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Stephen A Douglas - One of the best experts on this subject based on the ideXlab platform.
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role of p38 map kinase in postcapillary venule leukocyte adhesion induced by ischemia reperfusion injury
Pharmacological Research, 2005Co-Authors: Douglas G Johns, Zhaohui Ao, Robert N Willette, Colin H Macphee, Stephen A DouglasAbstract:Abstract Inflammation and leukocyte activation/infiltration play a major role in the initiation and progression of cardiovascular diseases including atherosclerosis and heart failure. Acute p38 mitogen-activated protein kinase (MAPK) pathway inhibition attenuates tissue damage and leukocyte accumulation in myocardial ischemia/reperfusion injury, although its effect on the acute phase of leukocyte recruitment has not been elucidated. The purpose of this study was to test the hypothesis that acute treatment of rats with a selective p38 inhibitor, SB-239063, inhibits ischemia/reperfusion-induced leukocyte-endothelial adhesion in vivo. Male Sprague–Dawley rats were treated with either SB-239063 (10 mg kg−1), dexamethasone (3 mg kg−1) or vehicle 1 h prior to ischemia. Postcapillary venules were observed microscopically in exteriorized, superfused cremaster tissue. Leukocytes were fluorescently labeled in vivo using intravenous rhodamine 6G. Leukocyte adhesion, rolling, and rolling velocities were quantitated prior to 30 min ischemia, and at several time points during a 90 min reperfusion period. Ischemia caused a 3-fold increase in adherent Leukocytes 5 min following reperfusion, a response that was maintained throughout the monitoring period (90 min) in vehicle-treated animals. SB-239063, at a dose known to inhibit p38 MAPK activity in vivo (10 mg kg−1), had no effect on ischemia/reperfusion-induced leukocyte adhesion, the number of rolling Leukocytes, rolling velocities during the reperfusion period or adhesion molecule expression (P-, E-selectin, VCAM-1, ICAM-1). In contrast, dexamethasone completely blocked leukocyte adhesion in response to ischemia/reperfusion, and reduced expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). We conclude that p38 MAPK may not play a role in initial leukocyte recruitment in response to ischemia/reperfusion injury, but could affect leukocyte emigration, thereby resulting in increased leukocyte accumulation in ischemic-reperfused tissue.
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Role of p38 MAP kinase in postcapillary venule leukocyte adhesion induced by ischemia/reperfusion injury.
Pharmacological Research, 2005Co-Authors: Douglas G Johns, Zhaohui Ao, Robert N Willette, Colin H Macphee, Stephen A DouglasAbstract:Abstract Inflammation and leukocyte activation/infiltration play a major role in the initiation and progression of cardiovascular diseases including atherosclerosis and heart failure. Acute p38 mitogen-activated protein kinase (MAPK) pathway inhibition attenuates tissue damage and leukocyte accumulation in myocardial ischemia/reperfusion injury, although its effect on the acute phase of leukocyte recruitment has not been elucidated. The purpose of this study was to test the hypothesis that acute treatment of rats with a selective p38 inhibitor, SB-239063, inhibits ischemia/reperfusion-induced leukocyte-endothelial adhesion in vivo. Male Sprague–Dawley rats were treated with either SB-239063 (10 mg kg−1), dexamethasone (3 mg kg−1) or vehicle 1 h prior to ischemia. Postcapillary venules were observed microscopically in exteriorized, superfused cremaster tissue. Leukocytes were fluorescently labeled in vivo using intravenous rhodamine 6G. Leukocyte adhesion, rolling, and rolling velocities were quantitated prior to 30 min ischemia, and at several time points during a 90 min reperfusion period. Ischemia caused a 3-fold increase in adherent Leukocytes 5 min following reperfusion, a response that was maintained throughout the monitoring period (90 min) in vehicle-treated animals. SB-239063, at a dose known to inhibit p38 MAPK activity in vivo (10 mg kg−1), had no effect on ischemia/reperfusion-induced leukocyte adhesion, the number of rolling Leukocytes, rolling velocities during the reperfusion period or adhesion molecule expression (P-, E-selectin, VCAM-1, ICAM-1). In contrast, dexamethasone completely blocked leukocyte adhesion in response to ischemia/reperfusion, and reduced expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). We conclude that p38 MAPK may not play a role in initial leukocyte recruitment in response to ischemia/reperfusion injury, but could affect leukocyte emigration, thereby resulting in increased leukocyte accumulation in ischemic-reperfused tissue.
Douglas G Johns - One of the best experts on this subject based on the ideXlab platform.
