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PubMed1996

Ligand activation of overexpressed epidermal growth factor receptor results in loss of epithelial phenotype and impaired RGD-sensitive integrin function in HSC-1 cells.

Various human carcinomas overexpress epidermal growth factor receptor, and the degree of the expression correlates with their malignant phenotype. Because phenotypic transformation of cells involves qualitative and quantitative alteration of integrin function, we compared the effects of exogenous epidermal growth factor on cell-matrix interactions between HSC-1 human cutaneous squamous carcinoma cells overexpressing epidermal growth factor receptor and their revertant cells. Epidermal growth factor impaired RGD-sensitive cell spreading on fibrinogen, fibronectin, or vitronectin in the parent cells in a concentration-dependent manner; 50 ng epidermal growth factor per ml treatment for 1-24 h reduced cell spreading on these substrata by 75-95%. In the presence of epidermal growth factor, the parent HSC-1 cells lost their epithelial phenotype and did not form coherent colonies. This might involve the impaired RGD-sensitive integrin function, because treatment of the cells with the peptide GRGDS mimicked the effects of epidermal growth factor on cell and colony morphology. The revertant cells expressing about one-tenth the amount of epidermal growth factor receptor did not show reduced RGD-sensitive cell spreading or loss of epithelial phenotype in response to epidermal growth factor. Epidermal growth factor did not downregulate the subunits for the RGD-sensitive integrin receptors for fibrinogen, fibronectin, or vitronectin. Tyrosine phosphorylation of integrin beta subunits might be involved in the impairment of integrin function, because EGF tyrosine phosphorylated beta1, subunit in the parent, but not in the revertant cells. Our results suggest that the ligand activation of overexpressed epidermal growth factor receptor results in impairment of RGD-sensitive integrin function and loss of epithelial phenotype. This may be advantageous to epithelial tumor cells progressing along malignant pathways.

Down-Regulation↗
PubMed1992

Triflavin, an Arg-Gly-Asp-containing antiplatelet peptide inhibits cell-substratum adhesion and melanoma cell-induced lung colonization.

Triflavin, an Arg-Gly-Asp (RGD) containing peptide purified from Trimeresurus flavoviridis snake venom, inhibits human platelet aggregation by blocking fibrinogen binding to fibrinogen receptors associated with glycoprotein IIb/IIIa complex. In this study, we show that triflavin (1-30 micrograms/mouse) inhibits B16-F10 melanoma cell-induced lung colonization in C57BL/6 mice in a dose-dependent manner. In vitro, triflavin dose-dependently inhibits adhesion of B16-F10 melanoma cells to extracellular matrices (ECMs; i.e., fibronectin, fibrinogen, vitronectin, and collagen type I). Triflavin is approximately 600-800 times more potent than GRGDS at inhibiting cell adhesion. In addition, triflavin dose-dependently inhibits B16-F10 cell-induced platelet aggregation. These results imply that the inhibitory effect of triflavin on the adhesion of tumor cells to ECMs (e.g., fibronectin, vitronectin and collagen type I) and/or tumor cell-induced platelet aggregation may be partially responsible for its antimetastatic activity in C57BL/6 mice.

Animals↗
PubMed1995

Measurement of factor Xa-antithrombin III in plasma: relationship to prothrombin activation in vivo.

The M(r) of the complexes formed when factor Xa reacts with antithrombin III (ATIII) in plasma were estimated by gel filtration and SDS-polyacrylamide electrophoresis. The predominant species of factor Xa-ATIII detected after plasma and plasma to which factor Xa had been added were gel filtered on Sephadex G-200 and Sepharose 4B had apparent M(r) > 200,000, in which factor Xa-ATIII was associated with vitronectin. Addition of factor Xa-ATIII to ATIII-depleted plasma also resulted in the formation of factor Xa-ATIII-vitronectin complexes with M(r) > 200,000. Using polyclonal antibodies to human factor Xa-ATIII and ATIII as the capture and detector antibodies, respectively, a sensitive and specific enzyme-linked immunosorbent assay was developed to quantify factor Xa-ATIII in plasma. The relationship between factor Xa-ATIII production and prothrombinase activity in vivo was investigated by quantifying factor Xa-ATIII and prothrombin fragment 1 + 2 endogenous to the plasmas of blood donors and patients with Hodgkin's and non-Hodgkin's lymphoma. Whereas the concentrations of prothrombin fragment 1 + 2 in the 84 normal plasmas increased with age, those of factor Xa-ATIII (mean +/- SD of 34.7 +/- 13.8 pM) did not, and no correlation existed between the concentrations of the two parameters in normal plasmas. In contrast, a highly significant correlation between the concentrations of these two parameters was found in the plasmas of the cancer patients which coincidentally also had higher concentrations of both factor Xa-ATIII and prothrombin fragment 1 + 2 than the normal plasmas. Thus, ATIII may differentially influence prothrombinase formation and activity in normal individuals and cancer patients.

