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Yann R. Chemla - One of the best experts on this subject based on the ideXlab platform.
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Mapping cell surface Adhesion by rotation tracking and Adhesion footprinting.
Scientific reports, 2017Co-Authors: Yann R. ChemlaAbstract:Rolling Adhesion, in which cells passively roll along surfaces under shear flow, is a critical process involved in inflammatory responses and cancer metastasis. Surface Adhesion properties regulated by Adhesion receptors and membrane tethers are critical in understanding cell Rolling behavior. Locally, Adhesion molecules are distributed at the tips of membrane tethers. However, how functional Adhesion properties are globally distributed on the individual cell's surface is unknown. Here, we developed a label-free technique to determine the spatial distribution of adhesive properties on Rolling cell surfaces. Using dark-field imaging and particle tracking, we extract the rotational motion of individual Rolling cells. The rotational information allows us to construct an Adhesion map along the contact circumference of a single cell. To complement this approach, we also developed a fluorescent Adhesion footprint assay to record the molecular Adhesion events from cell Rolling. Applying the combination of the two methods on human promyelocytic leukemia cells, our results surprisingly reveal that Adhesion is non-uniformly distributed in patches on the cell surfaces. Our label-free Adhesion mapping methods are applicable to the variety of cell types that undergo Rolling Adhesion and provide a quantitative picture of cell surface Adhesion at the functional and molecular level.
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Mapping cell surface Adhesion by rotation tracking and Adhesion footprinting.
Scientific Reports, 2017Co-Authors: Isaac T. S. Li, Taekjip Ha, Yann R. ChemlaAbstract:Rolling Adhesion is the behaviour that leukocytes and circulating tumour cells exhibit as they passively roll along blood vessel walls under flow. It plays a critical role in capturing cells in the blood, guiding them toward inflammation sites, and activating cell signalling pathways to enable their subsequent transmigration. Rolling Adhesion is mediated by catch-bond-like interactions between selectins expressed on endothelial cells lining blood vessels and P-selectin glycoprotein ligand-1 found at microvilli tips of leukocytes. Despite our understanding of individual components of this process, how the molecular details of Adhesion bonds scale to cell-surface Adhesion and Rolling behaviour remains poorly understood. Here, we developed 2 label-free methods that map the functional Adhesion sites and their strength on a leukocyte surface. The first method relies on tracking the rotational angle of a single Rolling cell, which confers advantages over standard methods that track the centre-of-mass alone. Constructing the Adhesion map from the instantaneous angular velocity reveals that the Adhesion profile along the Rolling circumference is inhomogeneous. We corroborated these findings with a second method that allowed us to obtain a footprint of molecular Adhesion events using DNA-based molecular force probes. Our results reveal that Adhesion at the functional level is not uniformly distributed over the leukocyte surface as previously assumed, but is instead patchy.
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Rotation Tracking and Adhesion Footprinting Reveal Asymmetric Rolling Adhesion Mechanism
Biophysical Journal, 2016Co-Authors: Yann R. ChemlaAbstract:Rolling Adhesion is the behaviour that leukocytes and circulating tumour cells exhibit as they passively roll along blood vessel walls under flow. It plays a critical role in capturing cells in the blood, guiding them toward inflammation sites, and activating cell signalling pathways to enable their subsequent transmigration. Rolling Adhesion is mediated by catch-bond-like interactions between selectins expressed on endothelial cells lining blood vessels and P-selectin glycoprotein ligand-1 (PSGL-1) found at microvilli tips of leukocytes. Despite our understanding of individual components of this process, how the molecular details of Adhesion bonds scale to cell-surface Adhesion and Rolling behaviour remains poorly understood. Here, we developed a method that maps the functional Adhesion sites and their strength on a leukocyte surface. The method relies on tracking the rotational angle of a single Rolling cell, which confers advantages over standard methods that track the centre-of-mass alone. Constructing the Adhesion map from the instantaneous angular velocity reveals that the Adhesion profile along the Rolling circumference is inhomogeneous. We corroborated these findings by obtaining a footprint of molecular Adhesion events using DNA-based molecular force probes. Our results reveal that Adhesion at the functional level is not uniformly distributed over the leukocyte surface as previously assumed, but is instead patchy.
