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PubMed2005

Inflammatory leukocytes and iron turnover in experimental hemorrhagic lung trauma.

To monitor cascade of events following alveolar extravasation of blood due to exposure to shock wave (SW), we conducted spatiotemporal assessment of myeloperoxidase (MPO), heme oxygenase 1 (HO-1), Cu,Zn superoxide dismutase (SOD-1), transferrin (TRF), 3-nitrotyrosine (3NTyr), alveolar endothelial cadherin (VE-CDH), and the CD11b adhesion molecules on leukocytes using electron microscopy, electron paramagnetic resonance spectroscopy, immunofluorescence imaging, and immunoblotting. Accumulation of HO-1, MPO, 3NTyr, and SOD-1 in HIL at the first 12 h was associated with transmigration of inflammatory leucocytes (ILK) into hemorrhagic lesions (HLs). Biodegradation of extravasated hemoglobin (exvHb) and deposition of iron in alveoli occurred at 3-56 h post-exposure and was preceded by LKC degranulation and accumulation of MPO, HO-1, and SOD-1 in HLs. These alterations were accompanied by appearance of heme and non-heme iron complexes in HLs. A significant increase in TRF-bound [Fe(3+)] (i.e., 14.6 +/- 5.3 microM vs. 4.8 +/- 2.1 microM immediately after exposure) and non-TRF complexes of [Fe(3+)] (i.e., 4.5 +/- 1.8 microM vs. < 0.3 microM immediately after exposure) occurred at 24 h post-exposure. Transmigrations of ILK, nitroxidative stress, and iron deposition in endothelial and epithelial cells were accompanied by destruction of endothelial integrity at 3 h post-exposure, and alveolar capillary network and necrotic changes in the pulmonary epithelial cells at 24-56 h post-exposure.

Animals↗
PubMed2003

Aprotinin inhibits leukocyte-endothelial cell interactions after hemorrhage and reperfusion.

BACKGROUND: The serine protease inhibitor aprotinin has been successfully used to reduce blood loss in patients undergoing cardiac operations. We studied aprotinin for its ability to modulate leukocyte-endothelial cell interactions after ischemia and reperfusion. METHODS: The effects of aprotinin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation and immunohistochemical analysis. The inflammatory cascade (leukocyte rolling, firm adherence, and transmigration) was studied after thrombin stimulation and after hemorrhage and reperfusion. RESULTS: Intravenous bolus administration of aprotinin treatment (20,000 U/kg) significantly reduced leukocyte rolling from 55 +/- 8 to 17 +/- 3 cells/min (p < 0.01) and adherent cells from 12 +/- 2 to 7 +/- 1.4 cells (p < 0.05) along the venous endothelium of the rat mesentery after thrombin activation. In addition, aprotinin pretreatment significantly inhibited transmigration of leukocytes from 11.3 +/- 1.2 to 6.0 +/- 1.1 cells (p < 0.05) through the microvascular endothelial wall. Similarly, aprotinin decreased leukocyte-endothelium interaction after hemorrhagic shock. Moreover, immunohistochemistry demonstrated that aprotinin significantly attenuated P-selectin expression by the intestinal vascular endothelium. CONCLUSIONS. Our data demonstrate that aprotinin potently inhibits recruitment of leukocytes in the microvasculature by interfering with endothelial cell-polymorphonuclear neutrophil interaction, and is a potent endothelial protective agent in clinically relevant doses. Thus, aprotinin pretreatment may be useful for primary prevention of inflammatory tissue injury mediated by ischemia-reperfusion injury such as shock, trauma, open heart operation, or other extensive vascular surgical procedures.

Animals↗
PubMed1999

Role of the beta2-integrins and immunoglobulin superfamily members in myocardial ischemia-reperfusion.

Leukocytes play a key role in the inflammatory processes such as ischemia-reperfusion of the coronary vasculature. Their interaction with the endothelium is closely regulated. The first step in the process is the rolling of leukocytes (eg, neutrophils) along the microvascular endothelium. This is regulated by the selectin family of cell adhesion molecules, primarily P-selectin. The next step in the inflammatory cascade is the firm adhesion of these neutrophils to the activated or dysfunctional endothelium. This process is governed by the beta2-integrins on the leukocytes (eg, CD11/CD18) and by ICAM-1 on the activated endothelium. CD11/CD18 is a beta2-integrin, and ICAM-1 is a member of the immunoglobulin superfamily of adhesion glycoproteins. By their interaction, neutrophils flatten out and adhere to the vascular endothelium. Many of these adhered neutrophils are then able to transmigrate across the endothelium to the site of the inflammation (ie, the focus of the ischemia-reperfusion). This transmigration is primarily stimulated by PECAM-1, another member of the immunoglobulin superfamily. These processes are discussed in this brief review.