Adult↗
PubMed1988

cDNA clones for human platelet GPIIb corresponding to mRNA from megakaryocytes and HEL cells. Evidence for an extensive homology to other Arg-Gly-Asp adhesion receptors.

Platelet glycoprotein (GP) IIb is one of the two subunits of the common platelet adhesion receptor, GPIIb-IIIa. The isolation, characterization and sequencing of cDNA clones encoding for the two polypeptide chains of GPIIb are described. A number of clones were isolated from lambda gt11 libraries constructed with mRNA from an erythroleukemic cell line, HEL, and human megakaryocytes. Two of these clones, lambda IIb1, from HEL cells, and lambda IIb2, from megakaryocytes, cross-hybridized and were selected for detailed analysis. The identification of these as authentic GPIIb clones was based on immunological criteria and confirmed by the presence of nucleotide sequences in each insert encoding for known protein sequences of platelet GPIIb. These clones contained inserts of 1.54 kb and 1.39 kb, respectively, with an overlapping sequence of 801 bp. The nucleotide sequence of the overlapping region was identical indicating that HEL cells produce a protein closely related, if not identical, to platelet GPIIb. The determined nucleotide sequence of two inserts included a coding sequence for 648 amino acid residues, a TAG stop codon and 185 nucleotides of 3' non-coding sequence followed by a poly(A) tail. The coding sequence contained a portion of the heavy chain, the junction between the heavy and light chains and the entire light chain including a potential transmembrane-spanning domain and a short cytoplasmic tail. When these cDNA were used to probe for GPIIb mRNA, a single mRNA species of 3.9 kb was identified in both HEL cells and human megakaryocytes. A comparison of the deduced amino acid sequence for GPIIb with those of the alpha subunit of the vitronectin and the fibronectin receptors revealed extensive homologies. These homologies further establish that GPIIb-IIIa from platelets, together with the vitronectin and the fibronectin receptors, are members of a supergene family of adhesion receptors with a recognition specificity for Arg-Gly-Asp amino acid sequences.

Amino Acid Sequence↗
PubMed2004

Adherence of Brucella to human epithelial cells and macrophages is mediated by sialic acid residues.

The basis for the interaction of Brucella species with the surface of epithelial cells before migration in the host within polymorphonuclear leucocytes is largely unknown. Here, we studied the ability of Brucella abortus and Brucella melitensis to adhere to cultured epithelial (HeLa and HEp-2) cells and THP-1-derived macrophages, and to bind extracellular matrix proteins (ECM). The brucellae adhered to epithelial cells forming localized bacterial microcolonies on the cell surface, and this process was inhibited significantly by pretreatment of epithelial cells with neuraminidase and sodium periodate and by preincubation of the bacteria with heparan sulphate and N-acetylneuraminic acid. Trypsinization of epithelial cells yielded increased adherence, suggesting unmasking of target sites on host cells. Notably, the brucellae also adhered to cultured THP-1 cells, and this event was greatly reduced upon removal of sialic acid residues from these cells with neuraminidase. B. abortus bound in a dose-dependent manner to immobilized fibronectin and vitronectin and, to a lesser extent, to chondroitin sulphate, collagen and laminin. In sum, our data strongly suggest that the adherence mechanism of brucellae to epithelial cells and macrophages is mediated by cellular receptors containing sialic acid and sulphated residues. The recognition of ECM (fibronectin and vitronectin) by the brucellae may represent a mechanism for spread within the host tissues. These are novel findings that offer new insights into understanding the interplay between Brucella and host cells.

Animals↗
PubMed2004

Release of endothelium-associated proteins into blood by injection of heparin in normal subjects and in patients with Type 1 diabetes.

