporal efficacy of early second-look lysis of adhesions in reducing postoperative adhesions in a murine model.

OBJECTIVE: Our aim was to determine whether early second-look lysis of adhesions reduces postoperative adhesions. STUDY DESIGN: With the murine uterine horn model, early second-look lysis of adhesions was performed 5, 7, 14, and 21 days after an electrocautery injury. Sites with adhesions (between 36 and 46/time point) underwent lysis of adhesions. Fourteen days later, a reviewer blinded to the treatment assessed adhesion formation, including adhesions not present at early second-look lysis of adhesions (eg, de novo adhesions). RESULTS: The rate of adhesion formation was 49% of control sites, unchanged when the early second-look lysis of adhesions was performed at 5 (44.4%) and 7 (39.5%) days, reduced at 14 days (28.6%), and increased at 21 days (74%). The pattern of de novo adhesions was similar, 17.6% when the early second-look lysis of adhesions was performed at 5 days, 10% at 7 days, 0% at 14 days, and 28.6% at 21 days. The only histologic difference between the groups was neovascularity at day 21. CONCLUSIONS: Early second-look lysis of adhesions was effective in reducing postoperative adhesions only when performed at 14 days in this model, suggesting that the specific cellular events occurring at the time of the early second-look lysis of adhesions are critical to efficacy.

Animals↗
PubMedDate not supplied

Activation of endothelial cells in preeclampsia: increased neutrophil-endothelial adhesion correlates with up-regulation of adhesion molecule P-selectin in human umbilical vein endothelial cells isolated from preeclampsia.

OBJECTIVE: Increased endothelial activation has been suggested to be important in the pathophysiology for preeclampsia. Our objective was to examine whether in preeclampsia neutrophil adherence to endothelial cells is increased and whether endothelial cell-surface adhesion molecule expression is up-regulated. METHODS: Endothelial cells were isolated from normal (n = 10) and preeclamptic (n = 9) human umbilical veins (HUVECs). Neutrophils were isolated from normal, healthy, nonpregnant female volunteers. Freshly isolated neutrophils were labeled with 51Cr, and labeled neutrophils were coincubated with confluent normal and preeclamptic endothelial monolayers. Adhesion assays were then performed. To determine whether in preeclampsia endothelial cellular-surface adhesion molecules are responsible for increased neutrophil-endothelial adhesion, cellular adhesion molecule expression of P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), and E-selectin were examined by an enzyme-linked binding assay. Furthermore, adhesion assays were also performed on HUVECs pretreated with antibodies against P-selectin, ICAM-1, VCAM-1, and E-selectin. RESULTS: Neutrophil adhesion to the HUVECs from preeclamptic pregnancies was significantly increased compared with neutrophil adhesion to the HUVECs from normal pregnancies (P < .01). Expression of cellular-surface adhesion molecule of P-selectin was significantly higher (P < .01) and ICAM-1 was significantly lower (P < .05) in HUVECs isolated from preeclampsia than from normal controls, whereas there was no difference for VCAM-1 and E-selectin expression between HUVECs from normal and preeclamptic pregnancies. No differences were found for neutrophil-endothelial adhesion on normal HUVECs pretreated with anti-P-selectin, anti-ICAM-1, anti-VCAM-1, and anti-E-selectin compared with the untreated cells. However, pretreatment of preeclampsia HUVECs with anti-P-selectin, anti-ICAM-1, anti-VCAM-1, and anti-E-selectin completely or partially blocked the neutrophil-endothelial adhesion compared to the untreated cells. CONCLUSION: There is a significant increase in neutrophil adhesion to HUVECs that are isolated from preeclamptic pregnancies compared with normal controls. This increase appears to be a result of up-regulation of the cell-surface adhesion molecule P-selectin. Elevated P-selectin expression may play a significant role in neutrophil-endothelial hyperadhesiveness and contribute to vascular complications associated with preeclampsia.

Antibodies↗
PubMed1993

Two distinct adhesion systems are responsible for EDTA-sensitive adhesion in Dictyostelium discoideum.