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Tracking Rotation during Leukocyte Rolling Reveals Asymmetric Adhesion Properties
Biophysical Journal, 2015Co-Authors: Yann R. ChemlaAbstract:Leukocytes are responsible for fighting infections in the body. When injuries occur, selectin molecules are expressed on the surface of nearby blood vessel walls. These selectin molecules transiently adhere to leukocytes flowing in the bloodstream and capture them, leading to leukocyte Rolling towards the injury site. Rolling Adhesion is critical for leukocytes to locate injury sites and to activate various signaling pathways for subsequent transmigration and chemotaxis.Individual Adhesion components involved in Rolling Adhesion, such as Adhesion molecules and membrane tethers have been characterized. However, models incorporating these properties are still unable to describe fully the Rolling behavior. Current models assume uniformly distributed Adhesion properties on cell surfaces due to the lack of measurements quantifying this distribution. Here, we determined experimentally the spatial distribution of adhesive properties on leukocyte surfaces. We used dark-field imaging and particle tracking techniques to extract not only the translational but also the rotational motion of a single Rolling cell. The additional rotational information allows us to map precisely the whole cell motion and Adhesion properties to a particular cell orientation. We find that the Adhesion properties of the leukocyte surface are far from homogenous, with large, localized patches on the cell surface exhibiting strong or weak adhesive properties. This finding provides new insight into leukocyte Adhesion properties, such as the asymmetric distribution of receptor and microvilli on Rolling cells, and could lead to better modeling of Rolling Adhesion.
Daniel A. Hammer - One of the best experts on this subject based on the ideXlab platform.
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Rolling Adhesion of αL I Domain Mutants Decorrelated from Binding Affinity
Journal of molecular biology, 2006Co-Authors: Lauren R. Pepper, Daniel A. Hammer, Eric T. BoderAbstract:Activated lymphocyte function-associated antigen-1 (LFA-1, αLβ2 integrin) found on leukocytes facilitates firm Adhesion to endothelial cell layers by binding to intercellular Adhesion molecule-1 (ICAM-1), which is up-regulated on endothelial cells at sites of inflammation. Recent work has shown that LFA-1 in a pre-activation, low-affinity state may also be involved in the initial tethering and Rolling phase of the Adhesion cascade. The inserted (I) domain of LFA-1 contains the ligand-binding epitope of the molecule, and a conformational change in this region during activation increases ligand affinity. We have displayed wild-type I domain on the surface of yeast and validated expression using I domain specific antibodies and flow cytometry. Surface display of I domain supports yeast Rolling on ICAM-1-coated surfaces under shear flow. Expression of a locked open, high-affinity I domain mutant supports firm Adhesion of yeast, while yeast displaying intermediate-affinity I domain mutants exhibit a range of Rolling phenotypes. We find that Rolling behavior for these mutants fails to correlate with ligand binding affinity. These results indicate that unstressed binding affinity is not the only molecular property that determines adhesive behavior under shear flow.
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Rolling Adhesion kinematics of yeast engineered to express selectins.
Biotechnology progress, 2003Co-Authors: Sujata K. Bhatia, Raymond T. Camphausen, Jeffrey Swers, K. Dane Wittrup, Daniel A. HammerAbstract:Selectins are cell Adhesion molecules that mediate capture of leukocytes on vascular endothelium as an essential component of the inflammatory response. Here we describe a method for yeast surface display of selectins, together with a functional assay that measures Rolling Adhesion of selectin-expressing yeast on a ligand-coated surface. E-selectin-expressing yeast roll specifically on surfaces bearing sialyl-Lewis-x ligands. Observation of yeast Rolling dynamics at various stages of their life cycle indicates that the kinematics of yeast motion depends on the ratio of the bud radius to the parent radius (B/P). Large-budded yeast "walk" across the surface, alternately pivoting about bud and parent. Small-budded yeast "wobble" across the surface, with bud pivoting about parent. Tracking the bud location of budding yeast allows measurement of the angular velocity of the yeast particle. Comparison of translational and angular velocities of budding yeast demonstrates that selectin-expressing cells are Rolling rather than slipping across ligand-coated surfaces.
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Cell separation mediated by differential Rolling Adhesion.