AIMS: Disturbances in heparan sulphate proteoglycans in patients with diabetic nephropathy might contribute to the pathogenesis of vascular disease in these patients. To investigate this possible link, we measured the heparin-induced, immediate release of eight proteins with heparan sulphate binding properties in patients with nephropathy. METHODS: We studied three groups, Type 1 diabetic patients with (n = 10) or without (n = 15) albuminuria and matched controls (n = 12). Blood samples were obtained before and 5 min after the injection of 40 anti-Xa IU low molecular weight heparin/kg body weight. RESULTS: Lipoprotein lipase increased more in diabetic patients without albuminuria than in controls and patients with albuminuria [261 (170-293) vs. 177 (103-438), P < 0.05 and 203 (159-280) mU/ml, P < 0.05]. Total tissue factor pathway inhibitor increased more in the diabetic patients [284 (198-449) and 275 (243-399)] than in the controls [221 (169-289) ng/ml, P < 0.005]. Vitronectin increased significantly only in the diabetic patients with albuminuria. The remaining proteins did not increase significantly (antithrombin, von Willebrand factor, fibronectin) or increased equally in the three investigated groups (extracellular superoxid dismutase and platelet factor 4). CONCLUSIONS: The different release of lipoprotein lipase and vitronectin in diabetic subjects with and without albuminuria may reflect novel aspects of vascular derangement in patients with albuminuria.

Adult↗
PubMed2005

Fibronectin promotes brain capillary endothelial cell survival and proliferation through alpha5beta1 and alphavbeta3 integrins via MAP kinase signalling.

We showed previously that blood vessel maturation in the CNS is associated with a developmental switch in brain capillary endothelial cells (BCEC), from fibronectin signalling during angiogenesis to laminin signalling in the adult. To investigate the functional significance of this switch, we have examined the response of BCEC to different extracellular matrix (ECM) proteins. This showed that BCEC proliferation was significantly promoted by fibronectin (28.2 +/- 4.0%) and by vitronectin (14.8 +/- 2.1%) compared with uncoated glass (7.2 +/- 0.7%), while BCEC survival was significantly promoted by fibronectin (1130 +/- 131 cells), vitronectin (830 +/- 63 cells), collagen IV (703 +/- 77 cells) and laminin (680 +/- 34 cells) compared with the uncoated glass (367 +/- 48 cells). Biochemical studies showed that BCEC express a limited repertoire of integrins, including the beta1 integrins, alpha3beta1, alpha5beta1 and alpha6beta1, and the alphavbeta3 integrin. Function-blocking studies showed that the response to fibronectin was mediated equally by the alpha5beta1 and alphavbeta3 integrins. Analysis of signalling pathways revealed that fibronectin stimulated activation of the p44/p42 MAP kinase signalling pathway and pharmacological inhibitors of this pathway blocked BCEC proliferation on fibronectin. Taken together, these findings show that fibronectin exerts a strong angiogenic influence on endothelial cells (EC) in the CNS, and that this is mediated through the alpha5beta1 and alphavbeta3 integrins via MAP kinase signalling. In addition to a fundamental role in development, these findings may also have implications in pathological conditions of the CNS where fibronectin is re-expressed.

Animals↗
PubMed1999

Specific interactions between Porphyromonas gingivalis fimbriae and human extracellular matrix proteins.

The interactions of the extracellular matrix (ECM) proteins (laminin, elastin, fibronectin, type I collagen, thrombospondin and vitronectin) with the fimbriae of Porphyromonas gingivalis were analyzed based on surface plasmon resonance (SPR) spectroscopy using a biomolecular interaction analyzing system (BIAcore). The BIAcore profiles demonstrated that fimbriae specifically bound to all of the ECM proteins with significant association constants (Ka). Vitronectin showed the highest affinity to fimbriae (Ka = 3.79 x 10(6) M-1), while the affinity of laminin was lowest (Ka = 2.15 x 10(6) M-1). A synthetic peptide which is a potent inhibitor of fimbrial binding to salivary proteins was not significantly effective on the fimbrial interactions with the ECM proteins. Using polystyrene microtiter plates revealed that P. gingivalis fimbriae bound markedly to immobilized fibronectin and type I collagen, while the interaction of fimbriae with the other ECM proteins was not clearly demonstrated. These results suggest that interactions between fimbriae and the ECM proteins occur with specific affinities which are not mediated by mechanisms identical to those of salivary proteins. It was also shown that SPR spectroscopy is a useful method to analyze these specific interactions.

