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Biomedical subjects

Daniel A Hammer

Publications and source records attributed to Daniel A Hammer.

At least 37 records · Page 2Linked to original sources
PubMed2005

Dynamic heterodimer-functionalized surfaces for endothelial cell adhesion.

The functionalization of hydrogels for receptor-mediated cell adhesion is one approach for targeted cell and tissue engineering applications. In this study, polyacrylamide gel surfaces were functionalized with specific cell adhesion ligands via the self-assembly of a peptide-based heterodimer. The system was comprised of a cysteine-terminated monomer, A (MW approximately 5400), grafted to the polyacrylamide gels and a complementary ligand presenting monomer, B(X) (MW approximately 5800) that was designed to heterodimerize with A. Two ligand presenting monomers were synthesized: one presenting the RGDS ligand, B(D), for receptor-mediated cell adhesion, and the other, a control monomer presenting the nonadhesive RGES ligand, B(E). Assembly of the peptide pair A-B(X) by association of the monomers into a coiled coil was verified by circular dichroism in solution. Binding studies were conducted to determine the dissociation constant of the pair A-B(X), which was found to be K(D) approximately 10(-8) m. Polyacrylamide gels functionalized with A-B(X) heterodimers were evaluated for cell adhesion using bovine aortic endothelial cells (BAECs). Endothelial cells cultured on the A-B(D) functionalized surfaces demonstrated typical cell morphologies and expected spreading behavior as a function of the density of RGDS ligand, calculated as the amount of B(D) associated with grafted A on the surface of the gels. In contrast, A-B(E) linked surfaces supported no cell adhesion. The adhesion of the substrate was dynamically altered through the reassembly of A-B(X) dimers as B(D) molecules in the solution replaced B(E) molecules at the substrate. The molecular constructs described here demonstrate the potential to design a broad family of switchable peptides that impart the dynamic control of biofunctionality at an interface, which would be useful for precise manipulation of cell physiology.

Adsorption↗
PubMed2005

In vitro characterization of leukocyte mimetic for targeting therapeutics to the endothelium using two receptors.

Selectins (E- and P-selectin) and other endothelial expressed leukocyte adhesion molecules (ELAMs) are potential targets for site-specific delivery of therapeutics to the vascular endothelium due to their specific and highly regulated expression in vascular disease. It was recently shown that degradable microspheres coated with antibodies against E-selectin or other ELAMs can target inflammation in vivo. However, targeting ELAMs alone cannot differentiate between normal and diseased state, as a basal level of these LAMs are expressed on endothelium in healthy tissues. Furthermore, leukocytes usually employ two separate adhesion molecules in parallel to home to diseased tissues, and we recently quantified the advantages of a two-receptor display for the targeting of leukocyte mimetics (Eniola AO, Willcox PJ, Hammer DA. Interplay between rolling and firm adhesion elucidated with a cell-free system engineered with two distinct receptor-ligand pairs. Biophys J 2003;85:2720-31). Here, we describe a leukocyte mimetic for targeting therapeutics to the vasculature in inflammatory diseases via two receptors, selectin and intercellular cell adhesion molecule-1 (ICAM-1), where biodegradable, polymer microspheres were co-functionalized with the selectin ligand, sialyl Lewis(X) (sLe(X)), and an antibody against ICAM-1, anti-ICAM-1 (aICAM-1). These two-receptor targeted particles, at given ratios of sLe(X)/aICAM-1, firmly adhere to substrate surface in flow only when both targeting ligands can interact with their respective receptors, mimicking the multi-step in vivo leukocyte adhesion in inflammation. Thus, we have faithfully recreated the specificity and extent of leukocyte adhesion in a platform that can allow for local delivery of therapeutics.

Animals↗
PubMed2005

Tensional homeostasis and the malignant phenotype.

Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.

3T3 Cells↗
PubMed2004

Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation.