Biotechnology and bioengineering, 2001Co-Authors: Adam W. Greenberg, Daniel A. HammerAbstract:Recently, we showed a correlation between the maturity of hematopoietic stem and progenitor cells during development and Rolling efficiency on selectins. These findings motivated us to explore a novel separation that exploits differences in selectin-mediated Rolling Adhesion between populations of cells. We extend the use of a previously developed cell-free system to study the separation of populations of sialyl Lewis x (sLe(x))-coated microspheres designed to roll with different average velocities on L-selectin chimeric substrates under well-defined flow. Results show that a separation that exploits differences in average Rolling velocities between cell or microsphere populations is attainable. Excellent recovery and purity values for the slower Rolling, or more desirable, populations are obtained and can be estimated from Rolling velocity measurements. We also assess the feasibility of a selectin-mediated separation of adult bone marrow cell populations using previously obtained Rolling velocity and Rolling flux data for CD34+ and CD34- adult bone marrow cells on L-selectin substrates. We believe that a cell separation mediated by differential Rolling Adhesion can be used to enrich populations of hematopoietic stem and progenitor cells from an adult bone marrow cell preparation and that this method possesses several major advantages over existing antibody-mediated cell-affinity chromatography technologies.
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Tyrosine sulfation enhances but is not required for PSGL-1 Rolling Adhesion on P-selectin.
Biophysical journal, 2001Co-Authors: Stephen D. Rodgers, Raymond T. Camphausen, Daniel A. HammerAbstract:P-selectin glycoprotein ligand-1 (PSGL-1) is a large (240 kDa) glycoprotein found on the surface of nearly all leukocytes. The mature molecule is decorated with multiple N- and O-linked glycans and displays copies of the tetrasaccharide sialyl-Lewis(x) (sLe(X)), as well as a cluster of three tyrosine sulfate (tyr-SO(3)) groups near the N-terminus of the processed protein. Previous studies have suggested that PSGL-1 needs to be tyrosine-sulfated, in addition to glycosylated with sLe(X), to successfully interact with P-selectin. To better understand how biochemical features of the PSGL-1 ligand are related to its Adhesion phenotype, we have measured the dynamics of Adhesion under flow of a series of well-defined PSGL-1 variants that differ in their biochemical modification, to both P- and E-selectin-coated substrates. These variants are distinct PSGL-1 peptides: one that possesses sLe(X) in conjunction with three N-terminal tyr-SO(3) groups (SGP3), one that possesses sLe(X) without tyrosine sulfation (GP1), and one that lacks sLe(X) but has three N-terminal tyr-SO(3) groups (SP3). Although all peptides expressing sLe(X), tyr-SO(3), or both supported some form of Rolling Adhesion on P-selectin, only peptides expressing sLe(X) groups showed Rolling Adhesion on E-selectin. On P-selectin, the PSGL-1 peptides demonstrated a decreasing strength of Adhesion in the following order: SGP3 > GP1 > SP3. Robust, Rolling Adhesion on P-selectin was mediated by the GP1 peptide, despite its lack of tyrosine sulfation. However, the addition of tyrosine sulfation to glycosylated peptides (SGP3) creates a super ligand for P-selectin that supports slower Rolling Adhesion at all shear rates and supports Rolling Adhesion at much higher shear rates. Tyrosine sulfation has no similar effect on PSGL-1 Rolling on E-selectin. Such functional distinctions in Rolling dynamics are uniquely realized with a cell-free system, which permits precise, unambiguous identification of the functional activity of adhesive ligands. These findings are consistent with structural and functional characterizations of the interactions between these peptides and E- and P-selectin published recently.