Animals↗
PubMed2005

Adherence of Staphylococcus epidermidis to extracellular matrix proteins and effects of fibrinogen-bound bacteria on oxidase activity and apoptosis in neutrophils.

Staphylococcus epidermidis often causes foreign-body infections such as those associated with hip prostheses, but the underlying pathogenic mechanisms are not fully understood. We performed spectrophotometry to study the ability of S. epidermidis to bind to immobilised fibrinogen, fibronectin, vitronectin, and collagen. The strains were isolated from infected hip prostheses or from normal flora and the well-known protein-binding strain Staphylococcus aureus Cowan was used as positive control. We also analysed the interaction between neutrophils and a fibrinogen-bound prosthesis-derived strain of S. epidermidisby measuring chemiluminescence to determine the neutrophil oxidative response and binding of annexin V to indicate neutrophil apoptosis. We found that binding of S. epidermidis to extracellular matrix proteins varied under different growth conditions, and that prosthesis isolates adhered better to vitronectin than did strains from normal flora. The oxidative response caused by fibrinogen-bound S. epidermidis was not above the background level, which was in marked contrast to the distinct response induced by fibrinogen-associated S. aureus Cowan. Furthermore, fibrinogen-adhering S. epidermidis retarded neutrophil apoptosis. We conclude that surface-bound S. epidermidis induces only a weak inflammatory response, which in combination with the ability of the adherent bacteria to retard neutrophil apoptosis may contribute to low-grade inflammation and loosening of prostheses.

Apoptosis↗
PubMed1993

Rapid detection and characterization of sialic acid-specific lectins of Helicobacter pylori.

A particle agglutination assay (PAA) using fetuin (Ft) covalently coupled to carboxylate-modified latex (CML) particles was evaluated for rapid detection of sialic acid-specific haemagglutinins/lectins (SALs) of Helicobacter pylori isolates which bind sialoglycoconjugates. Sixty-three percent (20/32) of the isolates examined gave a positive PAA test. Cell-bound SALs were extracted by washing the bacteria with deionized water or isotonic saline, and their expression was influenced by pH and culture conditions. The Ft-CML reactivity of the PAA-positive isolates was inhibited by bovine submaxillary mucin, transferrin, fetuin, orosomucoid, vitronectin and lactoferrin in a manner which suggested that the isolates contain a lectin recognizing the alpha(2-6) linkage of terminal sialic acid. Western blots of strain NCTC 11637 SALs probed with horseradish peroxidase (HRP)-labelled Ft identified three bands (MW 64 kD, 62 kD, 56 kD) which also reacted with HRP-labelled mucin, transferrin, lactoferrin, orosomucoid, vitronectin and laminin. Sera from patients with a H. pylori infection and one polyclonal rabbit antiserum (strain NCTC 11637) also reacted with the SALs. Immunogold labelling of a polyclonal rabbit antiserum raised against the 64 kD protein of strain NCTC 11637 that reacted strongly with Ft-CML showed that abundant SALs were loosely cell-associated with the cell surface of both spiral and coccoidal forms of H. pylori. SALs were also present in low amounts on the surface of strain NCTC 11638 and 66, a clinical isolate that did not react with Ft-CML.

Animals↗
PubMed1999

The terminal complement complex is generated in chronic leg ulcers in the absence of protectin (CD59).

Loss of membrane complement regulators accompanied by complement activation is suggested to be involved in the pathophysiological processes leading to tissue damage in myocardial ischaemia. In the present study we have investigated whether the same phenomenon may occur in ischaemic and/or venous hypertension leg ulcers. The deposition of complement, plasma complement regulators and expression of membrane regulators were detected by immunohistochemical methods, including immunofluorescence with antibodies against C3d, the terminal complement complex (TCC), vitronectin, clusterin, decay-accelerating factor (CD55) and protectin (CD59). Eleven frozen biopsies from ischaemic leg ulcers, 10 biopsies from venous hypertension leg ulcers, and 10 biopsies from normal skin were studied. In 9 of 11 ischaemic and in 5 of 10 venous hypertension leg ulcers, marked staining for TCC was found around the capillaries, most often at the ulcer margin. No TCC staining was found in normal skin. Staining for TCC was always accompanied by staining for clusterin and vitronectin and C3d. In normal skin, CD59 was found on the elastic fibers in the dermis, on the muscle coat, the Schwann sheath and acinar cells. Semiquantitative measurement of CD59 showed marked increased staining intensity in the endothelium in venous hypertension ulcers and diminished intensity in ischaemic ulcers compared to normal skin. No such difference could be observed for CD55. When TCC was positive in the capillary walls, weak or no staining for CD59 was found. A significantly higher ratio of TCC/CD59 was found in the ischaemic compared to venous ulcers (p = 0.018). This was due to a marked difference between the ulcer margins (p = 0.013). Localized areas in the venous ulcers had the same pattern as that seen in the ischaemic ulcers. Our results suggest that loss of CD59 may enhance deposition of TCC and that complement-dependent inflammation may be an important factor in the tissue-damaging processes seen in chronic leg ulcers.