Coagulation has long been known to facilitate metastasis. To pinpoint the steps where coagulation might play a role in the metastasis, we used three-dimensional visualization of direct infusion of fluorescence labeled antibody to observe the interaction of tumor cells with platelets and fibrinogen in isolated lung preparations. Tumor cells arrested in the pulmonary vasculature were associated with a clot composed of both platelets and fibrin(ogen). Initially, the cells attached to the pulmonary vessels were rounded. Over the next 2 to 6 hours, they spread on the vessel surface. The associated clot was lysed coincident with tumor cell spreading. To assess the importance of clot formation, we inhibited coagulation with hirudin, a potent inhibitor of thrombin. The number of tumor cells initially arrested in the lung of hirudin-treated mice was essentially the same as in control mice. However, tumor cell spreading and subsequent retention of the tumor cells in the lung was markedly inhibited in the anticoagulated mice. These associations of the tumor cells with platelets were independent of tumor cell expression of P-selectin ligands. This work identifies tumor cell spreading onto the vascular surface as an important component of the metastatic cascade and implicates coagulation in this process.

Adenocarcinoma↗
PubMed2004

Nano-to-micro scale dynamics of P-selectin detachment from leukocyte interfaces. III. Numerical simulation of tethering under flow.

Transient capture of cells or model microspheres from flow over substrates sparsely coated with adhesive ligands has provided significant insight into the unbinding kinetics of leukocyte:endothelium adhesion complexes under external force. Whenever a cell is stopped by a point attachment, the full hydrodynamic load is applied to the adhesion site within an exceptionally short time-less than the reciprocal of the hydrodynamic shear rate (e.g., typically <0.01 s). The decay in numbers of cells or beads that remain attached to a surface has been used as a measure of the kinetics of molecular bond dissociation under constant force, revealing a modest increase in detachment rate at growing applied shear stresses. On the other hand, when detached under steady ramps of force with mechanical probes (e.g., the atomic force microscope and biomembrane force probe), P-selectin:PSGL-1 adhesion bonds break at rates that increase enormously under rising force, yielding 100-fold faster off rates at force levels comparable to high shear. The comparatively weak effect of force on tether survival in flow chamber experiments could be explained by a possible partition of the load amongst several bonds. However, a comprehensive understanding of the difference in kinetic behavior requires us to also inspect other factors affecting the dynamics of attachment-force buildup, such as the interfacial compliance of all linkages supporting the adhesion complex. Here, combining the mechanical properties of the leukocyte interface measured in probe tests with single-bond kinetics and the kinetics of cytoskeletal dissociation, we show that for the leukocyte adhesion complex P-selectin:PSGL-1, a detailed adhesive dynamics simulation accurately reproduces the tethering behavior of cells observed in flow chambers. Surprisingly, a mixture of 10% single bonds and 90% dimeric bonds is sufficient to fully match the data of the P-selectin:PSGL-1 experiments, with the calculated decay in fraction of attached cells still appearing exponential.

Binding Sites↗
PubMed2004

The effect of cellular receptor diffusion on receptor-mediated viral binding using Brownian adhesive dynamics (BRAD) simulations.

Brownian adhesive dynamics (BRAD) is a new method for simulating the attachment of viruses to cell surfaces. In BRAD, the motion of the virus is subject to stochastic bond formation and breakage, and thermal motion owing to collisions from the solvent. In the model, the virus is approximated as a rigid sphere and the cell surface is approximated as a rigid plane coated with receptors. In this article, we extend BRAD to allow for the mobility of receptors in the plane of the membrane, both before and after they are ligated by viral attachment proteins. Allowing the proteins to move within the membrane produced several differences in behavior from when the receptors are immobilized. First, the mean steady-state bond number is unaffected by changes in cellular receptor density because proteins are now free to diffuse into the contact area, and the extent of binding is dictated by the availability of viral attachment proteins. Second, the time required to reach steady-state binding increases as both the cellular receptor number decreases and the receptor mobility decreases. This is because receptor diffusion is a slower process than the binding kinetics of the proteins. Decreasing the rate of protein binding was found to decrease the fraction of viruses bound to steady state, but not the extent of binding for those viruses that were bound. Increasing the binding rate increased the fraction of viruses bound, until no further viruses could bind. Alterations in receptor binding kinetics had no discernable effect on the mean steady-state bond number between virus and cell, because interactions were of sufficiently high affinity that all available receptor-viral attachment proteins were destined to bind at steady state.

Algorithms↗
PubMed2004

A semianalytic model of leukocyte rolling.