Early in their developmental program, Dictyostelium discoideum exhibit EDTA-sensitive and EDTA-resistant adhesion. The molecules which mediate the adhesions have been called contact sites, with contact sites A mediating EDTA-resistant adhesion and contact sites B mediating EDTA-sensitive adhesion. The studies described here have revealed that prior to aggregation, a second EDTA-sensitive adhesion system emerges. In keeping with previously established nomenclature, the molecules mediating the newly discovered adhesion system have been called contact sites C. Unlike contact sites B, contact sites C are unaffected by a contact sites B-blocking peptide. Contact sites C-mediated adhesion is also distinct from contact sites B-mediated adhesion in that contact sites C-mediated adhesion is EGTA-resistant and in the presence of EDTA it can be rescued by the addition of Mg2+. Thus Mg2+ may be the cation present under physiological conditions that is essential for contact sites C activity. Unlike contact sites B-mediated adhesion, contact sites C-mediated adhesion is not observed in growing amoebae. Contact sites C-mediated adhesion first becomes apparent within hours after the initiation of development and its strength appears to increase throughout the first 10 h of the developmental program. A mutant lacking the EDTA-resistant contact sites A exhibits normal contact sites B- and C-mediated adhesion, demonstrating that both EDTA-sensitive adhesion systems are independent of contact sites A. Thus aggregating D. discoideum amoebae possess three distinct adhesion systems, one of them is EDTA-resistant and the other two are EDTA-sensitive.

Animals↗
PubMed2005

The involvement of adhesion molecules and lipid mediators in the adhesion of human platelets to eosinophils.

Platelet-leukocyte interactions represent an important determinant of the inflammatory response. Although mechanisms of platelet-neutrophil adhesion were studied extensively, little is known on the mechanisms of platelet-eosinophil interactions. The aim of the present study was to analyze the involvement of adhesion molecules and lipid mediators in platelet-eosinophil adhesion as compared to platelet-neutrophil adhesion. For that purpose human platelets, eosinophils and neutrophils were isolated and platelet-eosinophil and platelet-neutrophil adhesion induced by thrombin (30 mU/ml), LPS (0.01 microg/ml) and fMLP (1 microM) was quantified using the "rosettes" assay. The involvement of adhesion molecules such as selectin P, glycoprotein IIb/IIIa (GPIIb/IIIa) and lipid mediators such as of thromboxane A2 (TXA2), platelet activating factor (PAF) and cysteinyl leukotrienes (cysLTs) were studied using monoclonal antibodies and pharmacological inhibitors, respectively. Thrombin (30 mU/ml), LPS (0.01 microg/ml) and fMLP (1 microM) each of them induced platelet-eosinophil adhesion that was even more pronounced as compared with platelet-neutrophil adhesion induced by the same stimulus. Anti-CD62P antibody (1 microg/ml) and anti-GP IIb/IIIa antibody (abciximab-3 microg/ml) strongly inhibited platelet-eosinophil as well as platelet-neutrophil adhesion. Aspirin inhibited platelet-eosinophil adhesion, while MK 886-a FLAP inhibitor (10 microM), or WEB 2170-a PAF receptor antagonist (100 microM) were less active. On the other hand aspirin, MK 886 and WEB 2170 all three of them inhibited platelet-neutrophil adhesion. In summary, platelets adhered avidly to eosinophils both after activation of platelets by thrombin, eosinophils by fMLP or simultaneous activation of platelets and eosinophils by LPS. Similarly to platelet-neutrophil interaction adhesion of platelets to eosinophils involved not only adhesion molecules (selectin P, GPIIb/IIIa), but also lipid mediators such as TXA2. The involvement of PAF and cysteinyl leukotrienes in platelet-eosinophil adhesion was less pronounced as compared to platelet-neutrophil adhesion.

Abciximab↗
PubMed2002

[N acetyl-aspartyl glutamic acid (NAAGA) inhibits the adhesion of leukocytes to activated endothelial cells and down-modulates the cytokine-induced expression of adhesion molecules].

