scholarly journals TNF-α activation of arterioles and venules alters distribution and levels of ICAM-1 and affects leukocyte-endothelial cell interactions

2006 ◽  
Vol 291 (5) ◽  
pp. H2116-H2125 ◽  
Author(s):  
Ronen Sumagin ◽  
Ingrid H. Sarelius
Keyword(s):  
Spatial Distribution ◽  
Endothelial Cell ◽  
Inflammatory Responses ◽  
Leukocyte Adhesion ◽  
Leukocyte Rolling ◽  
Cremaster Muscle ◽  
Rolling Velocity ◽  
Tnf Α ◽  
Arteriolar Wall ◽  
Microvessel Wall

The observation that leukocyte-endothelial cell (EC) interactions are localized to specific regions on the microvessel wall suggests that adhesion molecule distribution is not uniform. We investigated ICAM-1 distribution and leukocyte-EC interactions in blood-perfused microvessels (<80 μm) in cremaster muscle of anesthetized mice, using intravital confocal microscopy and immunofluorescent labeling. Variability of ICAM-1 expression directly determines leukocyte adhesion distribution within the venular microcirculation and contributes to leukocyte rolling in arterioles during inflammation. The number of rolling interactions increased with ICAM-1 intensity ( r2 = 0.69, P < 0.05), and rolling velocity was lower in regions of higher ICAM-1 intensity. In controls, venular ICAM-1 expression was approximately twofold higher than in arterioles. After TNF-α treatment, ICAM-1 expression was significantly increased, 2.8 ± 0.2-fold in arterioles and 1.7 ± 0.2-fold in venules ( P < 0.05). ICAM-1 expression on activated arteriolar ECs only reached the level of control venular ICAM-1. Arteriolar but not venular ECs underwent redistribution of ICAM-1 among cells; some cells increased and some decreased ICAM-1 expression, magnifying the variability of ICAM-1. TNF-α treatment increased the length of bright fluorescent regions per unit vessel length (42%, control; 70%, TNF-α) along the arteriolar wall, whereas no significant change was observed in venules (60%, control; 63%, TNF-α). The spatial distribution and expression levels of adhesion molecules in the microcirculation determine the timing and placement of leukocyte interactions and hence significantly impact the inflammatory response. That arteriolar ECs respond to TNF-α by upregulation of ICAM-1, although in a different way compared with venules, suggests an explicit role for arterioles in inflammatory responses.

Leukocyte adhesion in local versus hemorrhage-induced ischemia

1992 ◽  
Vol 263 (3) ◽  
pp. H810-H815 ◽  
Author(s):  
M. A. Perry ◽  
D. N. Granger
Keyword(s):  
Endothelial Cell ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Leukocyte Rolling ◽  
Leukocyte Adherence ◽  
Rolling Velocity ◽  
Local Ischemia ◽  
Cell Adhesive ◽  
Local Restriction ◽  
Adhesive Interactions

The objective of this study was to compare the leukocyte-endothelial cell adhesive interactions elicited in postcapillary venules by either local ischemia-reperfusion or hemorrhage-reperfusion. Leukocyte rolling, adherence, and emigration were monitored in cat mesenteric venules exposed to an 85% reduction in blood flow (induced by either hemorrhage or local restriction of arterial inflow) for 1 h, followed by 1 h reperfusion. Leukocyte-endothelial cell interactions, venular diameter, and red blood cell velocity were measured during baseline, ischemia, and reperfusion periods. Both local and hemorrhage-induced ischemia reperfusion caused a reduction in leukocyte rolling velocity and increases in leukocyte adherence and emigration. Quantitatively, the adherence and emigration responses in both ischemia models were nearly identical. However, the two models differed in their response to immunoneutralization of the leukocyte adhesion glycoprotein CD11/CD18 with monoclonal antibody (MAb) IB4. The MAb had a more profound effect in attenuating leukocyte adherence and emigration in the local ischemia model. These results indicate that different factors may contribute to leukocyte-endothelial cell adhesive interactions observed in local vs. systemic models of ischemia-reperfusion.

