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PubMed2003

Dehydroepiandrosterone protects the microcirculation of muscle flaps from ischemia-reperfusion injury by reducing the expression of adhesion molecules.

Adhesion molecules contribute to ischemia-reperfusion injury by increasing the endothelial adhesion and extravasation of leukocytes. Scientific evidence suggests that presurgical treatment with dehydroepiandrosterone may protect the microvasculature against this damage, but the exact mechanism is not known. The purpose of this study was to investigate the effects of presurgical dehydroepiandrosterone treatment on microcirculatory hemodynamic parameters and the expression of adhesion molecules in a rat cremaster muscle flap model. Twenty male rats were randomly assigned to three experimental groups. In group I (n = 5), the muscle flaps did not receive presurgical treatment. In group II (n = 6), propylene glycol (30 mg/kg), the vehicle for dehydroepiandrosterone, was injected intravenously before ischemia was induced. In group III (n = 9), dehydroepiandrosterone (30 mg/kg) was injected intravenously before ischemia was induced. All flaps were subjected to 6 hours of ischemia and 90 minutes of reperfusion. Microcirculatory variables (functional capillary density, red blood cell velocity in the main flap arteriole, and numbers of rolling, sticking, and transmigrating leukocytes), blood levels of three adhesion molecules (L-selectin, Mac-1 integrin, and CD44), and the numbers of leukocytes expressing those molecules were analyzed. Analysis of the microcirculatory parameters revealed that dehydroepiandrosterone treatment before ischemia had significant preservative effects on the red blood cell velocity and functional capillary density 30 and 90 minutes after reperfusion, compared with the control and vehicle-treated groups. Leukocyte-endothelial cell interactions were also affected by dehydroepiandrosterone treatment, as reflected by significant decreases in the numbers of sticking and transmigrating leukocytes 30 and 90 minutes after reperfusion. In dehydroepiandrosterone-treated animals, leukocytes exhibited lower levels of expression of adhesion molecules after the onset of ischemia, compared with the control groups. In this study, intravenous dehydroepiandrosterone administration reduced the activation of leukocytes and improved red blood cell velocity and capillary perfusion in the muscle flap microcirculation during ischemia-reperfusion injury. This protective effect was most likely the result of delayed expression of Mac-1 integrin, L-selectin, and CD44 molecules on leukocytes.

Animals↗
PubMed2005

Escherichia coli modulates extraintestinal spread of Staphylococcus aureus.

Staphylococcus aureus remains one of the most frequent causes of life-threatening systemic infection in surgical and trauma patients. It is understood that S. aureus colonization predisposes to complicating infection, but extraintestinal dissemination of S. aureus from the intestinal lumen to the draining mesenteric lymph nodes has not been systematically studied. After oral inoculation with high numbers of S. aureus, otherwise normal mice had low levels of cecal S. aureus (6.7 log10/g) and the incidence of extraintestinal dissemination was 30%. As expected, parenteral Escherichia coli lipopolysaccharide (LPS) was associated with increased numbers of cecal S. aureus, but the incidence of translocation remained unchanged. Purified LPS had no effect on S. aureus internalization by cultured HT-29 enterocytes and no effect on S. aureus transmigration through confluent enterocytes. To begin to clarify the effect of alterations in cecal bacteria on S. aureus translocation, mice were orally inoculated with E. coli and S. aureus. Compared with mice inoculated with S. aureus alone, these mice had increased numbers of cecal E. coli and S. aureus, and the incidence of S. aureus translocation nearly doubled from 46% to 88%. Experiments with HT-29 enterocytes indicated that viable E. coli had no effect on S. aureus internalization, but viable E. coli was at least 40 times more potent in inducing S. aureus transmigration across confluent enterocytes compared with a corresponding amount of purified LPS. Thus, S. aureus disseminated from the intestinal tract of normal mice by a mechanism that could involve paracellular migration across the intestinal epithelial barrier.

Animals↗
PubMed2006

Leukocyte-endothelial interactions via ICAM-1 are detrimental in polymicrobial sepsis.

Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the transmigration of polymorphonuclear neutrophils (PMN) in sepsis. Moreover, the transmigration rate of leukocytes from the blood via endothelial adhesion molecules into tissues correlates with the severity of multi organ failure. We examined the effect of the deletion of the ICAM-1 gene in polymicrobial sepsis using a cecal ligation and puncture (CLP) sepsis model in mice. Twenty male ICAM-1 knockout (KO) mice and 20 wild-type (WT) male C57BL/6 mice were studied. CLP was performed. At several time points during a 96-hour postoperative observation period, we measured mortality, body weight, and temperature. The delayed type of hypersensitivity (DTH) reaction was determined by pinna swelling after sensitization with 50 microL of dinitrofluorobenzene (DNFB) 1%. Lymphocyte subpopulations (CD4, CD8, and CD56) and cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and interleukin-10 (IL-10)] were measured using flow cytometry and ELISA testing, respectively. Also, a histologic examination of the liver and lung was performed. CLP-induced mortality was lower in the ICAM-1 group compared to normal mice (5% vs 45.0%). So were the ratios of lymphocyte subpopulations in the KO versus the WT group [CD4: 16.4 +/- 1.6% vs 25.7 +/- 4.7%; CD8: 18.3 +/- 1.4% vs 34.9 +/- 2.9%; natural killer (NK) cells: 5.6 +/- 0.3% vs 49.5 +/- 0.7%; P < 0.01]. And also the cytokine blood levels of the KO mice were significantly lower versus the WT mice (TNF-alpha: 67.2 +/- 42.2 vs 823.9 +/- 170.5 pg/mL; IL-1beta: 5.9 +/- 0.9 vs 296.2 +/- 66.2 pg/mL; IL-6: 223.1 +/- 48.8 vs 3062.5 +/- 1222.8 pg/mL; IL-10: 34.6 +/- 5.8 vs 1565.6 +/- 448.8 pg/mL; P < 0.01). With respect to the histology, significantly less leukocyte invasion and organ damage (eg, hydropic degeneration) were present in the ICAM-1-/- group compared to controls in liver and lung tissues. The DTH reaction was significantly decreased in ICAM-1-/- mice versus WT mice (0.34 vs 0.41 mm; P < 0.05). Our results demonstrate a significant reduction of mortality after septic challenge in ICAM-1-/- mice compared to normal mice. This is associated with a decrease in lymphocyte subpopulations, cytokine levels, and DTH type 4 reaction, possibly reflecting an overall attenuation of the immune system.

Animals↗
PubMed2006

Endothelial cell-T lymphocyte interactions: IP[corrected]-10 stimulates rapid transendothelial migration of human effector but not central memory CD4+ T cells. Requirements for shear stress and adhesion molecules.

The chemokine interferon (IFN)-gamma-inducible protein of 10 kDa (IP-10; CXCL10) has been implicated in recruitment of T cells into rejecting allografts yet appears ineffective at stimulating human peripheral blood CD4 T cells to transmigrate across tumor necrosis factor (TNF)-treated human endothelial cell (EC) monolayers in vitro. The same cells rapidly (within 15 min) transmigrate across TNF-treated EC monolayers overlaid with stromal cell-derived factor-1 alpha (SDF-1 alpha) and subjected to shear stress. The effector memory subset within the CD4 T cell population, defined as CD45RO, CD62L and CCR7, which constitutes less than 10% of total CD4 T cells, does respond to IP-10 but requires enrichment to be observed in this model. Central memory T cells do not respond to IP-10. Transendothelial migration of effector memory CD4 T cells requires TNF-pretreatment of the EC monolayer and application of venular shear force during the assay. TNF treatment of ECs may be effectively replaced by transduction of vascular cell adhesion molecule-1 or intercellular adhesion molecule-1 but not E-selectin.

CD4-Positive T-Lymphocytes↗
PubMed2005

Junctional adhesion molecules (JAM)-B and -C contribute to leukocyte extravasation to the skin and mediate cutaneous inflammation.