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Sialyl LewisX-Mediated, PSGL-1-Independent RollingAdhesion on P-selectin
Biophysical journal, 2000Co-Authors: Stephen D. Rodgers, Raymond T. Camphausen, Daniel A. HammerAbstract:Selectin-mediated cell Adhesion is an essential component of the inflammatory response. In an attempt to unambiguously identify molecular features of ligands that are necessary to support Rolling Adhesion on P-selectin, we have used a reconstituted ("cell-free") system in which ligand-coated beads are perfused over soluble P-selectin surfaces. We find that beads coated with the saccharides sialyl Lewis(x) (sLe(x)), sialyl Lewis(a) (sLe(a)), and sulfated Lewis(x) (HSO(3)Le(x) support Rolling Adhesion on P-selectin surfaces. Although it has been suggested that glycosylation and sulfation of P-selectin glycoprotein ligand-1 (PSGL-1) is required for high-affinity binding and Rolling on P-selectin, our findings indicate that sulfation of N-terminal tyrosine residues is not required for binding or Rolling. However, beads coated with a tyrosine-sulfated, sLe(x)-modified, PSGL-1-Fc chimera support slower Rolling on P-selectin than beads coated with sLe(x) alone, suggesting that sulfation improves Rolling Adhesion by modulating binding to P-selectin. In addition, we find it is not necessary that P-selectin carbohydrate ligands be multivalent for robust Rolling to occur. Our results demonstrate that beads coated with monovalent sLe(x), exhibiting a more sparse distribution of carbohydrate than a similar amount of the multivalent form, are sufficient to yield Rolling Adhesion. The relative abilities of various ligands to support Rolling on P-selectin are quantitatively examined among themselves and in comparison to human neutrophils. Using stop-time distributions, Rolling dynamics at video frame rate resolution, and the average and variance of the Rolling velocity, we find that P-selectin ligands display the following quantitative trend, in order of decreasing ability to support Rolling Adhesion on P-selectin: PSGL-1-Fc > sLe(a) approximately sLe(x) > HSO(3)Le(x).
A M Joussen - One of the best experts on this subject based on the ideXlab platform.
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contribution of tnf alpha to leukocyte Adhesion vascular leakage and apoptotic cell death in endotoxin induced uveitis in vivo
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Kan Koizumi, Vassiliki Poulaki, S Doehmen, Gerhard Welsandt, Sven Radetzky, A Lappas, Norbert Kociok, B Kirchhof, A M JoussenAbstract:PURPOSE:To investigate the effect of TNF-alpha on leukocyte Adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis (EIU) in the rat. METHODS:EIU was induced in Long-Evans rats by a single footpad injection of lipopolysaccharide (LPS; 350 microg/kg) from Salmonella typhimurium. A single injection of recombinant TNF receptor P75 (etanercept) was given subcutaneously 24 hours before the administration of LPS. Twenty-four hours after administration of LPS, leukocyte Adhesion was evaluated in vivo with SLO-acridine orange angiography and ex vivo with concanavalin A lectin staining of retinal flatmounts. Neutrophil activation was quantified by a myeloperoxidase activity assay. Vascular leakage was assessed by Evans blue extravasation. Retinal cell death was assessed with TUNEL staining and quantified with a modified ELISA protocol. Involvement of caspase-3 and -8 was determined by M30 antibody staining, Western blot analysis, and a test for enzymatic activity. RESULTS:Twenty-four hours after the LPS injection, significant increases in leukocyte Rolling, Adhesion, and activation were observed. In addition, increased levels of apoptosis in the vascular endothelium and the ganglion cell and inner nuclear layers and activation of caspase-8 and -3 were observed. After administration of the TNF-alpha inhibitor, significant reduction in the leukocyte Rolling, Adhesion, activation, and apoptosis in all the affected layers was observed. The quantitative analysis of vascular leakage revealed a significant decrease after treatment with etanercept. Retinal cell death quantification showed a significant decrease after treatment with the TNF-alpha inhibitor. CONCLUSIONS:Anti-TNF-alpha treatment reduces the LPS-induced increases in leukocyte Rolling, Adhesion, and vascular leakage in this rat model of inflammatory uveitis. These results suggest the involvement of TNF-alpha in inflammatory uveitis and its potential use as a therapeutic agent in the reduction of ocular inflammation.
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Contribution of TNF-alpha to leukocyte Adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo.