Control of leukocyte rolling velocity in TNF-α–induced inflammation by LFA-1 and Mac-1

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 336-341 ◽  
Author(s):  
Jessica L. Dunne ◽  
Christie M. Ballantyne ◽  
Arthur L. Beaudet ◽  
Klaus Ley
Keyword(s):  
Leukocyte Adhesion ◽  
Leukocyte Rolling ◽  
Rolling Velocity ◽  
Slowing Down ◽  
Tnf Α ◽  
Adhesion Efficiency ◽  
Factor Α ◽  
Rolling Leukocytes ◽  
Necrosis Factor ◽  
Β2 Integrins

Previously it was shown that β2-integrins are necessary for slow leukocyte rolling in inflamed venules. In this study, mice that are deficient for either one of the β2-integrins, αLβ2 (LFA-1) or αMβ2 (Mac-1), were used to determine which of the β2-integrins are responsible for slowing rolling leukocytes. The cremaster muscles of these mice were treated with tumor necrosis factor-α and prepared for intravital microscopy. The average rolling velocities in venules were elevated in LFA-1−/−mice (11.0 ± 0.7 μm/s) and Mac-1−/− mice (10.1 ± 1.1 μm/s) compared to wild-type mice (4.8 ± 0.3 μm/s;P &lt; .05), but were lower than in CD18−/−mice (28.5 ± 2.1 μm/s). When both LFA-1 and Mac-1 were absent or blocked, rolling velocity became dependent on shear rate and approached that of CD18−/− mice. In addition, leukocyte adhesion efficiency was decreased in LFA-1−/− mice to near CD18−/− levels, but decreased only slightly in Mac-1−/− mice. Thus, both LFA-1 and Mac-1 contribute to slowing down rolling leukocytes, although LFA-1 is more important than Mac-1 in efficiently inducing firm adhesion.

Preconditioning and adenosine in I/R-induced leukocyte-endothelial cell interactions

1998 ◽  
Vol 274 (4) ◽  
pp. H1230-H1238 ◽  
Author(s):  
Paul Kubes ◽  
Derrice Payne ◽  
Lena Ostrovsky
Keyword(s):  
Endothelial Cell ◽  
Leukocyte Adhesion ◽  
Vascular Dysfunction ◽  
Ischemia Reperfusion ◽  
Microvascular Dysfunction ◽  
Cell Interactions ◽  
Minor Role ◽  
Neutrophil Adhesion ◽  
Rolling Velocity

Recently, it was reported that preconditioning reduced leukocyte adhesion following ischemia-reperfusion (I/R). We further examined the effects of preconditioning and adenosine not only on neutrophil adhesion but also on neutrophil rolling and vascular dysfunction. Intravital microscopy revealed a decrease in neutrophil rolling velocity; a profound increase in neutrophil rolling, adhesion, and microvascular dysfunction; and a reduction in venular shear rates associated with 60 min ischemia and 60 min reperfusion in the feline mesentery. Preconditioning (5 min ischemia/10 min reperfusion) prevented subsequent I/R-induced slow neutrophil rolling, neutrophil adhesion, and microvascular dysfunction but did not affect the flux of rolling neutrophils. Adenosine deaminase A1and A2adenosine-receptor antagonists had only minor effects on the preconditioning responses. Pretreatment of vessels with exogenous adenosine reduced neutrophil adhesion and microvascular permeability and improved neutrophil rolling velocity and shear forces associated with I/R, but the flux of rolling neutrophils was not affected. Finally, in vitro experiments revealed that adenosine had absolutely no direct effect on neutrophil-endothelial cell interactions. In conclusion, our data suggest that adenosine plays only a minor role in preconditioned vessels and that adenosine per se may not directly affect neutrophil-endothelial cell interactions.

Molecular determinants of lipid mediator-induced leukocyte adherence and emigration in rat mesenteric venules

1994 ◽  
Vol 266 (3) ◽  
pp. H847-H853 ◽  
Author(s):  
B. J. Zimmerman ◽  
J. W. Holt ◽  
J. C. Paulson ◽  
D. C. Anderson ◽  
M. Miyasaka ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Platelet Activating Factor ◽  
Leukotriene B4 ◽  
Intercellular Adhesion Molecule ◽  
Lipid Mediator ◽  
Leukocyte Rolling ◽  
Leukocyte Adherence ◽  
Intercellular Adhesion Molecule 1 ◽  
Rolling Velocity ◽  
Molecular Determinants