Rolling allows leukocytes to maintain adhesion to vascular endothelium and to molecularly coated surfaces in flow chambers. Using insights from adhesive dynamics, a computational method for simulating leukocyte rolling and firm adhesion, we have developed a semianalytic model for the steady-state rolling of a leukocyte. After formation in a force-free region of the contact zone, receptor-ligand bonds are transported into the trailing edge of the contact zone. Rolling velocity results from a balance of the convective flux of bonds and the rate of dissociation at the back edge of the contact zone. We compare the model's results to that of adhesive dynamics and to experimental data on the rolling of leukocytes, with good agreement. We calculate the dependence of rolling velocity on shear rate, intrinsic forward and reverse reaction rates, bond stiffness, and reactive compliance, and use the model to calculate a state diagram relating molecular parameters and the dynamic state of adhesion. A dimensionless form of the analytic model permits exploration of the parameters that control rolling. The chemical affinity of a receptor-ligand pair does not uniquely determine rolling velocity. We elucidate a fundamental relationship between off-rate, ligand density, and reactive compliance at the transition between firm and rolling adhesion. The model provides a rapid method for screening system parameters for the potential to mediate rolling.

Animals↗
PubMed2004

Rheology of binary colloidal structures assembled via specific biological cross-linking.

The selectivity and range of energies offered by specific biological interactions serve as valuable tools for engineering the assembly of colloidal particles into novel materials. In this investigation, high affinity biological interactions between biotin-coated "A" particles (RA = 0.475 microm) and streptavidin-coated "B" particles (RB = 2.75 microm) drive the self-assembly of a series of binary colloidal structures, from colloidal micelles (a large B particle coated by smaller A particles) to elongated chain microstructures (alternating A and B particles), as the relative number of small (A) to large (B) particles (2 < or = NA/NB < or = 200) is decreased at a low total volume fraction (10(-4) < or = phiT < or = 10(-3)). At a significantly higher total volume fraction (phiT > or = 10(-1)) and a low number ratio (NA/NB = 2), the rheological behavior of volume-filling particle networks connected by streptavidin-biotin bonds is characterized. The apparent viscosity (eta) as a function of the shear rate gamma, measured for networks at phiT = 0.1 and 0.2, exhibits shear-rate-dependent flow behavior, and both the apparent viscosity and the extent of shear thinning increase upon an increase of a factor of 2 in the total volume fraction. Micrographs taken before and after shearing show a structural breakdown of the flocculated binary particle network into smaller flocs, and ultimately a fluidlike suspension, with increasing shear rate. Rheological measurements provide further proof that suspension microstructure is governed by specific biomolecular interactions, as control experiments in which the streptavidin molecules on particles were blocked displayed Newtonian flow behavior. This investigation represents the first attempt at measuring the rheology of colloidal suspensions where assembly is driven by biomolecular cross-linking.

Biotin↗
PubMed2004

The effect of polymer chain length and surface density on the adhesiveness of functionalized polymersomes.

Giant cell-like polymer vesicles, polymersomes, made from the diblock copolymer poly(ethylene oxide)-polybutadiene (PEO-PBD), have bilayer structures similar to the cell membrane but have superior and tunable properties for storage and stability. We have modified the terminal hydroxyl of the hydrophilic block with biotin-lysine (biocytin), a biologically derived group that imparts specific adhesiveness to a polymer colloid coated with avidin. The functionalized polymer will form vesicles, either on its own or when mixed with unmodified block copolymers that also form vesicles. The incorporation and mixing of the functionalized polymer into vesicle bilayers is measured using a fluorescent version ofbiocytin with confocal microscopy. The fluorescence signal associated with the vesicle is in proportion with the concentration of functional polymer added during vesicle construction. The adhesiveness of polymer vesicles containing functionalized biotinylated polymer to avidin coated microspheres is measured with micropipet aspiration. Two types of polymer vesicles were constructed: one where the functionalized polymer (molecular weight (MW), 10400 Da) was longer than the surrounding unfunctionalized polymer (MW, 3600 Da) and one where the functionalized polymer (MW, 10400 Da) was the same length as the unfunctionalized polymer. In all cases, the avidin-biotin bonds form kinetically trapped crossbridges that impart little tension as they form but require significantly more tension to break. The relative length of the functionalized polymer on the surface of the vesicle is an important determinant for the adhesion of a polymer vesicle but not for the adsorption of soluble avidin. Greater adhesion strengths are seen where the functionalized polymer is longer than the surrounding polymer. The concentration of functionalized polymer at which adhesion is maximal depends on the relative lengths of the polymers. When the functionalized polymer is the same length as the surface brush of the polymersome membrane, the critical tension is maximal at 10 mol % functionalized polymer concentration. However, when the biocytin groups are attached to a polymer which is larger than the surface brush, the critical tension is maximal at 55 mol % functionalized polymer. These results indicate that polymer mixing and length can control the interfacial adhesion of polymer brushes and must be understood to tune polymersome adhesiveness.