Investigative ophthalmology & visual science, 2003Co-Authors: Kan Koizumi, Vassiliki Poulaki, S Doehmen, Gerhard Welsandt, Sven Radetzky, A Lappas, Norbert Kociok, B Kirchhof, A M JoussenAbstract:PURPOSE To investigate the effect of TNF-alpha on leukocyte Adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis (EIU) in the rat. METHODS EIU was induced in Long-Evans rats by a single footpad injection of lipopolysaccharide (LPS; 350 microg/kg) from Salmonella typhimurium. A single injection of recombinant TNF receptor P75 (etanercept) was given subcutaneously 24 hours before the administration of LPS. Twenty-four hours after administration of LPS, leukocyte Adhesion was evaluated in vivo with SLO-acridine orange angiography and ex vivo with concanavalin A lectin staining of retinal flatmounts. Neutrophil activation was quantified by a myeloperoxidase activity assay. Vascular leakage was assessed by Evans blue extravasation. Retinal cell death was assessed with TUNEL staining and quantified with a modified ELISA protocol. Involvement of caspase-3 and -8 was determined by M30 antibody staining, Western blot analysis, and a test for enzymatic activity. RESULTS Twenty-four hours after the LPS injection, significant increases in leukocyte Rolling, Adhesion, and activation were observed. In addition, increased levels of apoptosis in the vascular endothelium and the ganglion cell and inner nuclear layers and activation of caspase-8 and -3 were observed. After administration of the TNF-alpha inhibitor, significant reduction in the leukocyte Rolling, Adhesion, activation, and apoptosis in all the affected layers was observed. The quantitative analysis of vascular leakage revealed a significant decrease after treatment with etanercept. Retinal cell death quantification showed a significant decrease after treatment with the TNF-alpha inhibitor. CONCLUSIONS Anti-TNF-alpha treatment reduces the LPS-induced increases in leukocyte Rolling, Adhesion, and vascular leakage in this rat model of inflammatory uveitis. These results suggest the involvement of TNF-alpha in inflammatory uveitis and its potential use as a therapeutic agent in the reduction of ocular inflammation.
Ronald J. Korthuis - One of the best experts on this subject based on the ideXlab platform.
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Intravital microscopic methods to evaluate anti-inflammatory effects and signaling mechanisms evoked by hydrogen sulfide.
Methods in Enzymology, 2015Co-Authors: Mozow Y. Zuidema, Ronald J. KorthuisAbstract:Abstract Hydrogen sulfide (H 2 S) is an endogenous gaseous signaling molecule with potent anti-inflammatory properties. Exogenous application of H 2 S donors, administered either acutely during an inflammatory response or as an antecedent preconditioning intervention that invokes the activation of anti-inflammatory cell survival programs, effectively limits leukocyte Rolling, Adhesion and emigration, generation of reactive oxygen species, chemokine and cell Adhesion molecule expression, endothelial barrier disruption, capillary perfusion deficits, and parenchymal cell dysfunction and injury. This chapter focuses on intravital microscopic methods that can be used to assess the anti-inflammatory effects exerted by H 2 S, as well as to explore the cellular signaling mechanisms by which this gaseous molecule limits the aforementioned inflammatory responses. Recent advances include use of intravital multiphoton microscopy and optical biosensor technology to explore signaling mechanisms in vivo .
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Intravital microscopic methods to evaluate anti-inflammatory effects and signaling mechanisms evoked by hydrogen sulfide.
Methods in enzymology, 2015Co-Authors: Mozow Y. Zuidema, Ronald J. KorthuisAbstract:Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule with potent anti-inflammatory properties. Exogenous application of H2S donors, administered either acutely during an inflammatory response or as an antecedent preconditioning intervention that invokes the activation of anti-inflammatory cell survival programs, effectively limits leukocyte Rolling, Adhesion and emigration, generation of reactive oxygen species, chemokine and cell Adhesion molecule expression, endothelial barrier disruption, capillary perfusion deficits, and parenchymal cell dysfunction and injury. This chapter focuses on intravital microscopic methods that can be used to assess the anti-inflammatory effects exerted by H2S, as well as to explore the cellular signaling mechanisms by which this gaseous molecule limits the aforementioned inflammatory responses. Recent advances include use of intravital multiphoton microscopy and optical biosensor technology to explore signaling mechanisms in vivo.
Kan Koizumi - One of the best experts on this subject based on the ideXlab platform.