Animals↗
PubMed1998

Effects of LEX032, a novel recombinant serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester induced leukocyte-endothelial cell interactions.

We studied the effects of LEX032, a novel serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester (L-NAME) induced leukocyte-endothelium interactions in vivo, utilizing intravital microscopy of the rat mesentery. Superfusion of the rat mesentery with 50 microM L-NAME, a nitric oxide (NO) inhibitor, for 90 min resulted in a significant and time-dependent increase in leukocyte rolling, leukocyte adherence, and transmigration of leukocytes, compared to control rats superfused with Krebs-Henseleit (K-H) solution. However, systemic administration of LEX032 (15 mg/kg bolus injection followed by a 15 mg/kg per hour infusion) to L-NAME superfused rats significantly attenuated leukocyte rolling and adherence along the venular endothelium of the rat mesentery, and also inhibited transmigration of leukocytes through the microvascular endothelial wall. Moreover, no significant changes were observed in mean arterial blood pressure or local venular shear rates following systemic administration of LEX032. Our data demonstrate that systemic inhibition of serine proteases by LEX032 reduces enhanced leukocyte-endothelium interactions provoked by inhibition of NO synthesis. These results also explain some of the beneficial effects exerted by serine protease inhibitors in ischemia-reperfusion and other inflammatory states.

Animals↗
PubMed2002

A novel chemokine, Leukotactin-1, induces chemotaxis, pro-atherogenic cytokines, and tissue factor expression in atherosclerosis.

Chemokines such as monocyte chemoattractant protein (MCP) -1 and interleukin (IL)-8 are known to be involved in various processes in atherosclerosis such as plaque formation, plaque rupture, and thrombus formation. We investigated whether a new chemokine, Leukotactin (LKN)-1, is involved in atherosclerosis. We tested the expression of LKN-1 by immunohistochemical methods in carotid atherosclerotic plaque specimen. Induction of pro-inflammatory cytokines, transmigration, and tissue factor (TF) expression were tested in THP-1 cells and human peripheral blood monocytes treated with recombinant human LKN-1. Immunohistochemical analyses revealed that expression of LKN-1 occurs in regions of plaques rich in foam cells. In a Boyden chamber assay, THP-1 cells treated with 0.01--10 nM of LKN-1 transmigrated through gelatin coated filters in a dose dependent manner. LKN-1 also induced the transient expression of TNF-alpha, IL-8, and MCP-1 within 15 min of the treatment of the THP-1 cells. When peripheral blood monocytes were treated with LKN-1, expression levels of TF and TF-mediated procoagulating activity were induced in a time- and dose-dependent manner. These results raise the possibility that LKN-1 is another chemokine that is involved in the atherogenesis. LKN-1 may chemoattract immune cells into the plaque, induce pro-inflammatory cytokines, and produce thrombi by inducing TF expression.

Aged↗
PubMed1999

Downregulation by tumor necrosis factor-alpha of monocyte CCR2 expression and monocyte chemotactic protein-1-induced transendothelial migration is antagonized by oxidized low-density lipoprotein: a potential mechanism of monocyte retention in atherosclerotic lesions.

The subintimal infiltration with monocytes is crucially involved in the development of complex atherosclerotic plaques. Monocyte chemotactic protein-1 (MCP-1) and its receptor CCR2 are important for monocyte extravasation and formation of atherosclerotic lesions. However, mechanisms of monocyte persistence in atherosclerotic plaques remain to be elucidated. Flow cytometric analysis revealed that monocytoid Mono Mac 6 cells that had transmigrated endothelium towards a MCP-1 gradient expressed higher levels of CCR2 than the non-migratory fraction, while input cells were intermediate, suggesting that high CCR2 levels are essential for transendothelial chemotaxis. Pretreatment of Mono Mac 6 cells or isolated human blood monocytes with the inflammatory cytokine tumor necrosis factor (TNF)-alpha dose- and time-dependently reduced MCP-1-induced transendothelial chemotaxis, which was inhibited by the CCR2 receptor antagonist 9-76 analog. This was paralleled by a decrease in CCR2 surface protein and mRNA expression. as assessed by flow cytometry and reverse transcription-polymerase chain reaction, inferring that inhibition of monocyte transmigration was due to downregulation of CCR2 to levels insufficient for chemotaxis. In contrast, treatment of monocytes with oxidized low-density protein (oxLDL) containing oxidized lipids, such as cholesteryl linoleate 13-hydroxide. but not with LDL, increased CCR2 protein and mRNA expression. Notably, oxLDL counteracted the TNF-alpha-mediated downregulation of CCR2 and CCR2-dependent transendothelial chemotaxis. Macrophage-colony-stimulating factor hardly affected CCR2 expression and function, suggesting that differentiation was not responsible for effects on CCR2. In conclusion, TNF-alpha impairs MCP-1-induced transendothelial migration of monocytes by downregulating CCR2 which appears critical for migration. Exposure to oxLDL antagonized the effects of TNF-alpha, and may thus contribute to monocyte retention and perpetuation of a chronic inflammatory reaction in unstable atherosclerotic lesions.