Adhesiveness↗
PubMed2004

Oligomerization of fusogenic peptides promotes membrane fusion by enhancing membrane destabilization.

A key element of membrane fusion reactions in biology is the involvement of specific fusion proteins. In many viruses, the proteins that mediate membrane fusion usually exist as homotrimers. Furthermore, they contain extended triple-helical coiled-coil domains and fusogenic peptides. It has been suggested that the coiled-coil domains present the fusogenic peptide in a conformation or geometry favorable for membrane fusion. To test the hypothesis that trimerization of fusogenic peptide is related to optimal fusion, we have designed and synthesized a triple-stranded coiled-coil X31 peptide, also known as the ccX31, which mimics the influenza virus hemagglutinin fusion peptide in the fusion-active state. We compared the membrane interactive properties of ccX31 versus the monomeric X31 fusogenic peptide. Our data show that trimerization enhances peptide-induced leakage of liposomal contents and lipid mixing. Furthermore, studies using micropipette aspiration of single vesicles reveal that ccX31 decreases lysis tension, tau(lysis), but not area expansion modulus, Ka, of phospholipid bilayers, whereas monomeric X31 peptide lowers both tau(lysis) and Ka. Our results are consistent with the hypothesis that oligomerization of fusogenic peptide promotes membrane fusion, possibly by enhancing localized destabilization of lipid bilayers.

Dimerization↗
PubMed2004

Platelet receptor glycoprotein VI-mediated adhesion to type I collagen under hydrodynamic flow.

Glycoprotein VI (GPVI) is a platelet receptor that directly binds collagen. It has been shown by expressing GPVI in rat basophilic leukemia (RBL-2H3) cells that GPVI mediates adhesion to type I collagen under static conditions. However, the ability of GPVI to secure adhesion to collagen type I under flow has not been measured. We studied the interaction of GPVI and type I collagen under hydrodynamic flow using RBL-2H3 cells transfected with the GPVI receptor. We found that GPVI-expressing RBL-2H3 cells adhere to collagen under flow, significantly more so than non-GPVI-expressing RBL-2H3 cells. Inhibition of GPVI by the 11A12 anti-GPVI antibody significantly blocks adhesion to collagen, indicating that GPVI specifically interacts with collagen. Probing the role of signaling in GPVI binding to collagen, we used mutants of GPVI and observed that signal transduction did not inhibit adhesion. To test the correlation between receptor expression and adhesion, we tested three GPVI-expressing RBL-2H3 cell lines (A, B, and C) with different levels of receptor expression. At a single shear rate, the level of adhesion increases monotonically with surface expression. The results, using this model cell line, indicate that GPVI is capable of mediating adhesion to collagen under shear, in a density-dependent fashion that is independent of GPVI signaling.

Animals↗
PubMed2004

Brownian adhesive dynamics (BRAD) for simulating the receptor-mediated binding of viruses.

