A2A adenosine receptor-mediated inhibition of renal injury and neutrophil adhesion

2000 ◽  
Vol 279 (5) ◽  
pp. F809-F818 ◽  
Author(s):  
Mark D. Okusa ◽  
Joel Linden ◽  
Liping Huang ◽  
Jayson M. Rieger ◽  
Timothy L. Macdonald ◽  
...  
Keyword(s):  
Renal Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Plasma Creatinine ◽  
Intercellular Adhesion Molecule ◽  
Neutrophil Adhesion ◽  
Myeloperoxidase Activity ◽  
Sprague Dawley ◽  
Intercellular Adhesion Molecule 1 ◽  
Peritubular Capillaries

We sought to determine the mechanisms responsible for the reduced renal tissue injury by agonists of A2A adenosine receptors (A2A-ARs) in models of ischemia-reperfusion (I/R) injury. DWH-146e, a selective A2A-AR agonist, was administered subcutaneously to Sprague-Dawley rats and C57BL/6 mice via osmotic minipumps, and animals were subjected to I/R. I/R led to an increase in plasma creatinine and kidney neutrophil infiltration. Infusion of DWH-146e at 10 ng · kg−1 · min−1 produced a 70% reduction in plasma creatinine as well as a decrease in neutrophil density in outer medulla and cortex and myeloperoxidase activity in the reperfused kidney. Myeloperoxidase activity in kidney correlated with the degree of renal injury. P-selectin and intercellular adhesion molecule 1 (ICAM-1) immunoreactivity were most prominent in endothelial cells of peritubular capillaries and interlobular arteries of cortex and outer and inner medulla of vehicle-treated mice whose kidneys were subjected to I/R. DWH-146e treatment led to a pronounced decrease in P-selectin- and ICAM-1-like immunoreactivity. These data are consistent with our hypothesis that A2A-AR agonists limit I/R injury due to an inhibitory effect on neutrophil adhesion.

CXCR4 antagonism as a therapeutic approach to prevent acute kidney injury

2014 ◽  
Vol 307 (7) ◽  
pp. F783-F797 ◽  
Author(s):  
A. Zuk ◽  
M. Gershenovich ◽  
Y. Ivanova ◽  
R. T. MacFarland ◽  
S. P. Fricker ◽  
...  
Keyword(s):  
Renal Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Myeloperoxidase Activity ◽  
Long Term Effects ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Before And After

We examined whether antagonism of the CXCR4 receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR4 is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSCs). Plerixafor (AMD3100, Mozobil) is a small-molecule CXCR4 antagonist that mobilizes HSCs into the peripheral blood and also modulates the immune response in in vivo rodent models of asthma and rheumatoid arthritis. Treatment with plerixafor before and after ischemic clamping ameliorated kidney injury in a rat model of bilateral renal ischemia-reperfusion. Serum creatinine and blood urea nitrogen were significantly reduced 24 h after reperfusion, as were tissue injury and cell death. Plerixafor prevented the renal increase in the proinflammatory chemokines CXCL1 and CXCL5 and the cytokine IL-6. Flow cytometry of kidney homogenates confirmed the presence of significantly fewer leukocytes with plerixafor treatment; additionally, myeloperoxidase activity was reduced. AMD3465, a monocyclam analog of plerixafor, was similarly renoprotective. Four weeks postreperfusion, long-term effects included diminished fibrosis, inflammation, and ongoing renal injury. The mechanism by which CXCR4 inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of proinflammatory chemokines/cytokines, rather than a HSC-mediated effect. The data suggest that CXCR4 antagonism with plerixafor may be a potential option to prevent AKI.

scholarly journals Synthetic Colloids Attenuate Leukocyte-Endothelial Interactions by Inhibition of Integrin Function