Arteriosclerosis↗
PubMed2003

Intracellular survival of Staphylococcus aureus within cultured enterocytes.

BACKGROUND: Little is known about the mechanisms involved in bacterial translocation from the intestinal lumen to extraintestinal sites. Because Staphylococcus aureus can colonize the intestinal tract, and because the intestinal tract is a reservoir for antibiotic resistant S. aureus, experiments were designed to clarify the interactions of S. aureus with cultured intestinal epithelial cells, and assays included measurements of bacterial internalization, enterocyte apoptosis, and epithelial barrier function. METHODS AND RESULTS: Mature, confluent enterocytes were incubated 1 h with S. aureus, and the gentamicin protection assay was used to quantify intracellular bacterial survival at various time intervals up to 120 h later. Enterocyte apoptosis was assessed using Annexin V, and the permeability of confluent enterocyte cultures was measured by transepithelial electrical resistance and by transmigration of Escherichia coli across confluent enterocytes.S. aureus was internalized by cultured enterocytes and remained viable for up to 120 h within both HT-29 and Caco-2 enterocytes. S. aureus intracellular survival was associated with enterocyte apoptosis and with decreased transepithelial electrical resistance across confluent Caco-2 enterocytes. S. aureus intracellular survival over time was also associated with increased E. coli transmigration across confluent Caco-2, but not HT-29, enterocytes. CONCLUSIONS: S. aureus appeared to survive within cultured enterocytes for prolonged time periods, up to several days. Survival of S. aureus within host eukaryotic cells, such as enterocytes, might facilitate persistence of S. aureus in infected tissue despite appropriate antibiotic therapy.

Apoptosis↗
PubMed2001

Migration of human granulocytes through reconstituted basement membrane is not dependent on matrix metalloproteinase-9 (MMP-9).

Transmigration of human granulocytes across a basal lamina equivalent was studied in vitro. Transwell inserts were coated with Matrigel, a reconstituted basement membrane. Granulocytes (2x10(6)) were applied to the upper chamber. As chemoattractant interleukin-8 (IL-8; 25 ng/ml) was added to the lower chamber. After 1 h of migration, cells were counted in the lower chamber. Specific hydroxamate inhibitors of MMPs (BB-3103, Ro 31-9790) or of serine proteases (Pefabloc, leupeptin) were added at various concentrations to both chambers before the start of migration. Additional experiments were performed with alpha(2)-macroglobulin, a natural inhibitor of MMPs and a monoclonal antibody which specifically blocks the activity of MMP-9. Migration of granulocytes through Matrigel could not be reduced significantly by any of the MMP inhibitors. A dose-dependent impairment of transmigration was only found with Pefabloc, however, this substance also induced severe morphological changes of the cells. The other inhibitor of serine proteases, leupeptin, did not influence migration at all.

Basement Membrane↗
PubMed2002

Regulatory effects of estriol on T cell migration and cytokine profile: inhibition of transcription factor NF-kappa B.

The protective role of pregnancy in autoimmune conditions, such as multiple sclerosis (MS), is potentially associated with immune regulation by sex hormones produced during pregnancy. This study was undertaken to examine the regulatory effects of estriol on the T cell functions, including transmigration and the cytokine production. The results revealed for the first time that estriol significantly inhibited T cell transmigration at a concentration range typical of pregnancy, which correlated with decreased T cell expression of matrix metalloproteinase-9. Estriol was also found to alter the cytokine profile of T cells toward Th2 phenotype by up-regulating the production of IL-10 and inhibiting TNFalpha secretion of T cells. However, the inhibitory effects of estriol on T cells were not antigen-dependent. Further characterization indicated that estriol inhibited nuclear transcription factor kappa B (NF-kappa B), which controls a variety of immune-related genes. This study provides new evidence that estriol is a potent regulator for the T cell functions potentially through its interaction with the NF-kappa B signaling pathway.