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role of p38 map kinase in postcapillary venule leukocyte adhesion induced by ischemia reperfusion injury
Pharmacological Research, 2005Co-Authors: Douglas G Johns, Zhaohui Ao, Robert N Willette, Colin H Macphee, Stephen A DouglasAbstract:Abstract Inflammation and leukocyte activation/infiltration play a major role in the initiation and progression of cardiovascular diseases including atherosclerosis and heart failure. Acute p38 mitogen-activated protein kinase (MAPK) pathway inhibition attenuates tissue damage and leukocyte accumulation in myocardial ischemia/reperfusion injury, although its effect on the acute phase of leukocyte recruitment has not been elucidated. The purpose of this study was to test the hypothesis that acute treatment of rats with a selective p38 inhibitor, SB-239063, inhibits ischemia/reperfusion-induced leukocyte-endothelial adhesion in vivo. Male Sprague–Dawley rats were treated with either SB-239063 (10 mg kg−1), dexamethasone (3 mg kg−1) or vehicle 1 h prior to ischemia. Postcapillary venules were observed microscopically in exteriorized, superfused cremaster tissue. Leukocytes were fluorescently labeled in vivo using intravenous rhodamine 6G. Leukocyte adhesion, rolling, and rolling velocities were quantitated prior to 30 min ischemia, and at several time points during a 90 min reperfusion period. Ischemia caused a 3-fold increase in adherent Leukocytes 5 min following reperfusion, a response that was maintained throughout the monitoring period (90 min) in vehicle-treated animals. SB-239063, at a dose known to inhibit p38 MAPK activity in vivo (10 mg kg−1), had no effect on ischemia/reperfusion-induced leukocyte adhesion, the number of rolling Leukocytes, rolling velocities during the reperfusion period or adhesion molecule expression (P-, E-selectin, VCAM-1, ICAM-1). In contrast, dexamethasone completely blocked leukocyte adhesion in response to ischemia/reperfusion, and reduced expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). We conclude that p38 MAPK may not play a role in initial leukocyte recruitment in response to ischemia/reperfusion injury, but could affect leukocyte emigration, thereby resulting in increased leukocyte accumulation in ischemic-reperfused tissue.
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Role of p38 MAP kinase in postcapillary venule leukocyte adhesion induced by ischemia/reperfusion injury.
Pharmacological Research, 2005Co-Authors: Douglas G Johns, Zhaohui Ao, Robert N Willette, Colin H Macphee, Stephen A DouglasAbstract:Abstract Inflammation and leukocyte activation/infiltration play a major role in the initiation and progression of cardiovascular diseases including atherosclerosis and heart failure. Acute p38 mitogen-activated protein kinase (MAPK) pathway inhibition attenuates tissue damage and leukocyte accumulation in myocardial ischemia/reperfusion injury, although its effect on the acute phase of leukocyte recruitment has not been elucidated. The purpose of this study was to test the hypothesis that acute treatment of rats with a selective p38 inhibitor, SB-239063, inhibits ischemia/reperfusion-induced leukocyte-endothelial adhesion in vivo. Male Sprague–Dawley rats were treated with either SB-239063 (10 mg kg−1), dexamethasone (3 mg kg−1) or vehicle 1 h prior to ischemia. Postcapillary venules were observed microscopically in exteriorized, superfused cremaster tissue. Leukocytes were fluorescently labeled in vivo using intravenous rhodamine 6G. Leukocyte adhesion, rolling, and rolling velocities were quantitated prior to 30 min ischemia, and at several time points during a 90 min reperfusion period. Ischemia caused a 3-fold increase in adherent Leukocytes 5 min following reperfusion, a response that was maintained throughout the monitoring period (90 min) in vehicle-treated animals. SB-239063, at a dose known to inhibit p38 MAPK activity in vivo (10 mg kg−1), had no effect on ischemia/reperfusion-induced leukocyte adhesion, the number of rolling Leukocytes, rolling velocities during the reperfusion period or adhesion molecule expression (P-, E-selectin, VCAM-1, ICAM-1). In contrast, dexamethasone completely blocked leukocyte adhesion in response to ischemia/reperfusion, and reduced expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). We conclude that p38 MAPK may not play a role in initial leukocyte recruitment in response to ischemia/reperfusion injury, but could affect leukocyte emigration, thereby resulting in increased leukocyte accumulation in ischemic-reperfused tissue.
D N Granger - One of the best experts on this subject based on the ideXlab platform.