The objective of this study was to identify the molecular determinants of leukocyte rolling, adherence, and emigration elicited in postcapillary venules by the lipid mediators leukotriene B4 (LTB4) or platelet-activating factor (PAF). Leukocyte-endothelial cell adhesion and shear rate were monitored in rat mesenteric venules during superfusion with either LTB4 or PAF in the presence or absence of monoclonal antibodies (MAbs) directed against either leukocyte (CD18, CD11b) or endothelial cell [intercellular adhesion molecule 1 (ICAM-1), E-selectin, P-selectin] adhesion glycoproteins. In untreated animals and in animals receiving a nonbinding control MAb, LTB4 and PAF increased the number of both adherent (8- and 4-fold, respectively) and emigrated (14- and 8-fold, respectively) leukocytes, while reducing leukocyte rolling velocity (36 and 33%, respectively). The LTB4- and PAF-induced leukocyte adherence and emigration were significantly attenuated by pretreatment with MAbs directed against CD18, CD11b, ICAM-1, and E-selectin, but not P-selectin. The reduction in leukocyte rolling velocity induced by LTB4 was not affected by any of the MAbs; however, both P- and E-selectin MAbs significantly attenuated the reduction in leukocyte rolling velocity elicited by PAF. The results of this study indicate that the leukocyte adherence and emigration induced by both LTB4 and PAF are mediated by CD11b/CD18 on leukocytes and by ICAM-1 and E-selectin on endothelial cells. The molecular determinant of leukocyte rolling appears to be mediator specific, with the selectins mediating the rolling elicited by PAF.

A Novel Selectin Antagonist, GMI-1070, Prevents Vaso-Occlusion in Sickle Cell Mice by Inhibiting Leukocyte Adhesion and Activation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2245-2245
Author(s):  
Jungshan Chang ◽  
John Patton ◽  
Arun Sarkar ◽  
John L. Magnani ◽  
Paul S. Frenette
Keyword(s):  
Sickle Cell ◽  
Intravital Microscopy ◽  
Competitive Inhibition ◽  
Leukocyte Adhesion ◽  
Fold Increase ◽  
Surgical Trauma ◽  
Mouse Bone Marrow ◽  
Leukocyte Rolling ◽  
Tnf Α ◽  
Adherent Leukocytes

Abstract Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p&lt; 0.001). Furthermore GMI-1070 and GMI-1077 significantly reduced the recruitment of adherent leukocytes (914±172 and 1433±119 cells/mm2, respectively) compared to sickle mice injected with PBS control (2400±392 cells/mm2, p&lt; 0.001). Although the reduction in leukocyte adhesion was not as marked as with anti-P and E-selectins (61±25 cells/mm2, p&lt; 0.001), GMI-1070, in particular, dramatically inhibited the capture of sickle RBCs by adherent leukocytes (PBS: 0.9±0.4, GMI-1077: 0.6±0.2, GMI-1070: 0.07±0.05 and PES: 0.01±0.01 RBC interactions/WBC/min, p&lt; 0.05) and markedly improved the blood flow in venules (PBS: 312±24, GMI-1077: 398±41, GMI-1070: 710±68 and PES: 683±75 nL/s, p&lt; 0.001), to levels observed in non-sickle mice. The increased leukocyte rolling fluxes by these glycomimetics suggest that they inhibit E-selectin &gt; P-selectin. Since the hallmark of E-selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p&lt;0.001). Consistent with these results, other studies using a parallel plate flow chamber (0.9 dynes/cm2) revealed that GMI-1070 was much more potent (1000-fold difference) in inhibiting the binding of human PMNs to TNF-α-stimulated (to induce E-selectin) endothelial cells (HUVEC) than with IL-4 and histamine stimulated HUVECs (to induce P-selectin). Further, competitive inhibition assays revealed that the IC50 of GMI-1070, relative to the standard glycyrrhizin, was much lower for E-selectin than P-selectin. These studies suggest that E-selectin-mediated adhesion/signaling may play a more important role than previously appreciated in the pathophysiology of SCD, and suggest that GMI-1070 may be beneficial for the treatment of sickle cell vaso-occlusion.

scholarly journals Protective Effects of Total Saponins of Aralia elata (Miq.) on Endothelial Cell Injury Induced by TNF-α via Modulation of the PI3K/Akt and NF-κB Signalling Pathways

2018 ◽  
Vol 20 (1) ◽  
pp. 36 ◽  
Author(s):  
Ping Zhou ◽  
Weijie Xie ◽  
Yun Luo ◽  
Shan Lu ◽  
Ziru Dai ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Early Event ◽  
Protective Effects ◽  
Bax Protein ◽  
Aralia Elata ◽  
Tnf Α ◽  
Anti Inflammatory