BACKGROUND: Cell adhesion plays a pivotal role in most ocular surface inflammatory diseases. Adhesion molecules mediate cell-to-cell and cell-to-matrix adhesion. Their expression is up-regulated by pro-inflammatory stimuli such as cytokines, histamine or complement-derived anaphylatoxins. The dipeptide N acetyl-aspartyl glutamic acid (NAAGA) is used as unpreserved topical eyedrops in the treatment of allergic conjunctivitis. NAAGA is known to inhibit leukotriene synthesis, histamine release by mast cells, and complement-derived anaphylatoxin production. PURPOSE: To investigate the potential capability of NAAGA to interfere with leukocyte adhesion to endothelial cells and modulate cytokine-induced expression of adhesion molecules. METHODS: Human blood-derived leukocytes were co-cultured with human umbilical vein endothelial cells (HUVECs) in the absence or the presence of 1000 UI/mL human recombinant TNFalpha, 10(-4) M histamine di-hydrochloride or 5x10(-6) M human recombinant C5a, and in the absence or presence of NAAGA (final concentration 2.45%). Adhesion of leukocytes to HUVECs was calculated by subtracting the number of nonadherent leukocytes from the total number of leukocytes. Expression of adhesion molecules was assessed by flow cytometry using anti-CD11b, anti-CD49d, anti-ICAM-1 (CD54), anti-ICAM-2 (CD102), anti-VCAM-1 (CD106) and anti-ELAM-1 (CD62E) monoclonal antibodies. RESULTS: NAAGA was found to totally inhibit adhesion of unstimulated leukocytes, or leukocytes activated with C5a, TNFalpha, or histamine, to TNFalpha-stimulated HUVECs (P=0.0001). Adhesion of leukocytes to unstimulated HUVECs was not modified by NAAGA. Similar results were obtained with endothelial cells stimulated by histamine or C5a. Taken together, these data indicate that NAAGA totally abrogates cell adhesion under inflammatory conditions, without interfering with the physiological adhesion of leukocytes to normal endothelium. At the molecular level, NAAGA inhibited histamine-induced expression of CD11b (P=0.0004) and CD49d (P=0.0045) on granulocytes. On TNFalpha-activated HUVECs, NAAGA induced a significant decrease in the VCAM-1 expression level (P<0.0001) and totally reversed TNFalpha-induced overexpression of ICAM-1 (P=0.0069), ICAM-2 and ELAM-1 (P<0.0001), without interfering with baseline expression of these molecules. CONCLUSION: These results show that the antiallergic compound NAAGA directly inhibits leukocyte adhesion to endothelial cells induced by pro-inflammatory stimuli, and abrogates TNFalpha-induced expression of adhesion molecules on granulocytes and endothelial cells. This capacity to block overexpression of selectins and integrins induced by pro-inflammatory stimuli confers to NAAGA a potential as an anti-inflammatory drug, since interfering with adhesion molecule expression is probably one of the most efficient ways to curb leukocyte recruitment to inflammatory sites.

Antigens, CD↗
PubMed2007

Regulation of implant surface cell adhesion: characterization and quantification of S-phase primary osteoblast adhesions on biomimetic nanoscale substrates.