Leukocyte extravasation is a finely tuned process, in which transmigration is the final step. Transmigration depends on molecules located at borders of endothelial cells; e.g., junctional adhesion molecules (JAM-A, -B and -C). In vivo blockade of JAM-A lead to decreased migration of monocytes into the skin. In contrast, the role of JAM-B and -C in development of cutaneous inflammation is unknown. We therefore elicited an allergic contact dermatitis in mice using 2,4-dinitro-1-fluorobenzene. RT-PCR and immunofluorescent staining of healthy skin revealed a constitutive JAM-B (66.4%+/-6.7% of all vessels) and -C expression (88.6+/-13.2%), which remained constant after induction of contact dermatitis. Functional studies, in which either JAM-B or -C neutralizing antibodies were injected into sensitized mice prior to allergen challenge showed a concentration-dependent reduction of the contact dermatitis. Decreased ear swelling was accompanied by reduction of leukocyte infiltration as analyzed by hematoxylin and eosin (H&E) histology and enzyme activity. Combined antibody treatment at doses of 1.25 mg per kg bodyweight lead to additive inhibition of allergic contact dermatitis, indicating that JAM-B and -C may have distinct functions. In conclusion, interactions with JAM-B and -C are essential for development of cutaneous inflammation.

Animals↗
PubMed1990

The 'Bayer bridges' confronted with results from improved electron microscopy methods.

In electron micrographs of conventionally prepared thin sections of Escherichia coli one observes (i) a wavy appearance of the two membranes showing frequent appositions (named adhesion sites) and (ii) intermembrane bridges after plasmolysis which, it is claimed, occur at the adhesion sites and are related to intermembrane protein transport (transmigration). When chemical fixation is replaced by cryofixation, the observations are very different. (a) The two membranes are equally spaced and no contacts, adhesions or other sorts of connections are visible. (b) After plasmolysis the protoplast is shrunken, but the typical bridges are no longer produced. (c) In addition, when peptidoglycan is stained on conventionally prepared sections, it is revealed as a 7-nm-thick sacculus which is not interrupted at the sites of apposition. In view of the new observations, the structural concepts derived from conventionally prepared material must be revised. It is proposed that the intermembrane space is entirely filled by a gel, the outer part of which is the 7 nm thick, very stable, chemically resistant peptidoglycan (or murein). The inner part is much less stable and is proposed to undergo rapid autolytic changes upon cell death. The large 'Bayer bridges' might then tentatively be explained as an artificial post-mortem enhancement of either a stream of proteins transmigrating across the periplasm or of a pre-existing, but not yet resolved, structure. This enhancement probably occurs during the 7-10 min between plasmolysis and fixation that are prescribed for the procedure necessary for revealing 'Bayer bridges'.

Bacterial Adhesion↗
PubMed2004

Human Fas-ligand expression on porcine endothelial cells does not protect against xenogeneic natural killer cytotoxicity.

Several human leukocyte subsets including natural killer (NK) cells, cytotoxic T lymphocytes (CTL), and polymorphonuclear neutrophils (PMN) participate in cellular immune responses directed against vascularized pig-to-human xenografts. As these leukocytes express the death receptor Fas either constitutively (PMN) or upon activation (NK, CTL), we explored in vitro whether the transgenic expression of Fas ligand (FasL) on porcine endothelial cells (EC) is a valuable strategy to protect porcine xenografts. The porcine EC line 2A2 was stably transfected with human FasL (2A2-FasL) and interactions of 2A2-FasL with human leukocytes were analyzed using functional assays for apoptosis, cytotoxicity, chemotaxis, adhesion under shear stress, and transmigration. FasL expressed on porcine EC induced apoptosis in human NK and T cells, but did not protect porcine EC against killing mediated by human NK cells. 2A2-FasL released soluble FasL, which induced strong chemotaxis in human PMN. Adhesion under shear stress of PMN on 2A2-FasL cells was increased whereas transendothelial migration was decreased. In contrast, FasL had no effect on the adhesion of NK cells but increased their transmigration through porcine EC. Although FasL expression on porcine EC is able to induce apoptosis in human effector cells, it did not provide protection against xenogeneic cytotoxicity. The observed impact of FasL on adhesion and transendothelial migration provides evidence for novel biological functions of FasL.

Animals↗
PubMed2006

Expression of human CD81 differently affects host cell susceptibility to malaria sporozoites depending on the Plasmodium species.