Adult↗
PubMed1999

Bacterial binding to extracellular matrix proteins -- in vitro adhesion.

A binding assay was developed and used to study the binding of oral streptococcus to immobilized human fibronectin, laminin, vitronectin, fibrinogen, heparin, and collagen IV. The protein binding was dependent on the broth used for bacterial growth. The binding after growth in brain heart infusion broth, trypticase soy broth, Todd-Hewitt broth, and Dulbecco's modified Eagle's medium was examined. Most of the strains were able to bind to immobilized fibronectin and laminin, and to a minor extent vitronectin. Binding was not observed on immobilized fibrinogen, collagen IV, or heparin. Measured surface hydrophobicity correlated well with the bacterial binding strength to the proteins. Streptococcal incubation with putative inhibitors indicates multiple binding mechanisms of a lectin-like and protein nature, possibly involving protein receptors.

Animals↗
PubMed1999

Designing biomaterials to direct biological responses.

We have set forth a design strategy for creating biomimetic materials that direct the formation of tissue surrounding implants or regeneration within porous scaffolds. Our studies have established that heterogeneous mimetic peptide surfaces (MPS) containing both the -RGD- (cell-binding) and-FHRRIKA- (putative heparin-binding) peptides, unique to BSP, in the ratio of 75:25 (MPS II) or 50:50 (MPS III) proved to be more biologically relevant and specific for RCO cell function. The initial response of human osteoblast-like cells to these surfaces was mediated by the collagen (alpha 2 beta 1) and vitronectin receptors (alpha v beta 3), whereas the vitronectin receptor alone dominated longer-term events (> 30 min). MPS II and III surfaces enhanced cell spreading and long-term events such as mineralization of the extracellular matrix compared to homogenous peptide surfaces and controls. Furthermore, extensive mineralization of the ECM deposited by RCOs occurred when the peptide was coupled to an interfacial interpenetrating polymer network (IPN) that resisted protein deposition (i.e., non-specific adsorption) and fouling. Work on thermo-reversible P(NIPAAm-co-AAc) hydrogels demonstrated the ability to create materials that can be delivered to the body in a minimally invasive manner and support tissue regeneration. These hydrogels can be modified to incorporate biofunctional components such as the biomimetic peptides, theoretically enhancing their ability to foster tissue regeneration. These results suggest that biomaterials can be engineered to mimic ECM components of bone (e.g., various organs) by grafting peptides in the appropriate ratios of the cell and heparin-binding domains, and ultimately modulate the expression of the osteoblast cell phenotype. Approaches similar to the one presented in this work can be used to design materials for hybrid artificial organs and other tissues.

Amino Acid Sequence↗
PubMed2001

Identification and characterization of a novel 38.5-kilodalton cell surface protein of Staphylococcus aureus with extended-spectrum binding activity for extracellular matrix and plasma proteins.