Integration of an orthopedic prosthesis for bone repair must be associated with osseointegration and implant fixation, an ideal that can be approached via topographical modification of the implant/bone interface. It is thought that osteoblasts use cellular extensions to gather spatial information of the topographical surroundings prior to adhesion formation and cellular flattening. Focal adhesions (FAs) are dynamic structures associated with the actin cytoskeleton that form adhesion plaques of clustered integrin receptors that function in coupling the cell cytoskeleton to the extracellular matrix (ECM). FAs contain structural and signalling molecules crucial to cell adhesion and survival. To investigate the effects of ordered nanotopographies on osteoblast adhesion formation, primary human osteoblasts (HOBs) were cultured on experimental substrates possessing a defined array of nanoscale pits. Nickel shims of controlled nanopit dimension and configuration were fabricated by electron beam lithography and transferred to polycarbonate (PC) discs via injection molding. Nanopits measuring 120 nm diameter and 100 nm in depth with 300 nm center-center spacing were fabricated in three unique geometric conformations: square, hexagonal, and near-square (300 nm spaced pits in square pattern, but with +/-50 nm disorder). Immunofluorescent labeling of vinculin allowed HOB adhesion complexes to be visualized and quantified by image software. Perhipheral adhesions as well as those within the perinuclear region were observed, and adhesion length and number were seen to vary on nanopit substrates relative to smooth PC. S-phase cells on experimental substrates were identified with bromodeoxyuridine (BrdU) immunofluorescent detection, allowing adhesion quantification to be conducted on a uniform flattened population of cells within the S-phase of the cell cycle. Findings of this study demonstrate the disruptive effects of ordered nanopits on adhesion formation and the role the conformation of nanofeatures plays in modulating these effects. Highly ordered arrays of nanopits resulted in decreased adhesion formation and a reduction in adhesion length, while introducing a degree of controlled disorder present in near-square arrays, was shown to increase focal adhesion formation and size. HOBs were also shown to be affected morphologicaly by the presence and conformation of nanopits. Ordered arrays affected cellular spreading, and induced an elongated cellular phenotype, indicative of increased motility, while near-square nanopit symmetries induced HOB spreading. It is postulated that nanopits affect osteoblast-substrate adhesion by directly or indirectly affecting adhesion complex formation, a phenomenon dependent on nanopit dimension and conformation.

Biomimetic Materials↗
PubMed1998

Influence of adhesion molecule expression by human brain microvessel endothelium on cancer cell adhesion.

Cultures of endothelial (En) cells derived from human brain microvessels were established in order to characterize adhesion molecule expression and to assay the adhesion properties of neoplastic cell lines to monolayers of En cells. Low constitutive expression of beta1 integrin (CD29), and ICAM-2 (CD102) was detected on human brain microvessel En cells. The beta1 chain of the VLA integrin family, ICAM-1, E-selectin (CD62E) and VCAM-1 (CD106) but not ICAM-2 and PECAM-1 (CD31) expression was upregulated by IL1-alpha, and TNF-alpha proinflammatory cytokines. High expression of PECAM-1 was found on non-activated human brain EN cells. In order to study the potential role of adhesion molecules in neoplastic cell adhesion two tumor cell lines were chosen. Adhesion of a cell line (DU145) derived from a cerebral metastasis of prostate carcinoma to human brain microvessel En cell monolayers was less pronounced compared to adhesion of a primary prostate carcinoma cell line (ND1). Adhesion of cerebral metastatic neoplastic cell line (DU145) was not significantly influenced by incubation of endothelial cells with different proinflammatory cytokines. The adhesion capability of primary prostate carcinoma line (NDI) was significantly upregulated by TNF-alpha proinflammatory cytokine. Furthermore, the adhesion of ND1 was partly inhibited using anti-E-selectin and VCAM-1 monoclonal antibodies. There was no significant effect of anti-adhesion antibodies on the adhesion characteristics of the cerebral metastatic (DU145) cell line. Our data demonstrate that different mechanisms are involved in the adhesion of neoplastic cells to cerebral En cells and turn our attention to the importance of adhesion molecule expression in the formation of metastases.

Antibodies, Monoclonal↗
PubMed2002

Mononuclear cell adhesion and cell adhesion molecule liberation after X-irradiation of activated endothelial cells in vitro.