Plasmodium sporozoites can enter host cells by two distinct pathways, either through disruption of the plasma membrane followed by parasite transmigration through cells, or by formation of a parasitophorous vacuole (PV) where the parasite further differentiates into a replicative exo-erythrocytic form (EEF). We now provide evidence that following invasion without PV formation, transmigrating Plasmodium falciparum and Plasmodium yoelii sporozoites can partially develop into EEFs inside hepatocarcinoma cell nuclei. We also found that rodent P. yoelii sporozoites can infect both mouse and human hepatocytes, while human P. falciparum sporozoites infect human but not mouse hepatocytes. We have previously reported that the host tetraspanin CD81 is required for PV formation by P. falciparum and P. yoelii sporozoites. Here we show that expression of human CD81 in CD81-knockout mouse hepatocytes is sufficient to confer susceptibility to P. yoelii but not P. falciparum sporozoite infection, showing that the narrow P. falciparum host tropism does not rely on CD81 only. Also, expression of CD81 in a human hepatocarcinoma cell line is sufficient to promote the formation of a PV by P. yoelii but not P. falciparum sporozoites. These results highlight critical differences between P. yoelii and P. falciparum sporozoite infection, and suggest that in addition to CD81, other molecules are specifically required for PV formation during infection by the human malaria parasite.

Animals↗
PubMed2006

Reciprocal upregulation of urokinase plasminogen activator and its inhibitor, PAI-2, by Borrelia burgdorferi affects bacterial penetration and host-inflammatory response.

The mammalian plasminogen activation system (PAS) is a complex system involved in multiple physiological and pathological processes. Borrelia burgdorferi interacts with certain components of the PAS. Here we further investigate this interaction to determine its effect on bacterial dissemination and host cell migration in vitro. We show that stimulation of monocytic cells with B. burgdorferi induces the transient production and secretion of urokinase plasminogen activator (uPA), shortly followed by its physiological inhibitor, plasminogen activator inhibitor-2 (PAI-2). Mono Mac 6 (MM6) cells as well as peripheral blood monocytes enhanced transmigration of B. burgdorferi across a barrier coated with fibronectin mediated by uPA. Moreover, the induction of PAI-2 or the addition of recombinant PAI-2 did not have a significant effect on the uPA-potentiated transmigration of B. burgdorferi. In contrast, the induction of PAI-2 by B. burgdorferi resulted in significantly diminished invasion by monocytic cells across a reconstituted basement membrane (matrigel), which could be partially restored by treatment with purified uPA. These results show that the PAS plays a twofold role in the pathogenesis of B. burgdorferi infection, both by enhancing bacterial dissemination and by diminishing host-cell inflammatory migration.

Borrelia burgdorferi↗
PubMed2005

DNA vaccination with naked DNA encoding MCP-1 and RANTES protects against renal injury in adriamycin nephropathy.

BACKGROUND: We have previously shown that monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T-cell expressed and secreted (RANTES) are significantly increased in renal cortex in adriamycin nephropathy. In this study, we tested the effect of DNA vaccination encoding the C-C chemokines MCP-1 and RANTES in a rat model of adriamycin nephropathy. METHODS: Both reverse transcription-polymerase chain reaction (RT-PCR) products of MCP-1 and RANTES used as constructs were cloned into a pTarget vector for naked DNA vaccination. Two hundred micrograms of DNA was injected into the tibialis anterior muscle four times at weekly intervals. One week after the last DNA vaccination, rats received adriamycin. All animals were sacrificed 4 weeks after adriamycin administration. Changes in renal function and histologic features were assessed. Enzyme-linked immunosorbent assay (ELISA) and Western blot were used for autoantibody determination. Antibody specificity was assessed in in vitro transmigration assays. RESULTS: Chemokine DNA vaccination significantly reduced proteinuria (P < 0.05) and ameliorated creatinine clearance (P < 0.05) at 2, 3, and 4 weeks after adriamycin administration. Morphometric analysis showed less glomerular sclerosis (P < 0.001) and interstitial infiltrates (P < 0.005) in chemokine DNA vaccination group compared with control groups. Anti-MCP-1 and RANTES autoantibodies were detected in higher concentrations in chemokine DNA vaccinated rats than in control rats (P < 0.001) and serum from vaccinated rats blocked T-cell transmigration to MCP-1 and RANTES. CONCLUSION: In this study, we have shown that naked DNA vaccination against MCP-1 and RANTES ameliorates the progression of renal disease in the rat adriamycin nephropathy model of chronic proteinuric renal disease. The protective mechanism may involve the production of autoantibodies against MCP-1 and RANTES.