Adult↗
PubMed2002

Increased sialyl Lewis(x) antigen-positive cells mediated by HTLV-1 infection in peripheral blood CD4(+) T lymphocytes in patients with HTLV-1-associated myelopathy.

Sialyl Lewis(x) antigen-positive (sLe(x+)) cells play an important role in the first step of transmigration of T lymphocytes through vascular endothelial cells into tissues. We compared the proportion of sLe(x+) cells in peripheral blood CD4(+) T lymphocytes between patients with HTLV-1-associated myelopathy (HAM) and control patients, by using flow cytometry. The percentage of sLe(x+) cells in peripheral blood CD4(+) T lymphocytes was significantly higher in HAM patients compared to control patients. Interferon-gamma (IFN-gamma), but not interleukin-4 (IL-4), production by the sLe(x+) cell population of peripheral blood CD4(+) T lymphocytes was significantly higher in HAM patients than in control patients. In addition, comparison of the HTLV-1 proviral load between sLe(x+) and sLe(x-) cells in peripheral blood CD4(+) T lymphocytes of HAM patients showed that the HTLV-1 proviral load was significantly higher (two- to eight-fold), concomitant with enhanced IFN-gamma production, in the sLe(x+) than in the sLe(x-) cell population. Our findings indicate that the sLe(x+) cell population, which has features of activated Th1 cells with up-regulated expression of E- and P-selectin ligands mediated by HTLV-1 infection, is increased in peripheral blood CD4(+) T lymphocytes in HAM patients, suggesting their involvement in transmigration of peripheral T lymphocytes from the peripheral blood into tissues.

Aged↗
PubMed2002

Glycosylation processing inhibition by castanospermine prevents experimental autoimmune encephalomyelitis by interference with IL-2 receptor signal transduction.

In this study, we explored the therapeutic targets of the glycosylation processing inhibitor, castanospermine (CAST), in murine passive transfer experimental autoimmune encephalomyelitis (EAE), a model disease of multiple sclerosis. By using lymphocytic-endothelial adhesion and transmigration assays, FACScan and Western blotting, we defined the effects of CAST on expression, function and signal transduction of glycoproteins crucial in the pathophysiology of this disease. CAST prevented clinical signs of EAE and completely inhibited inflammatory CNS infiltrates associated with this disease. Here, we showed that CAST blocks antigen-induced lymphocytic activation and clonal expansion in a dose-dependent manner. Importantly, we observed that CAST strongly impairs IL-2-induced signal transduction of the IL-2 receptor. In contrast, neither expression nor binding ability of the IL-2 receptor was affected by this drug. In addition, we were able to exclude major effects of CAST on expression and function of different glycoproteins important in antigen presentation as well as lymphocytic-endothelial adhesion and transmigration. In conclusion, CAST strongly interferes in the signal transduction of the IL-2 receptor. This could explain both inhibitory effects of CAST in clonal T cell expansion and development of transfer EAE. This relatively selective pharmacological effect of CAST highlights its potential as a novel immunomodulatory approach in multiple sclerosis.

Animals↗
PubMed2002

Transendothelial migration of leukocytes and signalling mechanisms in response to the neuropeptide secretoneurin.

Secretoneurin (SN), a newly discovered neuropeptide, may be implicated in inflammatory responses as it was shown to modulate leukocyte, endothelial and mesenchymal cell functions. Neutrophils placed above pulmonary arterial or venous endothelial monolayers migrated through this cellular barrier in response to apical or basal stimulation with SN in a dose-dependent manner. At optimal concentrations of 10(-6) to 10(-8) M, SN was nearly equally effective in stimulating neutrophil transmigration as was tumor necrosis factor-alpha at 10 ng/ml or a chemotactic gradient of formyl-Met-Leu-Phe (10(-8) M). Stimulation of transendothelial migration appears to be specific, since a trypsin digest of SN was ineffective and excess concentrations of anti-SN antibodies completely abolished the effect. Inhibition of cyclooxygenase or nitric oxide synthase did not affect the action of SN. Preincubation of endothelial cells with pertussistoxin (PTx) or choleratoxin (CTx), and the presence of staurosporine significantly inhibited transmigration, suggesting that SN uses a signalling pathway that is coupled to G-proteins and protein kinase C in endothelium. Moreover, SN treatment resulted in transient elevation of cytoplasmatic calcium concentration in endothelial cells. These data support the hypothesis that SN might contribute to neurogenic inflammation in vivo and reveal signalling mechanisms of SN in endothelial cells.