PURPOSE: Increased expression of cell adhesion molecules on endothelial cells is an important early event in inflammation. Low-dose radiotherapy is very effective anti-inflammatory treatment. The hypothesis that it may act by modulation of cell adhesion molecule expression in activated endothelial cells and the subsequent adhesion of mononuclear cells onto the activated endothelial cells was tested. MATERIALS AND METHODS: EA.hy.926 endothelial cells were irradiated with 0.3-10 Gy X-rays at different times before or after stimulation with TNFalpha. ICAM-1 or E-selectin expression was measured by ELISA and FACS. Isolated peripheral blood mononuclear cells were incubated with an activated and irradiated confluent monolayer of endothelial cells 4 h, 12 h or 24 h after stimulation, and adhesion was determined in dynamic and static adhesion assays. RESULTS: In the static adhesion assay, where integrin-mediated adhesion dominates, radiation doses of 0.3-0.6 Gy reduced the adhesion of mononuclear cells onto EA.hy.926-EC in vitro by 25-40% and 15-25% of the control level 4 h and 24 h after stimulation, respectively, but increased adhesion 12 h after stimulation. In the dynamic adhesion assay, where selectin-mediated adhesion dominates, radiation doses of 0.3-0.6 Gy reduced the adhesion events by 40-50% and 30-40% of the control level 4 h and 24 h after stimulation, respectively, and again increased adhesion 12h after stimulation. X-ray doses of < or =5 Gy did not induce ICAM-1 expression, or modulate TNFalpha-induced ICAM-1 expression. E-selectin expression was, however, increased in a dose-dependent way 6 h after irradiation. In contrast, X-irradiation 2-5 h before stimulation decreased the characteristic transient expression of E-selectin after TNFalpha stimulation. CONCLUSIONS: Modulation of E-selectin liberation on activated endothelial cells may be one mechanism to decrease leukocyte adhesion after low-dose irradiation in vitro, and could be involved in the therapeutic action of anti-inflammatory radiotherapy.

Cell Adhesion↗
PubMed2005

The role of adsorbed fibrinogen in platelet adhesion to polyurethane surfaces: a comparison of surface hydrophobicity, protein adsorption, monoclonal antibody binding, and platelet adhesion.

Ten specially synthesized polyurethanes (PUs) were used to investigate the effects of surface properties on platelet adhesion. Surface composition and hydrophilicity, fibrinogen (Fg) and von Willebrand's factor (vWf) adsorption, monoclonal anti-Fg binding, and platelet adhesion were measured. PUs preadsorbed with afibrinogenemic plasma or serum exhibited very low platelet adhesion, while adhesion after preadsorption with vWf deficient plasma was not reduced, showing that Fg is the key plasma protein mediating platelet adhesion under static conditions. Platelet adhesion to the ten PUs after plasma preadsorption varied greatly, but was only partially consistent with Fg adsorption. Thus, while very hydrophilic PU copolymers containing PEG that had ultralow Fg adsorption also had very low platelet adhesion, some of the more hydrophobic PUs had relatively high Fg adsorption but still exhibited lower platelet adhesion. To examine why some PUs with high Fg adsorption had lower platelet adhesion, three monoclonal antibodies (mAbs) that bind to sites in Fg thought to mediate platelet adhesion were used. The antibodies were: M1, specific to gamma-chain C-terminal; and R1 and R2, specific to RGD containing regions in the alpha-chain N- and C-terminal, respectively. Platelet adhesion was well correlated with M1 binding, but not with R1 or R2 binding. When these mAbs were incubated with plasma preadsorbed surfaces, they blocked adhesion to variable degrees. The ability of the R1 and R2 mAbs to partially block adhesion to adsorbed Fg suggests that RGD sites in the alpha chain may also be involved in mediating platelet adhesion and act synergistically with the C-terminal of the gamma-chain.

Adsorption↗
PubMed2006

Quantitative determination of adhesion patterns of cariogenic streptococci to various orthodontic adhesives.

OBJECTIVE: To investigate the adhesion of various cariogenic streptococci to orthodontic adhesives. MATERIALS AND METHODS: Five light-cure orthodontic adhesives (one fluoride-releasing composite, three non-fluoride-releasing composites, and one resin-modified glass ionomer cement) were used. The adhesive type, bacterial strain, incubation time, and saliva coating were studied. Thirty specimens of each adhesive were incubated with unstimulated whole saliva or phosphate-buffered saline for 2 hours. Binding assays were then performed by incubating tritium-labeled streptococci with the adhesives for 3 or 6 hours. RESULTS: The results showed a characteristic adhesion pattern according to the type of bacterial strains used. Streptococcus mutans LM7 showed the highest amount of adhesion, whereas S sobrinus B13 showed the lowest amount of adhesion. The cariogenic streptococci adhered to the glass ionomer significantly more than to the composites, whereas there was no significant difference in the adhesion amount among the four composites. The extended incubation time significantly increased bacterial adhesion. However, saliva coating did not significantly alter adhesion patterns of cariogenic streptococci. CONCLUSIONS: This study suggests that cariogenic streptococci can adhere diversely according to adhesive type and that the adhesion of the cariogenic streptococci is not influenced by its fluoride-releasing properties.