Animals↗
PubMed2001

Differential signaling for MCP-1-dependent integrin activation and chemotaxis.

Transmigration of monocytes to the subendothelial space is the initial step in atherosclerotic plaque formation and inflammation. Integrin activation and chemotaxis are two important functions in monocyte transmigration. To delineate the signaling cascades leading to integrin activation and chemotaxis by monocyte chemoattractant protein-1 (MCP-1), we investigated the roles of MAPK in THP-1 cells, a monocytic cell line. MCP-1 stimulated beta1 integrin-dependent, but not beta2 integrin-dependent cell adhesion in a time-dependent manner. MCP-1-mediated cell adhesion was inhibited by a MEK inhibitor, but not by a p38-MAPK inhibitor. By contrast, MCP-1-mediated chemotaxis was inhibited by the p38-MAPK inhibitor, but not by the MEK inhibitor. These data indicate that ERK is responsible for integrin activation and that p38-MAPK is responsible for chemotaxis mediated by MCP-1. This study demonstrates that two distinct MAPKs regulate two dependent signaling cascades, leading to integrin activation and chemotaxis induced by MCP-1 in THP-1 cells.

Cell Line↗
PubMed1993

Involvement of platelet-endothelial cell adhesion molecule-1 in neutrophil recruitment in vivo.

During inflammation, neutrophils migrate from the vascular lumen into extravascular sites. In vitro assays have suggested that platelet-endothelial cell adhesion molecule-1 [PECAM-1 (CD31)], a member of the immunoglobulin superfamily, is required for the transmigration of neutrophils across endothelial monolayers. Antibody to human PECAM-1, which cross-reacts with rat PECAM-1, was found to block not only in vivo accumulation of rat neutrophils into the peritoneal cavity and the alveolar compartment of the lung but also neutrophil accumulation in human skin grafts transplanted onto immunodeficient mice. On the basis of these findings in three different models of inflammation, it appears that PECAM-1 is required for neutrophil transmigration in vivo and may thus be a potential therapeutic target.

Animals↗
PubMed1998

Immune response against the exp-1 protein of Plasmodium falciparum results in antibodies that cross-react with human T-cell lymphotropic virus type 1 proteins.

To examine the role of the Plasmodium falciparum Exp-1 blood-stage protein in producing antibodies that cross-react with human T-cell lymphotropic virus type I (HTLV-I) proteins, we studied sera from Indonesian volunteers who seroconverted to malaria after transmigrating to an area where malaria is hyperendemic. Samples from Philippine volunteers, that were used in a prior study that examined malaria antibodies that cross-react with HTLV-I proteins, were also used. Eighty-three percent of the Indonesian transmigrants developed antibodies against the malaria Exp-1 protein by 6 months postmigration. Of these malaria seroconverters, 27% developed false-positive HTLV-I enzyme immunoassay (EIA) immunoreactivity, as indicated by indeterminate HTLV-I Western blot banding patterns. Five of the six Philippine samples tested were HTLV-I EIA false positive and Western blot indeterminate. When a recombinant Exp-1 protein was used in blocking experiments, the HTLV-I Western blot immunoreactivity of sera from both groups was either completely eliminated or greatly reduced. No effect on the Western blot immunoreactivity of truly HTLV-I-positive sera was seen. To determine if immunization with the recombinant Exp-1 protein could elicit the production of HTLV-I antibodies, six mice were inoculated with the recombinant protein. Following administration of three 50-microgram doses of the protein, four of the six mice developed antibodies that cross-reacted with HTLV-I proteins on Western blot. These results indicate that the immune response against the malaria Exp-1 protein may result in HTLV-I-cross-reacting antibodies that can lead to false-positive EIA and indeterminant Western blotting results.