The ability to attach to host ligands is a well-established pathogenic factor in invasive Staphylococcus aureus disease. In addition to the family of adhesive proteins bound to the cell wall via the sortase A (srtA) mechanism, secreted proteins such as the fibrinogen-binding protein Efb, the extracellular adhesion protein Eap, or coagulase have been found to interact with various extracellular host molecules. Here we describe a novel protein, the extracellular matrix protein-binding protein (Emp) initially identified in Western ligand blots as a 40-kDa protein due to its broad-spectrum recognition of fibronectin, fibrinogen, collagen, and vitronectin. Emp is expressed in the stationary growth phase and is closely associated with the cell surface and yet is extractable by sodium dodecyl sulfate. The conferring gene emp (1,023 nucleotides) encodes a signal peptide of 26 amino acids and a mature protein of a calculated molecular mass of 35.5 kDa. Using PCR, emp was demonstrated in all 240 S. aureus isolates of a defined clinical strain collection as well as in 6 S. aureus laboratory strains, whereas it is lacking in all 10 S. epidermidis strains tested. Construction of an allelic replacement mutant (mEmp50) revealed the absence of Emp in mEmp50, a significantly decreased adhesion of mEmp50 to immobilized fibronectin and fibrinogen, and restoration of these characteristics upon complementation of mEmp50. Emp expression was also demonstrable upon heterologous complementation of S. carnosus. rEmp expressed in Escherichia coli interacted with fibronectin, fibrinogen, and vitronectin in surface plasmon resonance experiments at a K(d) of 21 nM, 91 nM, and 122 pM, respectively. In conclusion, the biologic characterization of Emp suggests that it is a member of the group of secreted S. aureus molecules that interact with an extended spectrum of host ligands and thereby contribute to S. aureus pathogenicity.

Adhesins, Bacterial↗
PubMed1997

Role of Helicobacter pylori surface structures in bacterial interaction with macrophages.

BACKGROUND: Helicobacter pylori infection is associated with a marked infiltration of the gastric epithelium by neutrophils, macrophages, lymphocytes, and plasma cells. Despite the presence of phagocytes in close vicinty to H pylori microbes a great number of people are unable to eradicate bacteria. AIMS: To investigate the involvement of multiple bacterial 'adhesins' and some phagocytic receptors in the process of the ingestion of H pylori by macrophages. BACTERIA: H pylori strains differing in the expression of sialic acid dependent (sHA) or sialic acid independent (HA) haemagglutinin and heparan sulphate binding were selected for the study. METHODS: The uptake of fluorescein labelled H pylori bacteria by a homogenous macrophage cell line J 774A.1 was estimated in a quantitative fluorometric assay. RESULTS: The ingestion of H pylori 17874 and 25 strains expressing sHA was inhibited by the pretreatment of the bacteria with anti-sHA antibodies or fetuin as well as by treatment of the macrophages with neuraminidase. In contrast the uptake of H pylori 17875 strain expressing HA remained unchanged. The phagocytosis of all investigated bacteria was inhibited after the treatment with heparin, hyaluronic acid or vitronectin with fresh but not heat inactivated serum. CONCLUSIONS: The results suggest that H pylori surface compounds binding host proteins such as fetuin, heparin/haparan sulphate, hyaluronic acid, and vitronectin in the presence of complement, could allow the bacteria to avoid phagocytosis.

Adhesins, Bacterial↗
PubMed2006

Platelet inhibition with prasugrel (CS-747) compared with clopidogrel in patients undergoing coronary stenting: the subset from the JUMBO study.

BACKGROUND: Based on the preclinical and phase 1 studies, prasugrel, a novel platelet ADP P2Y12 receptor blocker, may be a more potent platelet inhibitor than clopidogrel. This study compared the antiplatelet properties of prasugrel in a small subset of patients enrolled in the JUMBO trial, and compared with historic clopidogrel treated controls. METHODS AND RESULTS: Nine patients undergoing coronary stenting were randomised to one of three arms of prasugrel (40 mg loading, and 7.5 mg maintenance, n = 1; 60/10 mg, n = 4; or 60/15 mg, n = 2), or clopidogrel (300/75 mg, n = 2). Aspirin and GP IIb/IIIa inhibitors were permitted. Platelet activity was assessed at baseline, at 4, and 24 hours, and at 30 days after stent implantation in substudy participants, and compared with 124 historic controls who received clopidogrel. Independent of the loading, or maintenance dose, patients treated with prasugrel exhibited significantly more potent platelet inhibition as determined by ADP, and collagen induced aggregation, Ultegra Analyser, and surface expression of PECAM-1, GPIIb/IIIa antigen, and activity with PAC-1 antibody, GPIb, P-selectin, CD40-ligand, GP37, and thrombospondin receptor expression when compared with those treated with clopidogrel. There were no differences between antiplatelet agents with regard to vitronectin, LAMP-1, PAR-1 (intact and cleaved epitopes) thrombin receptor expression, or formation of platelet-monocyte microparticles. Expression of GPIIb antigen, vitronectin, and LAMP-3 receptor were not affected by both agents. Two patients treated with prasugrel 10 mg/daily exhibited complete inhibition of collagen induced aggregation at 30 days. CONCLUSION: At the dosing regimens chosen in the JUMBO trial, it seems that prasugrel is a more potent antiplatelet agent than clopidogrel. Two episodes of profound platelet inhibition, which are not seen with clopidogrel, raise the possibility of higher bleeding risks especially during long term prasugrel use. Whether stronger platelet inhibition will yield better clinical outcomes and/or increased bleeding remains to be determined in an ongoing comparative phase 3 superiority trial (TRITON).