2005 ◽  
Vol 103 (4) ◽  
pp. 759-767 ◽  
Author(s):  
Boris Nohé ◽  
Tanja Johannes ◽  
Jörg Reutershan ◽  
Albert Rothmund ◽  
Helene A. Haeberle ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Adhesion Molecule ◽  
Cell Activation ◽  
Tissue Injury ◽  
Severe Infection ◽  
Intercellular Adhesion Molecule ◽  
Neutrophil Adhesion ◽  
Intercellular Adhesion Molecule 1 ◽  
Endothelial Cell Activation

Background It has been suspected that synthetic colloids may interfere with leukocyte adhesion by down-regulation of endothelial cell adhesion molecules. Although inhibition of endothelial inflammation might reduce leukocyte-related tissue injury, the same mechanism may be detrimental for host defense during severe infection. Regarding the widespread use of colloids, the authors performed a laboratory investigation to determine the mechanisms by which synthetic colloids interfere with leukocyte-endothelial interactions. Methods Adhesion molecule expression on native and cytokine-activated endothelium from umbilical veins was measured after pretreatment with gelatin and various preparations of dextran or hydroxyethyl starch. Inhibition of neutrophil adhesion to activated endothelium was examined in a flow chamber by perfusion of untreated and colloid-treated neutrophils over colloid-pretreated endothelium at 2 dyn/cm. Comparisons were made between untreated controls, colloid-pretreated endothelium, and colloid-cotreated neutrophils. Results Intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and P-selectin were not attenuated by any colloid. Accordingly, colloid pretreatment of endothelium alone did not reduce neutrophil adhesion. In contrast, when neutrophils were cotreated by addition of colloids to the perfusate immediately before perfusion, adhesion decreased by 31-51% (P < 0.05) regardless of the colloid type. As indicated by the twofold increased rolling fractions, this reduction was due to an inhibition of neutrophil integrins. Conclusions This study shows that synthetic colloids inhibit neutrophil adhesion by a neutrophil-dependent mechanism rather than interfering with endothelial cell activation. This suggests that inhibition of leukocyte sequestration by volume support is a common and transient phenomenon depending on the colloid concentration in plasma.

scholarly journals Does methylene blue attenuate inflammation in nonischemic lungs after lung transplantation?

2018 ◽  
Vol 44 (5) ◽  
pp. 378-382
Author(s):  
Marcus da Matta Abreu ◽  
Francine Maria de Almeida ◽  
Kelli Borges dos Santos ◽  
Emílio Augusto Campos Pereira de Assis ◽  
Rafael Kenji Fonseca Hamada ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Lung Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Lung Parenchyma ◽  
Saline Group ◽  
Intercellular Adhesion Molecule ◽  
Sprague Dawley ◽  
Intercellular Adhesion Molecule 1 ◽  
Sprague Dawley Rats

ABSTRACT Objective: To evaluate whether methylene blue (MB) could minimize the effects of ischemia-reperfusion injury in the nonischemic lung on a lung transplantation rodent model. Methods: Forty female Sprague-Dawley rats were divided into 20 donors and 20 recipients. The 20 recipient rats were divided into two groups (n = 10) according to the treatment (0.9% saline vs. 1% MB solutions). All animals underwent unilateral lung transplantation. Recipients received 2 mL of saline or MB intraperitoneally prior to transplantation. After 2 h of reperfusion, the animals were euthanized and histopathological and immunohistochemical analyses were performed in the nonischemic lung. Results: There was a significant decrease in inflammation-neutrophil count and intercellular adhesion molecule-1 (ICAM-1) expression in lung parenchyma were higher in the saline group in comparison with the MB group-and in apoptosis-caspase-3 expression was higher in the saline group and Bcl-2 expression was higher in MB group. Conclusions: MB is an effective drug for the protection of nonischemic lungs against inflammation and apoptosis following unilateral lung transplantation in rats.