Animals↗
PubMed1999

Orchestration of neutrophil movement by intestinal epithelial cells in response to Salmonella typhimurium can be uncoupled from bacterial internalization.

Intestinal epithelial cells respond to Salmonella typhimurium by internalizing this pathogen and secreting, in a polarized manner, an array of chemokines which direct polymorphonuclear leukocyte (PMN) movement. Notably, interleukin-8 (IL-8) is secreted basolaterally and directs PMN through the lamina propria, whereas pathogen-elicited epithelial chemoattractant (PEEC) is secreted apically and directs PMN migration across the epithelial monolayer to the intestinal lumen. While most studies of S. typhimurium pathogenicity have focused on the mechanism by which this bacterium invades its host, the enteritis characteristically associated with salmonellosis appears to be more directly attributable to the PMN movement that occurs in response to this pathogen. Therefore, we sought to better understand the relationship between S. typhimurium invasion and epithelial promotion of PMN movement. First, we investigated whether S. typhimurium becoming intracellular was necessary or sufficient to induce epithelial promotion of PMN movement. Blocking S. typhimurium invasion by preventing, with cytochalasin D, the epithelial cytoskeletal rearrangements which mediate internalization did not reduce the epithelial promotion of PMN movement. Conversely, bacterial attainment of an intracellular position was not sufficient to induce model epithelia to direct PMN transmigration, since neither basolateral invasion by S. typhimurium nor apical internalization of an invasion-deficient mutant (achieved by inducing membrane ruffling with epidermal growth factor) induced this epithelial cell response. These results indicate that specific interactions between the apical surface of epithelial cells and S. typhimurium, rather than simply bacterial invasion, mediate the epithelial direction of PMN transmigration. To further investigate the means by which S. typhimurium induces epithelia to direct PMN movement, we investigated whether the same signaling pathways regulate secretion of IL-8 and PEEC. IL-8 secretion, but not PEEC secretion, was activated by phorbol myristate acetate and blocked by an inhibitor (mg-132) of the proteosome which mediates NF-kappabeta activation. Further, secretion of IL-8, but not PEEC, was activated by an entry-deficient (HilDelta) S. typhimurium mutant or by basolateral invasion of a wild-type strain. Together, these results indicate that distinct signaling pathways mediate S. typhimurium invasion, induction of IL-8 secretion, and induction of PEEC secretion in model intestinal epithelia.

Animals↗
PubMed2005

Disruption of tight junctions during traversal of the respiratory epithelium by Burkholderia cenocepacia.

Burkholderia cenocepacia is an opportunistic bacterial species capable of causing life-threatening respiratory tract infection in persons with cystic fibrosis (CF). Unlike most other pathogens in CF, which typically remain confined to the endobronchial spaces, B. cenocepacia can traverse airway epithelium to cause bacteremia and sepsis. The mechanisms by which this occurs, however, are unknown. We examined the transmigration of B. cenocepacia through polarized respiratory epithelium. Representatives of three "epidemic" lineages common among CF patients in North America were able to traverse polarized 16HBE14o- cells in vitro. Transmigration of bacteria was associated with significant perturbations in epithelial permeability, as measured by a loss of transepithelial electrical resistance and increased flux of bovine serum albumin across the cell layer. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and trypan blue exclusion assays, as well as lactate dehydrogenase levels, did not indicate excessive cytotoxicity or cell death in infected cell layers. Rather, confocal fluorescence microscopy demonstrated the loss of occludin from tight junctions. In contrast, zonula occludens 1 was well preserved along intercellular borders. Western blot analysis showed a shift in the major occludin isoforms from high- to low-phosphorylation states during infection. These observations suggest that B. cenocepacia traverses polarized respiratory epithelium by the dephosphorylation and dissociation of occludin from the tight-junction complex.

Actins↗
PubMed2005

Borrelia burgdorferi, host-derived proteases, and the blood-brain barrier.