Acrylic Resins↗
PubMed2000

The state diagram for cell adhesion under flow: leukocyte rolling and firm adhesion.

Leukocyte adhesion under flow in the microvasculature is mediated by binding between cell surface receptors and complementary ligands expressed on the surface of the endothelium. Leukocytes adhere to endothelium in a two-step mechanism: rolling (primarily mediated by selectins) followed by firm adhesion (primarily mediated by integrins). Using a computational method called "Adhesive Dynamics," we have simulated the adhesion of a cell to a surface in flow, and elucidated the relationship between receptor-ligand functional properties and the dynamics of adhesion. We express this relationship in a state diagram, a one-to-one map between the biophysical properties of adhesion molecules and various adhesive behaviors. Behaviors that are observed in simulations include firm adhesion, transient adhesion (rolling), and no adhesion. We varied the dissociative properties, association rate, bond elasticity, and shear rate and found that the unstressed dissociation rate, k(r)(o), and the bond interaction length, gamma, are the most important molecular properties controlling the dynamics of adhesion. Experimental k(r)(o) and gamma values from the literature for molecules that are known to mediate rolling adhesion fall within the rolling region of the state diagram. We explain why L-selectin-mediated rolling, which has faster k(r)(o) than other selectins, is accompanied by a smaller value for gamma. We also show how changes in association rate, shear rate, and bond elasticity alter the dynamics of adhesion. The state diagram (which must be mapped for each receptor-ligand system) presents a concise and comprehensive means of understanding the relationship between bond functional properties and the dynamics of adhesion mediated by receptor-ligand bonds.

Cell Adhesion↗
PubMed2005

The role of the cytoskeleton in differentially regulating pressure-mediated effects on malignant colonocyte focal adhesion signaling and cell adhesion.

Increased extracellular pressure stimulates colon cancer cell adhesion by activating focal adhesion kinase (FAK) and Src. We investigated the role of the cytoskeleton in pressure-induced inside-out FAK and Src phosphorylation and pressure-stimulated adhesion. We perturbed actin polymerization with phalloidin, cytochalasin D and latrunculin B, and microtubule organization with colchicine and paclitaxol. We compared the effects of these agents on pressure-induced SW620 and human primary colon cancer cell adhesion and inside-out FAK/Src activation with outside-in adhesion-dependent FAK/Src activation. Cells pretreated with cytoskeletal inhibitors were subjected to 15 mmHg increased pressure and allowed to adhere to collagen I coated plates or prevented from adhesion to pacificated plates for 30 min. Phalloidin, cytochalasin D, latrunculin B and colchicine pretreatment completely prevented pressure-stimulated and significantly inhibited basal SW620 cell adhesion. Taxol did not inhibit pressure-induced colon cancer cell adhesion, but significantly lowered basal adhesion. Cytochalasin D and colchicine had similar effects in pressure-stimulated primary human malignant colonocytes. Phalloidin, cytochalasin D, latrunculin B and colchicine prevented pressure-induced SW620 FAK phosphorylation but not Src phosphorylation. FAK phosphorylation in response to collagen I adhesion was significantly attenuated but not completely prevented by these inhibitors. Although Src phosphorylation was not increased on adhesion, the cytoskeleton disrupting agents significantly lowered basal Src phosphorylation in adherent cells. These results suggest that both cytoskeleton-dependent FAK activation and cytoskeleton-independent Src activation may be required for extracellular pressure to stimulate colon cancer cell adhesion. Furthermore, the cytoskeleton plays a different role in pressure-activated FAK and Src signaling than in FAK and Src activation in adherent cells. We, therefore, hypothesize that cytoskeletal interactions with focal adhesion signals mediate the effects of extracellular pressure on colon cancer cell adhesion.

Cell Adhesion↗
PubMed2001

The de-adhesive activity of matricellular proteins: is intermediate cell adhesion an adaptive state?