NO donors prevent integrin-induced leukocyte adhesion but not P-selectin-dependent rolling in postischemic venules

1994 ◽  
Vol 267 (3) ◽  
pp. H931-H937 ◽  
Author(s):  
P. Kubes ◽  
I. Kurose ◽  
D. N. Granger
Keyword(s):  
Shear Rate ◽  
Tissue Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
No Donor ◽  
No Donors ◽  
In Vitro Data

The objective of this study was to examine the effect of nitric oxide (NO) donors on polymorphonuclear leukocyte (PMN) interactions in the microvasculature of postischemic tissue and to compare the antiadhesive properties of NO donors with the responses observed after immunoneutralization of three key adhesion glycoproteins (CD11/CD18, intercellular adhesion molecule-1, and P-selectin). Rolling and firm adhesion (adherence) of leukocytes and shear rate were monitored in cat mesenteric venules subjected to 60 min of ischemia (blood flow reduced to 20% of control), followed by 60 min of reperfusion. Immediately before reperfusion, the mesentery was superfused with a NO donor (3-morpholinosydonimine-N-ethyl-carbamide or spermine-NO) or a monoclonal antibody (MAb) against an adhesion glycoprotein that was administered intravenously. In untreated animals, a profound influx in rolling PMNs was observed during reperfusion that was subsequently followed by increased firm adhesion. The anti-P-selectin antibody completely abolished the rise in the flux of rolling PMNs, whereas the anti-CD18 antibody prevented firm adhesion. Both NO donors attenuated ischemia/reperfusion-induced leukocyte adhesion to a level comparable with that observed after administration of a MAb against CD11/CD18 without affecting PMN rolling. The antiadhesive effect of the NO donors could not be attributed solely to an improvement of venular wall shear rate. In vitro data did not reveal a direct effect of NO donors on the expression of CD18 or neutrophil adhesion to endothelial cells. These observations suggest that NO donors may provide protection from tissue injury by preventing PMN adhesion.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals PR-39, a proline/arginine-rich antimicrobial peptide, prevents postischemic microvascular dysfunction

1999 ◽  
Vol 277 (3) ◽  
pp. H1007-H1013 ◽  
Author(s):  
Ronald J. Korthuis ◽  
Dean C. Gute ◽  
Frank Blecha ◽  
Chris R. Ross
Keyword(s):  
Time Course ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Intercellular Adhesion Molecule ◽  
Neutrophil Adhesion ◽  
Intercellular Adhesion Molecule 1 ◽  
Protein Leakage ◽  
Oxidant Production

We and others have previously demonstrated that intestinal ischemia-reperfusion (I/R) is associated with a large increase in oxidant production that contributes to microvascular barrier disruption in the small bowel. It has been suggested that the bulk of tissue damage during reperfusion can be attributed to adherent, activated neutrophils. From these observations, we hypothesized that pretreatment with PR-39, an endogenous neutrophil antibacterial peptide that is also a potent inhibitor of the neutrophil NADPH oxidase, would prevent postischemic oxidant production and the development of oxidant-dependent sequelae to I/R such as increased venular protein leakage. To test this postulate, oxidant production, venular protein leakage, leukocyte adhesion, and leukocyte emigration were monitored during reperfusion in control (no ischemia) rat mesenteric venules and in mesenteric venules subjected to I/R alone or PR-39 + I/R. Treatment with a single intravenous bolus injection of PR-39 (administered at a dose to achieve an initial blood concentration of 5 μM) abolished I/R-induced leukocyte adhesion and emigration in vivo. In vitro studies indicated that PR-39 prevents platelet-activating factor-induced neutrophil chemotaxis as well as phorbol myristate acetate (PMA)-stimulated intercellular adhesion molecule-1 expression by cultured endothelial cells. PR-39 pretreatment of rat neutrophils also blocked PMA-stimulated neutrophil adhesion to activated endothelial monolayers. In vivo, I/R was associated with a marked and progressive increase in oxidant production and venular protein leakage during reperfusion, effects that were abolished by PR-39 treatment. The results of this study indicate that PR-39 completely abolishes postischemic leukocyte adhesion and emigration. The time course for inhibition of oxidant production by PR-39 suggests that its antiadhesive properties account for this effect of the peptide. PR-39 may thus be therapeutically useful for prevention of neutrophil adhesion and activation during the postischemic inflammatory response.