Animals↗
PubMed1999

Homocysteine provokes leukocyte-endothelium interaction by downregulation of nitric oxide.

Recent evidence indicates that chronic hyperhomocysteinemia, which is found in from 9 to 15% of the general population, is an independent risk factor for the development of atherosclerosis. We sought to elucidate the mechanism by which exposure of the vascular wall to high levels of homocysteine initiates this inflammatory reaction. We examined the acute effect of homocysteine on endothelial dysfunction in isolated rat arteries and on microcirculatory leukocyte-endothelium interaction in vivo. Intravital microscopy of rat mesenteric venules was performed by superfusing the mesentery with increasing concentrations of homocysteine (1-5 mmol/l). There was a significant concentration- and time-dependent increase in leukocyte rolling, adherence, and extravasation compared with control rats superfused with Krebs-Henseleit solution (p < 0.01). Moreover, immunohistochemical staining demonstrated significantly increased P-selectin and intercellular adhesion molecule-1 (ICAM-1) expression on intestinal venules after homocysteine superfusion. In contrast, mesenteric superfusion with the nitric oxide donor 4-hydroxymethyl-furazan-3-carboxylic acid oxide (CAS1609, 1 micromol/l) significantly attenuated homocysteine-induced leukocyte rolling, adherence, and transmigration to control levels (p < 0.01). CAS1609 also attenuated both P-selectin and ICAM-1 expression on mesenteric venules and decreased CD18 expression on isolated leukocytes. Superior mesenteric arteries incubated with 5 mmol/l homocysteine developed significant (p < 0.01) endothelial dysfunction (i.e., impaired relaxation to endothelium-dependent dilators). Acute hyperhomocysteinemia induces endothelial dysfunction, characterized by a loss of endothelium-derived nitric oxide, leading to an inflammatory state. This state results in increased leukocyte rolling, adherence, and transmigration by upregulation of cell adhesion molecules. Our data suggest that hyperhomocysteinemia inhibits the important homeostatic role of nitric oxide in preventing endothelial dysfunction.

Animals↗
PubMed2000

Platelet-endothelial cell adhesion molecule-1 (CD31) redistributes from the endothelial junction and is not required for the transendothelial migration of melanoma cells.

We have examined the role of platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) during the transendothelial migration of melanoma cells using a novel in vitro system. Comparable studies have suggested the involvement of PECAM-1 in leukocyte transendothelial migration. Such studies have been confirmed using in vivo models of inflammation. These studies prompted us to examine the role of PECAM-1 in tumor cell transendothelial migration. Anti-PECAM-1 monoclonal antibodies, known to block leukocyte transendothelial migration, were tested in co-cultures of human melanoma cells seeded on a monolayer of human lung microvascular endothelial cells. None of these antibodies inhibited the transmigration of melanoma cells. Moreover, confocal microscopy revealed the dissolution of the PECAM-1 adhesion complexes in the endothelial junctions associated with melanoma cells and the lack of PECAM-1 in heterotypic contacts between transmigrating melanoma cells and adjacent endothelial cells. These data, therefore, indicate that PECAM-1 is not required for the transendothelial migration of melanoma cells.

Adherens Junctions↗
PubMed2002

Interaction of disease-related antigen-reactive T-cell lines from multiple sclerosis patients with type IV collagen: role of integrin VLA-1 and effects of irradiation.

Multiple sclerosis (MS), a chronic demyelinating disease, is thought to be initiated by pathogenic T cells that transmigrate the vascular endothelium and enter the brain through vascular and parenchymal basement membranes (BM). Vaccination with T-cell lines reactive with myelin basic protein (MBP) and myelin oligodendrocytic glycoprotein (MOG) epitopes, expanded with interleukin-2 (IL-2), and attenuated by ionizing radiation is currently being evaluated as a therapeutic modality for this disease. We examined mechanisms potentially involved in pathogenic cell migration into the central nervous system (CNS) and the influence of irradiation on these processes. Seven of 7 autoantigen-responsive T-cell lines from MS patients adhered to collagen IV, the major collagenous constituent of BMs. This adhesion was inhibited almost completely by monoclonal antibody (MAb) to very late antigen (VLA)-1 and partially by anti-VLA-2. T-cell lines from healthy donors adhered more variably to collagen IV. Furthermore, patient derived T cells actively transmigrated through a collagen IV gel toward medium containing TNF-a, in a process that was inhibited by MAbs to VLA-1. Ionizing radiation at the dose used in vaccine preparation, inhibited morphological polarization associated with migratory capability, induced integrin clustering on the cell membrane, and abrogated adhesion to collagen IV. These findings may have important implications for understanding the pathogenesis of MS and how irradiation of potentially pathogenic T cells produces a reagent with possible therapeutic effects in T-cell vaccination (TCV).