Atherosclerosis is an arterial disease associated with inflammation. Hence, the discovery of novel therapeutic agents for suppressing inflammatory responses is urgent and vital for the treatment of atherosclerosis in cardiovascular diseases. The total saponins of Aralia elata (Miq.) Seem. (TAS) are the main components extracted from the Chinese traditional herb Longya Aralia chinensis L., a folk medicine used in Asian countries for treating numerous diseases, enhancing energy and boosting immunity. However, the protective effects of TAS against inflammation-triggered vascular endothelial dysfunction, a critical early event during the course of atherosclerosis, and the potential mechanisms of this protection have been not demonstrated. Accordingly, the aim of this study was to investigate the anti-inflammatory and anti-apoptotic effects and the protective mechanisms of TAS, and show how TAS ameliorates human umbilical vein endothelial cell (HUVEC) damage caused by tumour necrosis factor-α (TNF-α). The results indicated that TAS exerted cytoprotective effects by inhibiting TNF-α-triggered HUVEC apoptosis, mitochondrial membrane potential depolarisation, and the regulation of inflammatory factors (IL-6, MCP-1, and VCAM-1) while suppressing NF-κB transcription. Furthermore, this phenomenon was related to activation of the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway. Blocking the Akt pathway with LY294002, a PI3K inhibitor, reversed the cytoprotective effect of TAS against TNF-α-induced endothelial cell death. Moreover, LY294002 partially abolished the effects of TAS on the upregulation of the Bcl-2 family of proteins and the downregulation of Bax protein expression. In conclusion, the results of our study suggest that TAS suppresses the inflammation and apoptosis of HUVECs induced by TNF-α and that PI3K/Akt signalling plays a key role in promoting cell survival and anti-inflammatory reactions during this process.

Molecular mechanisms involved in superoxide-induced leukocyte-endothelial cell interactions in vivo

1994 ◽  
Vol 266 (2) ◽  
pp. H637-H642 ◽  
Author(s):  
J. P. Gaboury ◽  
D. C. Anderson ◽  
P. Kubes
Keyword(s):  
Molecular Mechanisms ◽  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Leukocyte Rolling ◽  
Rolling Velocity ◽  
Paf Receptor ◽  
Rolling Leukocytes ◽  
Adherent Leukocytes ◽  
Web 2086

Intravital microscopy was used to monitor leukocyte adherence, flux, rolling velocity, and number of rolling leukocytes (flux/velocity) in venules 25–40 microns in diameter. The superoxide-generating system, hypoxanthine and xanthine oxidase (HX/XO), was infused into the mesenteric circulation in untreated animals or in animals pretreated with either catalase (a hydrogen peroxide scavenger), WEB-2086 [a platelet-activating factor (PAF) receptor antagonist], or monoclonal antibodies directed against adhesion molecules CD18 (CL26) or P-selectin (PB1.3). HX/XO infusion caused a decrease in leukocyte rolling velocity and an increase in the number of rolling and adherent leukocytes. WEB-2086 prevented the increase in leukocyte adhesion and markedly increased leukocyte rolling velocity. PB1.3 abolished the HX/XO-associated rise in the flux of rolling leukocytes and proportionally decreased the number of adherent leukocytes. CL26 abolished HX/XO-induced leukocyte adhesion and also reduced the number of rolling leukocytes. In conclusion, P-selectin mediates the increased leukocyte flux induced by superoxide, whereas PAF and CD18 modulate leukocyte adhesion. PAF also reduces leukocyte rolling velocity, possibly as a result of CD18, but not P-selectin.

Superoxide mediates reperfusion-induced leukocyte-endothelial cell interactions

1989 ◽  
Vol 257 (5) ◽  
pp. H1740-H1745 ◽  
Author(s):  
M. Suzuki ◽  
W. Inauen ◽  
P. R. Kvietys ◽  
M. B. Grisham ◽  
C. Meininger ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Leukocyte Adhesion ◽  
Cell Interactions ◽  
Leukocyte Adherence ◽  
Microvascular Endothelium ◽  
Rolling Velocity ◽  
Blood Flows ◽  
Cell Velocity ◽  
Red Blood Cell Velocity ◽  
Neutrophil Adherence