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Molecular determinants of shear rate-dependent leukocyte adhesion in postcapillary venules
American Journal of Physiology-heart and Circulatory Physiology, 1993Co-Authors: Karine Bienvenu, D N GrangerAbstract:Recent studies have demonstrated that reductions in shear rate are associated with the recruitment of rolling and adherent Leukocytes in postcapillary venules. The objective of this study was to define the molecular determinants of the leukocyte-endothelial cell adhesive interactions elicited by low venular shear rates. Three different monoclonal antibodies (MAb) were used to assess the relative contributions of CD18 (MAb R15.7), intercellular adhesion molecule 1 (ICAM-1; MAb RR1/1), and P-selectin (MAb PB1.3) to shear rate-dependent leukocyte rolling and adherence. Erythrocyte velocity, vessel diameter, leukocyte adherence, and leukocyte rolling velocity were monitored in cat mesenteric venules (25-40 microns diam). Venular shear rate was varied in a stepwise fashion by graded occlusion of an arterial circuit between the femoral and superior mesenteric arteries. Shear rates were maintained at each level for a period of 2 min. The MAbs directed against either CD18 or ICAM-1, but not P-selectin, significantly attenuated the recruitment of adherent Leukocytes normally observed at low shear rates. However, the MAb against P-selectin, but not CD18 or ICAM-1, was effective in reducing the recruitment of rolling Leukocytes elicited by low shear rates. These observations indicate that shear rate-dependent recruitment of adherent Leukocytes involves an interaction between CD11/CD18 on Leukocytes and ICAM-1 on vascular endothelium, while P-selectin on endothelial cells mediates, at least part of, the recruitment of rolling Leukocytes.
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role of cd11 cd18 in shear rate dependent leukocyte endothelial cell interactions in cat mesenteric venules
Journal of Clinical Investigation, 1991Co-Authors: M A Perry, D N GrangerAbstract:In vivo microscopy was used to assess the relationships among shear rate (and shear stress), leukocyte rolling velocity, and leukocyte adherence in a cat mesentery preparation. Shear rate in individual venules and arterioles of 25-35 microns diameter were varied over a wide range by graded occlusion of an arterial loop. There was a linear decline in leukocyte rolling velocity (Vwbc) as red cell velocity (Vrbc) was reduced. The ratio Vwbc/Vrbc remained constant despite variations in shear stress from 5-25 dyn/cm2. A reduction in shear stress was associated with an increased leukocyte adherence, particularly when Vwbc was reduced below 50 microns/s. Reduction in wall shear rate below 500 s-1 in arterioles allowed 1-3 Leukocytes to adhere per 100 microns length of vessel, while venules exposed to the same shear rates had 5-16 adherent Leukocytes. In arterioles, leukocyte rolling was only observed at low shear rates. At shear rates less than 250 s-1 leukocyte rolling velocity was faster in arterioles than venules, and the ratio Vwbc/Vrbc for arterioles was 0.08 +/- 0.02, which was fourfold higher than the ratio obtained in venules at similar shear rates. Pretreatment with the CD18-specific antibody (mAb) IB4 increased leukocyte rolling velocity in venules by approximately 20 microns/s at red cell velocities below 2,000 microns/s. mAb IB4 largely prevented the leukocyte adherence to arterioles and venules, and increased the ratio Vwbc/Vrbc observed in venules at low shear elicit a CD18-dependent adhesive interaction between Leukocytes and microvascular endothelium, and that differences in shear rates cannot explain the greater propensity for leukocyte rolling and adhesion in venules than arterioles.
Richard M Ransohoff - One of the best experts on this subject based on the ideXlab platform.
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the blood brain barrier chemokines and multiple sclerosis
Biochimica et Biophysica Acta, 2011Co-Authors: David W Holman, Robyn S Klein, Richard M RansohoffAbstract:Abstract The infiltration of Leukocytes into the central nervous system (CNS) is an essential step in the neuropathogenesis of multiple sclerosis (MS). Leukocyte extravasation from the bloodstream is a multistep process that depends on several factors including fluid dynamics within the vasculature and molecular interactions between circulating Leukocytes and the vascular endothelium. An important step in this cascade is the presence of chemokines on the vascular endothelial cell surface. Chemokines displayed along the endothelial lumen bind chemokine receptors on circulating Leukocytes, initiating intracellular signaling that culminates in integrin activation, leukocyte arrest, and extravasation. The presence of chemokines at the endothelial lumen can help guide the movement of Leukocytes through peripheral tissues during normal immune surveillance, host defense or inflammation. The expression and display of homeostatic or inflammatory chemokines therefore critically determine which leukocyte subsets extravasate and enter the peripheral tissues. Within the CNS, however, infiltrating Leukocytes that cross the endothelium face additional boundaries to parenchymal entry, including the abluminal presence of localizing cues that prevent egress from perivascular spaces. This review focuses on the differential display of chemokines along endothelial surfaces and how they impact leukocyte extravasation into parenchymal tissues, especially within the CNS. In particular, the display of chemokines by endothelial cells of the blood brain barrier may be altered during CNS autoimmune disease, promoting leukocyte entry into this immunologically distinct site. Recent advances in microscopic techniques, including two-photon and intravital imaging have provided new insights into the mechanisms of chemokine-mediated capture of Leukocytes within the CNS.