Murine model of gastrointestinal ischemia associated with complement-dependent injury

2002 ◽  
Vol 93 (1) ◽  
pp. 338-345 ◽  
Author(s):  
Hui Zhao ◽  
Michael C. Montalto ◽  
Kristine J. Pfeiffer ◽  
Liming Hao ◽  
Gregory L. Stahl
Keyword(s):  
Murine Model ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Significant Loss ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Neutrophil Accumulation ◽  
Inflammatory Protein ◽  
Gastrointestinal Ischemia

Gastrointestinal ischemia-reperfusion (I/R) injury is often associated with remote tissue injury. Complement activation plays an important role in local and remote tissue injury associated with gastrointestinal I/R. We developed a new murine model of gastrointestinal I/R that has complement-dependent local and remote tissue injury. Twenty, but not thirty, minutes of gastrointestinal ischemia followed by 3 h of reperfusion induced a significant loss of intestinal lactate dehydrogenase that was significantly prevented by a murine anti-murine C5 monoclonal antibody. Anti-C5 also significantly decreased neutrophil infiltration into the gut and lung. Gastrointestinal I/R significantly increased pulmonary intercellular adhesion molecule-1 mRNA and protein expression that was significantly inhibited by anti-C5. Pulmonary macrophage inflammatory protein-2 mRNA was significantly induced by gastrointestinal I/R and inhibited by anti-C5 treatment. These data demonstrate that brief periods of murine gastrointestinal I/R activate complement, leading to tissue injury and neutrophil accumulation. Anti-C5 treatment attenuates tissue injury, neutrophil recruitment, and leukocyte adherence molecule and chemokine expression in the mouse. This model will be well suited to investigate the role of complement-mediated tissue injury and gene expression after gastrointestinal I/R.

scholarly journals Maraviroc-Mediated Lung Protection following Trauma-Hemorrhagic Shock

2016 ◽  
Vol 2016 ◽  
pp. 1-8
Author(s):  
Fu-Chao Liu ◽  
Chih-Wen Zheng ◽  
Huang-Ping Yu
Keyword(s):  
Water Content ◽  
Interleukin 1 ◽  
Intercellular Adhesion Molecule ◽  
Myeloperoxidase Activity ◽  
Sprague Dawley ◽  
Intercellular Adhesion Molecule 1 ◽  
Lung Water ◽  
Lung Protection ◽  
Anti Inflammatory ◽  
Lung Water Content

Objectives.The peroxisome proliferator-activated receptor gamma (PPARγ) pathway exerts anti-inflammatory effects in response to injury. Maraviroc has been shown to have potent anti-inflammatory effects. The aim of this study was to investigate whether PPARγplays an important role in maraviroc-mediated lung protection following trauma-hemorrhage.Methods.Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35–40 mmHg for 90 minutes), followed by fluid resuscitation. During resuscitation, a single dose of maraviroc (3 mg/kg, intravenously) with and without a PPARγinhibitor GW9662 (1 mg/kg, intravenously), GW9662, or vehicle was administered. Lung water content, tissue histology, and other various parameters were measured (n=8rats/group) 24 hours after resuscitation. One-way ANOVA and Tukey’s testing were used for statistical analysis.Results.Trauma-hemorrhage significantly increased lung water content, myeloperoxidase activity, intercellular adhesion molecule-1, interleukin-6, and interleukin-1βlevels. These parameters significantly improved in the maraviroc-treated rats subjected to trauma-hemorrhage. Maraviroc treatment also decreased lung tissue damage as compared to the vehicle-treated trauma-hemorrhaged rats. Coadministration of GW9662 with maraviroc abolished the maraviroc-induced beneficial effects on these parameters and lung injury.Conclusion.These results suggest that PPARγmight play a key role in maraviroc-mediated lung protection following trauma-hemorrhage.