Adolescent↗
PubMed1998

Ultrastructural study of development of hepatic necrosis induced by TNF-alpha and D-galactosamine.

Recent studies have suggested an association between tumor necrosis factor-alpha (TNF-alpha) and the development and progression of acute liver failure. To investigate the role of TNF-alpha in the mechanism of massive hepatic necrosis, we studied a mouse model of TNF-alpha and D-galactosamine (GalN) -induced hepatic necrosis by ultrastructural analysis. Administration of GalN caused edema of hepatocellular microvilli and widening of sinusoidal endothelial fenestrae (SEF); administration of TNF-alpha caused only a widening of the SEF. Massive hepatic necrosis with hemorrhage was seen 6 hr after concomitant administration of TNF-alpha and GalN. In the ultrastructural analysis, edema of the hepatocellular microvilli, widening of the SEF, and transmigration of red blood cells (RBC) and platelets to the space of Disse without exfoliation and necrosis of the sinusoidal endothelial cells were observed. Fibrin deposits were seen in areas adjacent to injured hepatocytes. The diameter of the SEF was significantly greater than in the nontreated group and the groups treated with TNF-alpha or GalN alone. These results suggest that as a consequence of the increase in diameter of the SEF, transmigration of RBCs and platelets to the space of Disse may have resulted in massive hepatic necrosis due to occlusion of the microcirculation.

Animals↗
PubMed2000

Cytomegalovirus-infected neuroblastoma cells exhibit augmented invasiveness mediated by beta1alpha5 integrin (VLA-5).

Previously, experimental in vivo results showed that the productively and persistently human cytomegalovirus (HCMV)-infected neuroblastoma cell line UKF-NB-4AD169 exhibits a more malignant phenotype than the non-infected variant UKF-NB-4. To prove the assumption that enhanced malignancy may be due to enhanced invasive potential of the infected cells we studied interactions of both lines with monolayers of cultured endothelial cells. UKF-NB-4AD169 cells adhered to and transmigrated through endothelial monolayer to a significantly higher extent compared with UKF-NB4. Furthermore, the adhesion of UKF-NB-4AD169 but not of UKF-NB4 resulted in focal disruption of the monolayer integrity which facilitates tumor cell transmigration. Blocking antibodies directed against the beta1 integrin chain as well as beta1alpha5 on the tumor cells specifically inhibited adhesion in a concentration-dependent manner. When UKF-NB-4 were pretreated with a beta1 integrin activating antibody, focal disruption of the endothelial integrity also occurred. These findings lead us to suggest that HCMV infection activates beta1alpha5 in the host neuroblastoma cell which in turn enables these cells to tightly adhere to endothelial cells. In the presence of the protease inhibitor phenantroline, beta1alpha5-mediated adhesion was not impaired whereas UKF-NB4AD169-mediated endothelial monolayer permeabilization was dose dependently inhibited. We conclude that human cytomegalovirus infection contributes to augmented neuroblastoma invasiveness via adhesion of activated beta1alpha5 and subsequent matrix digestion by proteases.

Antibodies, Blocking↗
PubMed2000

The role of the graft endothelium in transplant rejection: evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection.

In this review, we discuss the role of the allograft endothelium in the recruitment and activation of leukocytes during acute and chronic rejection. We discuss associations among endothelial activation responses, the expression of adhesion molecules, chemokines and chemokine receptors, and rejection; and we propose that endothelial vascular cellular adhesion molecule-1 (VCAM-1) may be used as a surrogate marker of acute rejection and allograft vasculopathy. In addition, we describe potential mechanistic interpretations of persistent endothelial cell (EC) expression of major histocompatibility complex (MHC) class II molecules in allorecognition. The graft endothelium may provide an antigen-specific signal to transmigrating, previously activated, T cells and may induce B7 expression on locally transmigrating leukocytes to promote costimulation. Taken together, these functions of the EC provide it with a potent regulatory role in rejection and in the maintenance of T-cell activation via the direct and/or the indirect pathways of allorecognition.

Biomarkers↗