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three or more routes for leukocyte migration into the central nervous system
Nature Reviews Immunology, 2003Co-Authors: Richard M Ransohoff, Pia Kivisakk, Grahame J KiddAbstract:Leukocyte migration into and through tissues is fundamental to normal physiology, immunopathology and host defence. Leukocyte entry into the central nervous system (CNS) is restricted, in part, because of the blood–brain barrier (BBB). During the past decade, crucial components that are involved in the process of leukocyte migration have been identified and progress has been made in understanding the mechanisms of neuroinflammatory reactions. In this review, present knowledge of the trafficking determinants that guide the migration of Leukocytes is superimposed onto the vascular and compartmental anatomy of the CNS. We discuss three distinct routes for Leukocytes to enter the CNS and consider how different populations of Leukocytes use trafficking signals to gain entry.
Sussan Nourshargh - One of the best experts on this subject based on the ideXlab platform.
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leukocyte migration into inflamed tissues
Immunity, 2014Co-Authors: Sussan Nourshargh, Ronen AlonAbstract:Leukocyte migration through activated venular walls is a fundamental immune response that is prerequisite to the entry of effector cells such as neutrophils, monocytes, and effector T cells to sites of infection, injury, and stress within the interstitium. Stimulation of Leukocytes is instrumental in this process with enhanced temporally controlled leukocyte adhesiveness and shape-changes promoting leukocyte attachment to the inner wall of blood vessels under hydrodynamic forces. This initiates polarized motility of Leukocytes within and through venular walls and transient barrier disruption facilitated sequentially by stimulated vascular cells, i.e., endothelial cells and their associated pericytes. Perivascular cells such as macrophages and mast cells that act as tissue inflammatory sentinels can also directly and indirectly regulate the exit of Leukocytes from the vascular lumen. In this review, we discuss current knowledge and open questions regarding the mechanisms involved in the interactions of different effector Leukocytes with peripheral vessels in extralymphoid organs.
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an anti platelet endothelial cell adhesion molecule 1 antibody inhibits leukocyte extravasation from mesenteric microvessels in vivo by blocking the passage through the basement membrane
Journal of Experimental Medicine, 1996Co-Authors: M W Wakelin, M J Sanz, A Dewar, Steven M Albelda, Simon W Larkin, N Boughtonsmith, T J Williams, Sussan NoursharghAbstract:Platelet-endothelial cell adhesion molecule-1 (PECAM-1, CD31) plays an active role in the process of leukocyte migration through cultured endothelial cells in vitro and anti-PECAM-1 antibodies (Abs) inhibit accumulation of Leukocytes into sites of inflammation in vivo. Despite the latter, it is still not clear at which stage of leukocyte emigration in vivo PECAM-1 is involved. To address this point directly, we studied the effect of an anti-PECAM-1 Ab, recognizing rat PECAM-1, on leukocyte responses within rat mesenteric microvessels using intravital microscopy. In mesenteric preparations activated by interleukin (IL)-1 beta, the anti-PECAM-1 Ab had no significant effect on the rolling or adhesion of Leukocytes, but inhibited their migration into the surrounding extravascular tissue in a dose-dependent manner. Although in some vessel segments these Leukocytes had come to a halt within the vascular lumen, often the Leukocytes appeared to be trapped within the vessel wall. Analysis of these sections by electron microscopy revealed that the Leukocytes had passed through endothelial cell junctions but not the basement membrane. In contrast to the effect of the Ab in mesenteric preparations treated with IL-1 beta, leukocyte extravasation induced by topical or intraperitoneal administration of the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was not inhibited by the anti-PECAM-1 Ab. These results directly demonstrate a role for PECAM-1 in leukocyte extravasation in vivo and indicate that this involvement is selective for leukocyte extravasation elicited by certain inflammatory mediators. Further, our findings provide the first in vivo indication that PECAM-1 may have an important role in triggering the passage of Leukocytes through the perivascular basement membrane.