Neurological manifestations of Lyme disease in humans are attributed in part to penetration of the blood-brain barrier (BBB) and invasion of the central nervous system (CNS) by Borrelia burgdorferi. However, how the spirochetes cross the BBB remains an unresolved issue. We examined the traversal of B. burgdorferi across the human BBB and systemic endothelial cell barriers using in vitro model systems constructed of human brain microvascular endothelial cells (BMEC) and EA.hy 926, a human umbilical vein endothelial cell (HUVEC) line grown on Costar Transwell inserts. These studies showed that B. burgdorferi differentially crosses human BMEC and HUVEC and that the human BMEC form a barrier to traversal. During the transmigration by the spirochetes, it was found that the integrity of the endothelial cell monolayers was maintained, as assessed by transendothelial electrical resistance measurements at the end of the experimental period, and that B. burgdorferi appeared to bind human BMEC by their tips near or at cell borders, suggesting a paracellular route of transmigration. Importantly, traversal of B. burgdorferi across human BMEC induces the expression of plasminogen activators, plasminogen activator receptors, and matrix metalloproteinases. Thus, the fibrinolytic system linked by an activation cascade may lead to focal and transient degradation of tight junction proteins that allows B. burgdorferi to invade the CNS.

Blood-Brain Barrier↗
PubMed2006

Structural adaptations in the murine colon microcirculation associated with hapten-induced inflammation.

BACKGROUND: Blood flowing across the vascular endothelium creates wall shear stress, dependent on velocity of flow and vessel geometry, that tends to disrupt lymphocyte-endothelial cell adhesion. OBJECTIVE: The microcirculation in a murine model of acute colitis was investigated to identify structural adaptations during acute colitis that may facilitate transmigration. METHODS: In 2,4,6-trinitrobenzenesulphonic acid-induced acute colitis, the infiltrating cells and colonic microcirculation was investigated by cellular topographic mapping, corrosion casting and three-dimensional scanning electron microscopy (SEM). Colonic blood velocimetry was performed using intravital microscopy. RESULTS: Clinical and histological parameters suggested a peak inflammatory response at 96 h (p<0.001). The infiltrating cells were spatially related to the mucosal capillary plexus by three-dimensional topographic mapping (p<0.001). In normal mice, corrosion casting and three-dimensional SEM showed a polygonal mucosal plexus supplied by ascending arteries and descending veins. After 2,4,6-trinitrobenzenesulphonic acid stimulation, three-dimensional SEM showed preserved branch angles (p = 0.52) and nominal vessel lengths (p = 0.93), but a significantly dilated mucosal capillary plexus (p<0.001). Intravital microscopy of the mucosal plexus showed a greater than twofold decrease in the velocity of flow (p<0.001). CONCLUSIONS: The demonstrable slowing of the velocity of flow despite an increase in volumetric flow suggests that these microvascular adaptations create conditions suitable for leucocyte adhesion and transmigration.

Acute Disease↗
PubMed2001

Human neutrophils facilitate tumor cell transendothelial migration.

Tumor cell extravasation plays a key role in tumor metastasis. However, the precise mechanisms by which tumor cells migrate through normal vascular endothelium remain unclear. In this study, using an in vitro transendothelial migration model, we show that human polymorphonuclear neutrophils (PMN) assist the human breast tumor cell line MDA-MB-231 to cross the endothelial barrier. We found that tumor-conditioned medium (TCM) downregulated PMN cytocidal function, delayed PMN apoptosis, and concomitantly upregulated PMN adhesion molecule expression. These PMN treated with TCM attached to tumor cells and facilitated tumor cell migration through different endothelial monolayers. In contrast, MDA-MB-231 cells alone did not transmigrate. FACScan analysis revealed that these tumor cells expressed high levels of intercellular adhesion molecule-1 (ICAM-1) but did not express CD11a, CD11b, or CD18. Blockage of CD11b and CD18 on PMN and of ICAM-1 on MDA-MB-231 cells significantly attenuated TCM-treated, PMN-mediated tumor cell migration. These tumor cells still possessed the ability to proliferate after PMN-assisted transmigration. These results indicate that TCM-treated PMN may serve as a carrier to assist tumor cell transendothelial migration and suggest that tumor cells can exploit PMN and alter their function to facilitate their extravasation.

Adenocarcinoma↗