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contribution of tnf alpha to leukocyte Adhesion vascular leakage and apoptotic cell death in endotoxin induced uveitis in vivo
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Kan Koizumi, Vassiliki Poulaki, S Doehmen, Gerhard Welsandt, Sven Radetzky, A Lappas, Norbert Kociok, B Kirchhof, A M JoussenAbstract:PURPOSE:To investigate the effect of TNF-alpha on leukocyte Adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis (EIU) in the rat. METHODS:EIU was induced in Long-Evans rats by a single footpad injection of lipopolysaccharide (LPS; 350 microg/kg) from Salmonella typhimurium. A single injection of recombinant TNF receptor P75 (etanercept) was given subcutaneously 24 hours before the administration of LPS. Twenty-four hours after administration of LPS, leukocyte Adhesion was evaluated in vivo with SLO-acridine orange angiography and ex vivo with concanavalin A lectin staining of retinal flatmounts. Neutrophil activation was quantified by a myeloperoxidase activity assay. Vascular leakage was assessed by Evans blue extravasation. Retinal cell death was assessed with TUNEL staining and quantified with a modified ELISA protocol. Involvement of caspase-3 and -8 was determined by M30 antibody staining, Western blot analysis, and a test for enzymatic activity. RESULTS:Twenty-four hours after the LPS injection, significant increases in leukocyte Rolling, Adhesion, and activation were observed. In addition, increased levels of apoptosis in the vascular endothelium and the ganglion cell and inner nuclear layers and activation of caspase-8 and -3 were observed. After administration of the TNF-alpha inhibitor, significant reduction in the leukocyte Rolling, Adhesion, activation, and apoptosis in all the affected layers was observed. The quantitative analysis of vascular leakage revealed a significant decrease after treatment with etanercept. Retinal cell death quantification showed a significant decrease after treatment with the TNF-alpha inhibitor. CONCLUSIONS:Anti-TNF-alpha treatment reduces the LPS-induced increases in leukocyte Rolling, Adhesion, and vascular leakage in this rat model of inflammatory uveitis. These results suggest the involvement of TNF-alpha in inflammatory uveitis and its potential use as a therapeutic agent in the reduction of ocular inflammation.
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Contribution of TNF-alpha to leukocyte Adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo.
Investigative ophthalmology & visual science, 2003Co-Authors: Kan Koizumi, Vassiliki Poulaki, S Doehmen, Gerhard Welsandt, Sven Radetzky, A Lappas, Norbert Kociok, B Kirchhof, A M JoussenAbstract:PURPOSE To investigate the effect of TNF-alpha on leukocyte Adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis (EIU) in the rat. METHODS EIU was induced in Long-Evans rats by a single footpad injection of lipopolysaccharide (LPS; 350 microg/kg) from Salmonella typhimurium. A single injection of recombinant TNF receptor P75 (etanercept) was given subcutaneously 24 hours before the administration of LPS. Twenty-four hours after administration of LPS, leukocyte Adhesion was evaluated in vivo with SLO-acridine orange angiography and ex vivo with concanavalin A lectin staining of retinal flatmounts. Neutrophil activation was quantified by a myeloperoxidase activity assay. Vascular leakage was assessed by Evans blue extravasation. Retinal cell death was assessed with TUNEL staining and quantified with a modified ELISA protocol. Involvement of caspase-3 and -8 was determined by M30 antibody staining, Western blot analysis, and a test for enzymatic activity. RESULTS Twenty-four hours after the LPS injection, significant increases in leukocyte Rolling, Adhesion, and activation were observed. In addition, increased levels of apoptosis in the vascular endothelium and the ganglion cell and inner nuclear layers and activation of caspase-8 and -3 were observed. After administration of the TNF-alpha inhibitor, significant reduction in the leukocyte Rolling, Adhesion, activation, and apoptosis in all the affected layers was observed. The quantitative analysis of vascular leakage revealed a significant decrease after treatment with etanercept. Retinal cell death quantification showed a significant decrease after treatment with the TNF-alpha inhibitor. CONCLUSIONS Anti-TNF-alpha treatment reduces the LPS-induced increases in leukocyte Rolling, Adhesion, and vascular leakage in this rat model of inflammatory uveitis. These results suggest the involvement of TNF-alpha in inflammatory uveitis and its potential use as a therapeutic agent in the reduction of ocular inflammation.