Current viral docking models have relied upon the assumption that bond formation and breakage are independent of viral and docking surface geometry, as well as the forces exerted on the bonds. This assumption, known as the equivalent site hypothesis (ESH), is examined in detail using a newly developed simulation technique-Brownian adhesive dynamics (BRAD). The simulation couples the thermal motion of viral particles with adhesive dynamics models to characterize the effect of bonding on viral motion. We use the binding of HIV-like particles to CD4 expressing cells as a model system to illustrate the utility of BRAD. Comparison of the transition rates between bound states predicted by ESH and the rates resulting from BRAD simulations show dramatic differences; at values of the equilibrium crosslinking constant, K(x)R(T), where ESH suggests all virus adhesion proteins will be bound (K(x)R(T) = 10(6)), BRAD predicts not all virus adhesion proteins will be bound. At values of the equilibrium crosslinking constant used in typical ESH calculations of virus docking (K(x)R(T) = 1) we find BRAD simulations predict no binding. The mean bond density from BRAD models is often much lower than that predicted by ESH for equivalent parameter values. BRAD suggests that the viruses are much less well bound than ESH predicts. The differences suggest that binding models for viruses need to be reexamined closely. BRAD is a simulation technique that will be useful for quantifying the receptor-mediated binding of a wide variety of viruses to cells.

Algorithms↗
PubMed2003

Localization of BCR-ABL to F-actin regulates cell adhesion but does not attenuate CML development.

We have previously found that P210BCR-ABL increases the adhesion of hematopoietic cell lines to fibronectin by a mechanism that is independent of tyrosine kinase activity. To investigate the pathway(s) by which P210BCR-ABL influences cell adhesion, we used a quantitative cell adhesion device that can discern small changes in cell adhesion to assay P210BCR-ABL with mutations in several critical domains. We expressed P210BCR-ABL mutants in 32D myeloblast cells and found that binding to fibronectin is mediated primarily by the alpha5beta1 integrin. We performed a structure/function analysis to map domains important for cell adhesion. Increased adhesion was mediated by 3 domains: (1) the N-terminal coiled-coil domain that facilitates oligomerization and F-actin localization; (2) bcr sequences between aa 163 to 210; and (3) F-actin localization through the C-terminal actin-binding domain of c-abl. We compared our adhesion results with the ability of these mutants to cause a chronic myelogenous leukemia (CML)-like disease in a murine bone marrow transplantation assay and found that adhesion to fibronectin did not correlate with the ability of these mutants to cause CML. Together, our results suggest that F-actin localization may play a pivotal role in modulating adhesion but that it is dispensable for the development of CML.

Actins↗
PubMed2003

Artificial polymeric cells for targeted drug delivery.

Selectins are optimal biological molecules for targeted delivery of therapeutic agents because of their localized and carefully regulated expression in several human diseases, and their highly specific interactions with their counter receptors. In this study, we describe a targeted delivery system that can potentially deliver anti-inflammatory drug to sites of chronic inflammation using Poly(lactic-co-glycolic acid) (PLGA) and selectin-ligand chemistry. Biotinylated-sialyl Lewis(x) (sLe(x)), a carbohydrate that serves as a ligand to selectins, was attached to the surface of avidin-linked PLGA microspheres. These carbohydrate-coated microspheres mimic the adhesive behavior of leukocytes on selectins in flow chambers, displaying slow rolling under flow. The rolling velocity of these artificial leukocytes is similar to that displayed by leukocytes rolling on P- or E-selectin coated surfaces. We can tune rolling velocity, and hence residence time of capsules on surfaces, by changing the density of sialyl Lewis(x) on the microsphere surfaces. Therefore, we have made a targeted drug delivery vehicle that mimics the adhesive properties of leukocytes and is biodegradable.

Drug Delivery Systems↗
PubMed2003

Interplay between rolling and firm adhesion elucidated with a cell-free system engineered with two distinct receptor-ligand pairs.