The objective of this study was to determine whether superoxide mediates the leukocyte-endothelial cell interactions elicited by reperfusion (reoxygenation) of ischemic (hypoxic) tissues. Mesenteric and intestinal blood flows were reduced to 20% of control for 1 h, followed by 1 h of reperfusion. Sixty minutes after reperfusion, red blood cell velocity (Vr), leukocyte rolling velocity (Vw), and the number of adherent leukocytes were measured in mesenteric venules. Then, either human superoxide dismutase (hSOD), hydrogen peroxide-inactivated hSOD, or MoAb IB4 (a monoclonal antibody against the leukocyte adhesion molecule CD18) was injected intravenously. Ten minutes later, repeat measurements were obtained and compared with pretreatment values. hSOD attenuated reperfusion-induced neutrophil adherence and increased Vw/Vr, an index of the fracture stress between leukocytes and endothelium. Peroxide-inactivated hSOD did not alter any parameter. MoAb IB4 attenuated reperfusion-induced adherence but did not alter Vw/Vr. In a correlate study, cultured bovine microvascular endothelium was exposed to 30 min of anoxia, followed by 60 min of reoxygenation. Cat neutrophils were added during reoxygenation. Reoxygenation-induced leukocyte adherence was attenuated by either hSOD or MoAb IB4 but not by inactivated hSOD. Adherence of phorbol 12-myristate 13-acetate-activated cat neutrophils to plastic was unaffected by hSOD or inactive hSOD, yet MoAb IB4 virtually abolished the response. These results indicate that superoxide mediates reperfusion-induced leukocyte adherence and that endothelial cells are required for this superoxide-mediated adherence.

Vascular protection by estrogen in ischemia-reperfusion injury requires endothelial nitric oxide synthase

2003 ◽  
Vol 284 (1) ◽  
pp. H133-H140 ◽  
Author(s):  
Alyson J. Prorock ◽  
Ali Hafezi-Moghadam ◽  
Victor E. Laubach ◽  
James K. Liao ◽  
Klaus Ley
Keyword(s):  
Nitric Oxide ◽  
Ischemia Reperfusion Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Strong Dependence ◽  
Fold Increase ◽  
No Production ◽  
Leukocyte Rolling ◽  
Vascular Protection ◽  
Rolling Velocity

Estrogen increases nitric oxide (NO) production by inducing the activity of endothelial NO synthase (eNOS) (Simoncini et al. Nature 407: 538, 2000). Ischemia (30 min) and reperfusion (I/R) increased the number of adherent leukocytes and decreased their rolling velocities in mouse cremaster muscle venules with a strong dependence on wall shear rate. Minimum rolling velocity at ∼5 min after the onset of reperfusion was accompanied by increased P-selectin expression. This preceded the peak in leukocyte adhesion (at 10–15 min). In untreated wild-type mice, I/R caused a decrease of leukocyte rolling velocity from 37 to 26 μm/s and a 2.0-fold increase in leukocyte adhesion. Both were completely abolished by 0.25 mg ip estrogen 1 h before surgery. In eNOS−/− mice, the decrease of leukocyte rolling velocity and increase in adhesion were similar but were only marginally improved by estrogen. We conclude that the protective effect of estrogen, as measured by leukocyte rolling and adhesion, is significantly reduced in eNOS−/− mice, suggesting that induction of eNOS activity is the major mechanism of vasoprotection by estrogen in this model.

Mechanisms of oxidized chylomicron-induced leukocyte-endothelial cell adhesion

1995 ◽  
Vol 268 (6) ◽  
pp. H2175-H2182
Author(s):  
H. Kurtel ◽  
L. Liao ◽  
M. B. Grisham ◽  
P. Tso ◽  
T. Y. Aw ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Thiobarbituric Acid ◽  
Leukocyte Rolling ◽  
Lipid Hydroperoxides ◽  
Adhesive Interactions ◽  
Oxidatively Modified ◽  
Endothelial Cell Adhesion

The objectives of this study were to determine whether oxidatively modified chylomicrons (oxCM) can elicit leukocyte-endothelial cell adhesion in the mesenteric microcirculation and to define the mechanisms underlying the oxCM-induced adhesive interactions. Oxidation of chylomicrons (CM) with the peroxyl radical generator 2,2'-azobis(2-amidinopropane)hydrochloride was associated with the formation of thiobarbituric acid-reactive substances and lipid hydroperoxides. Leukocyte rolling, adherence, and emigration as well as erythrocyte velocity were monitored in rat mesenteric venules infused with either native CM or oxCM. oxCM, but not native CM, increased the numbers of rolling, adherent, and emigrated leukocytes. The oxCM-induced leukocyte adherence was significantly blunted by pretreating the animals with either superoxide dismutase, a platelet-activating factor (PAF) receptor antagonist, or monoclonal antibodies (MAb) directed against either CD11/CD18 or intracellular adhesion molecule 1. A MAb against P-selectin reduced oxCM-induced leukocyte rolling but not adherence. These findings suggest that the increased plasma oxCM levels associated with ingestion of oxidized lipids may promote leukocyte adhesion through a mechanism that involves the superoxide anion, PAF, and adhesion receptors on leukocytes and endothelial cells.

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