The process of cellular de-adhesion is potentially important for the ability of a cell to participate in morphogenesis and to respond to injurious stimuli. Cellular de-adhesion is induced by the highly regulated matricellular proteins TSP1 and 2, tenascin-C, and SPARC. These proteins induce a rapid transition to an intermediate state of adhesiveness characterized by loss of actin-containing stress fibers and restructuring of the focal adhesion plaque that includes loss of vinculin and alpha-actinin, but not of talin or integrin. This process involves intracellular signaling mediators, which are engaged in response to matrix protein-receptor interactions. Each of these proteins employs different receptors and signaling pathways to achieve this common morphologic endpoint. What is the function of this intermediate adhesive state and what is the physiologic significance of this action of the matricellular proteins? Given that matricellular proteins are expressed in response to injury and during development, one can speculate that the intermediate adhesive state is an adaptive condition that facilitates expression of specific genes that are involved in repair and adaptation. Since cell shape is maintained in weakly adherent cells, this state might induce survival signals to prevent apoptosis due to loss of strong cell adhesion, but yet allow for cell locomotion. The three matricellular proteins considered here might each preferentially facilitate one or more aspects of this adaptive response rather than all of these equally. Currently, we have only preliminary data to support the specific ideas proposed in this article. It will be interesting in the next several years to continue to elucidate the biological roles of the intermediate adhesive state induced by these matricellular proteins. and focal adhesions in a cell that nevertheless maintains a spread, extended morphology and integrin clustering. TSP1, tenascin-C, and SPARC induce the intermediate adhesive state, as shown by the red arrows. The significance of each adhesive state for cell behavior is indicated beneath the cells. The weak adhesive state would be consistent with cells undergoing apoptosis during remodeling or those undergoing cytokinesis. The strong adhesive state is characteristic of a differentiated, quiescent cell, whereas cells in the intermediate adhesive state would include those involved in responding to injury during wound healing or in tissue remodeling during morphogenesis.

Adaptation, Physiological↗
PubMed1995

Identification of C1q as the heat-labile serum cofactor required for immune complexes to stimulate endothelial expression of the adhesion molecules E-selectin and intercellular and vascular cell adhesion molecules 1.

To examine the role of complement components as regulators of the expression of endothelial adhesive molecules in response to immune complexes (ICs), we determined whether ICs stimulate both endothelial adhesiveness for leukocytes and expression of E-selectin and intercellular and vascular cell adhesion molecules 1 (ICAM-1 and VCAM-1). We found that ICs [bovine serum albumin (BSA)-anti-BSA] stimulated endothelial cell adhesiveness for added leukocytes in the presence of complement-sufficient normal human serum (NHS) but not in the presence of heat-inactivated serum (HIS) or in tissue culture medium alone. Depletion of complement component C3 or C8 from serum did not prevent enhanced endothelial adhesiveness stimulated by ICs. In contrast, depletion of complement component C1q markedly inhibited IC-stimulated endothelial adhesiveness for leukocytes. When the heat-labile complement component C1q was added to HIS, the capacity of ICs to stimulate endothelial adhesiveness for leukocytes was completely restored. Further evidence for the possible role of C1q in mediating the effect of ICs on endothelial cells was the discovery of the presence of the 100- to 126-kDa C1q-binding protein on the surface of endothelial cells (by cytofluorography) and of message for the 33-kDa C1q receptor in resting endothelial cells (by reverse transcription-PCR). Inhibition of protein synthesis by cycloheximide blocked endothelial adhesiveness for leukocytes stimulated by either interleukin 1 or ICs in the presence of NHS. After stimulation with ICs in the presence of NHS, endothelial cells expressed increased numbers of adhesion molecules (E-selectin, ICAM-1, and VCAM-1). Endothelial expression of adhesion molecules mediated, at least in part, endothelial adhesiveness for leukocytes, since leukocyte adhesion was blocked by monoclonal antibodies directed against E-selectin. These studies show that ICs stimulate endothelial cells to express adhesive proteins for leukocytes in the presence of a heat-labile serum factor. That factor appears to be C1q.

Antigen-Antibody Complex↗