The firm arrest of leukocytes to the endothelium during inflammation is known to be mediated by endothelial intercellular adhesion molecules (ICAMs) binding to activated integrins displayed on leukocyte surface. Selectin-ligand interactions, which mediate rolling, are believed to be important for facilitating firm adhesion, either by activating integrins or by facilitating the transition to firm adhesion by making it easier for integrins to bind. Although leukocytes employ two distinct adhesion molecules that mediate different states of adhesion, the fundamental biophysical mechanisms by which two pairs of adhesion molecules facilitate cell adhesion is not well understood. In this work, we attempt to understand the interaction between two molecular systems using a cell-free system in which polystyrene microspheres functionalized with the selectin ligand, sialyl Lewis(X) (sLe(X)), and an antibody against ICAM-1, aICAM-1, are perfused over P-selectin/ICAM-1 coated surfaces in a parallel plate flow chamber. Separately, sLe(X)/P-selectin interactions support rolling and aICAM-1/ICAM-1 interactions mediate firm adhesion. Our results show that sLe(X)/aICAM-1 microspheres will firmly adhere to P-selectin/ICAM-1 coated surfaces, and that the extent of firm adhesion of microspheres is dependent on wall shear stress within the flow chamber, sLe(X)/aICAM-1 microsphere site density, and P-selectin/ICAM-1 surface density ratio. We show that P-selectin's interaction with sLe(X) mechanistically facilitates firm adhesion mediated by antibody binding to ICAM-1: the extent of firm adhesion for the same concentration of aICAM-1/ICAM-1 interaction is greater when sLe(X)/P-selectin interactions are present. aICAM-1/ICAM-1 interactions also stabilize rolling by increasing pause times and decreasing average rolling velocities. Although aICAM-1 is a surrogate for beta(2)-integrin, the kinetics of association between aICAM-1 and ICAM-1 is within a factor of 1.5 of activated integrin binding ICAM-1, suggesting the findings from this model system may be insightful to the mechanism of leukocyte firm adhesion. In particular, these experimental results show how two molecule systems can interact to produce an effect not achievable by either system alone, a fundamental mechanism that may pervade leukocyte adhesion biology.

Antigen-Antibody Complex↗
PubMed2003

The state diagram for cell adhesion mediated by two receptors.

Leukocyte recruitment from the bloodstream to surrounding tissues is an essential component of the immune response. Capture of blood-borne leukocytes onto vascular endothelium proceeds via a two-step mechanism, with each step mediated by a distinct receptor-ligand pair. Cells first transiently adhere, or "roll" (via interactions between selectins and sialyl-Lewis-x), and then firmly adhere to the vascular wall (via interactions between integrins and ICAM-1). We have reported that a computational method called adhesive dynamics (AD) accurately reproduces the fine-scale dynamics of selectin-mediated rolling. This paper extends the use of AD simulations to model the dynamics of cell adhesion when two classes of receptors are simultaneously active: one class (selectins or selectin ligands) with weakly adhesive properties, and the other (integrins) with strongly adhesive properties. AD simulations predict synergistic functions of the two receptors in mediating adhesion. At a fixed density of surface ICAM-1, increasing selectin densities lead to greater pause times and an increased tendency toward firm adhesion; thus, selectins mechanistically facilitate firm adhesion mediated by integrins. Conversely, at a fixed density of surface selectin, increasing ICAM-1 densities lead to greater pause times and an increased tendency to firm adhesion. We present this relationship in a two-receptor state diagram, a map that relates the densities and properties of adhesion molecules to various adhesive behaviors that they code, such as rolling or firm adhesion. We also present a state diagram for neutrophil activation, which relates beta(2)-integrin density and integrin-ICAM-1 kinetic on rate to neutrophil adhesive behavior. The predictions of two-receptor adhesive dynamics are validated by the ability of the model to reproduce in vivo neutrophil rolling velocities from the literature.

Binding Sites↗
PubMed2003

Hydrodynamic interactions between rolling leukocytes in vivo.

OBJECTIVE: The aim of this study was to characterize the hydrodynamic interactions between rolling and free-stream leukocytes in an in vivo model of selectin-mediated rolling, and to identify those physical mechanisms that influence the dynamics of transient adhesion with the walls of postcapillary venules. METHODS: Postcapillary venules of diameter 22-37 microm in the cheek pouch of anesthetized hamsters were visualized using intravital microscopy, with selectin-mediated rolling occurring in response to surgical preparation. RESULTS: Rolling velocity was found to be a strong function of the center-to-center separation with the nearest cell, and also was found to correlate strongly with the number of nearby cells. These effects are shown to be beyond that attributable to variations along the length of the vessel. Adherent leukocytes were observed to provide a nucleation site, precipitating further adhesion events of free-stream cells. CONCLUSIONS: The dynamics of the transient adhesion of leukocytes to the vessel wall in postcapillary venules is strongly dependent on the local concentration of adherent leukocytes, due to the complex hydrodynamics induced by their presence. The results are shown to agree well with theoretical considerations of the flow field induced by multiple nearby cells, suggesting a need for the future exploration of multicellular effects in the microcirculation.

Animals↗