Clopidogrel↗
PubMed1987

Cell surface receptors for extracellular matrix molecules.

Table 2 lists most of the extracellular matrix and related receptors identified to date. The wide range of binding affinities of these receptors for their ligands may be important to their function. The affinity of integrins for fibronectin is moderate, with a dissociation constant in the micromolar range. This affinity level leads to relatively rapid dissociation and reformation of receptor-ligand complexes. Thus changes in component concentration can shift binding equilibria within minutes (the time scale of many biologic phenomena) and change the number or organization of adhesive complexes. This type of interaction would be useful in motile cells, in which adhesions must form and dissociate rapidly. In contrast, the affinity of the 68-kDa laminin receptor for its ligand is three orders of magnitude higher. Such levels of affinity would be useful in stabilizing tissue. Members of the integrin family appear to recognize an RGD sequence on the ligands to which they bind. Since there are many ligands containing the RGD sequence, the question of specificity arises. Avian integrin shows little specificity and appears to behave as a multifunctional, promiscuous receptor for extracellular matrix molecules. Figure 1 summarizes our current view of the structural and functional features of avian integrin. In contrast, the mammalian receptors for vitronectin and fibronectin are specific for their respective ligands. More than one of these receptors may be present simultaneously on a cell surface, e.g. fibroblasts express receptors for fibronectin, laminin, and vitronectin at the same time. This multiplicity of receptors provides potential mechanisms for generating the adhesive differences among cells believed to play a prominent role in morphogenesis. Further adhesive differences may stem from the formation of different combinations of various alpha- and beta-subunits expressed in the cell. The mechanism of regulation of adhesive interactions with the extracellular matrix is only beginning to be explored. There are several levels at which this regulation might occur. Integrin appears to be more regionalized in more developed cells that are integral parts of tissue structures. Changes in receptor distribution could alter the relative strength of adhesive interactions. In certain instances, avian integrin disappears, or its concentration is reduced, e.g. during the development of embryonic lung (Chen et al 1986) and erythroid cells (Patel & Lodish 1985). Post-translational modifications provide yet another mechanism for regulating integrin-ligand binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Role of phosphatidylinositol 3-kinase-gamma in mediating lung neutrophil sequestration and vascular injury induced by E. coli sepsis.

We addressed the in vivo role of phosphatidylinositol 3-kinase-gamma (PI3K-gamma) in signaling the sequestration of polymorphonuclear leukocytes (PMNs) in lungs and in the mechanism of inflammatory lung vascular injury. We studied mice with deletion of the p110 catalytic subunit of PI3K-gamma (PI3K-gamma(-/-) mice). We measured lung tissue PMN sequestration, microvascular permeability, and edema formation after bacteremia induced by intraperitoneal Escherichia coli challenge. PMN infiltration into the lung interstitium in PI3K-gamma(-/-) mice as assessed morphometrically was increased 100% over that in control mice within 1 h after bacterial challenge. PI3K-gamma(-/-) mice also developed a greater increase in lung microvascular permeability after E. coli challenge, resulting in edema formation. The augmented lung tissue PMN sequestration in PI3K-gamma(-/-) mice was associated with increased expression of the PMN adhesive proteins CD47 and beta(3)-integrins. We observed increased association of CD47 and beta(3)-integrins with the extracellular matrix protein vitronectin in lungs of PI3K-gamma(-/-) mice after E. coli challenge. PMNs from these mice also showed increased beta(3)-integrin expression and augmented beta(3)-integrin-dependent PMN adhesion to vitronectin. These results point to a key role of PMN PI3K-gamma in negatively regulating CD47 and beta(3)-integrin expression in gram-negative sepsis. PI3K-gamma activation in PMNs induced by E. coli may modulate the extent of lung tissue PMN sequestration secondary to CD47 and beta(3)-integrin expression. Therefore, the level of PI3K-gamma activation may be an important determinant of PMN-dependent lung vascular injury.

Animals↗