scholarly journals Ischemic postconditioning ameliorates acute kidney injury induced by limb ischemia/reperfusion via transforming TLR4 and NF-κB signaling in rats

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Zhongdi Liu ◽  
Wei Huang ◽  
Yifan Chen ◽  
Zhe Du ◽  
Fengxue Zhu ◽  
...  
Keyword(s):  
Renal Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Limb Ischemia ◽  
Ischemic Postconditioning ◽  
Inflammatory Factors ◽  
Sprague Dawley ◽  
Expression Levels ◽  
Anesthesia Procedure

Abstract Background The present study investigated the influence of ischemic postconditioning (I-postC) on the adjustment of renal injury after limb ischemia-reperfusion (I/R) injury, to elucidate the mechanisms of the Toll-like receptor 4 (TLR 4)/NF-κB signaling pathway using histopathological and immunohistochemical methods. Methods Male Sprague-Dawley rats were randomly assigned to five groups (numbered from 1 to 5): the sham group (Group 1, only the anesthesia procedure was conducted without limb I/R), the I/R group (Group 2, 4 h of reperfusion was conducted following 4 h limb ischemia under anesthesia), the I/R + I-postC group (Group 3, 4 h of ischemia and 4 h of reperfusion was conducted; before perfusion, 5 min of limb ischemia and 5 min of reperfusion were performed in the rats and repeated 3 times), the I/R + TAK group (Group 4, rats were injected with TLR4 antagonist TAK through the caudal vein before limb ischemia and reperfusion under anesthesia), the TAK group (Group 5, rats were injected with TAK, and the anesthesia procedure was conducted without limb I/R). Histological changes in the kidney in different groups were observed, and the extent of tubular injury was assessed. Changes in biochemical indexes and the expression of inflammatory factors, TLR4, and NF-κB were also evaluated. Results Compared with rats in the I/R group, the secretion of inflammatory factors and the expression levels of TLR4 and NF-κB were decreased in rats in the I/R + I-postC group. Histological analysis revealed renal injury, including inflammatory cell infiltration, dilatation of the tubuli lumen, congestion in glomerular capillaries, degeneration of tubuli epithelial cells, and necrosis was ameliorated by I-postC. Immunohistochemical studies showed that I/R-induced elevation in TLR4 and NF-κB expression was reduced by I-postC treatment. Moreover, the expression levels of TLR4, NF-κB, and inflammatory factors in rats in the I/R + TAK group were also decreased, and the renal pathological lesion was alleviated, which was similar to that in rats in the I/R + I-postC group. Conclusions The present findings suggest that I-postC can reduce tissue injury and kidney inflammation induced by limb I/R injury, possibly via inhibition of the TLR4 and NF-κB pathways.

Oxygen radicals trigger activation of NF-κB and AP-1 and upregulation of ICAM-1 in reperfused canine heart

2002 ◽  
Vol 282 (5) ◽  
pp. H1778-H1786 ◽  
Author(s):  
Haiying Fan ◽  
Baogui Sun ◽  
Qiuping Gu ◽  
Anne Lafond-Walker ◽  
Suyi Cao ◽  
...  
Keyword(s):  
Dna Binding ◽  
Protein Expression ◽  
Vascular Endothelium ◽  
Oxygen Radicals ◽  
Nuclear Dna ◽  
Ischemia Reperfusion ◽  
Intercellular Adhesion Molecule ◽  
Radical Scavenger ◽  
Myeloperoxidase Activity ◽  
Canine Heart

We investigated whether oxygen radicals generated during ischemia-reperfusion trigger postischemic inflammation in the heart. Closed-chest dogs underwent 90-min coronary artery occlusion, followed by 1- or 3-h reperfusion: 10 dogs received the cell-permeant oxygen radical scavenger N-(2-mercaptopropionyl)-glycine (MPG; 8 mg · kg−1 · h−1intracoronary) beginning 5 min before reperfusion, and 9 dogs received vehicle. Blood flow (microspheres), intercellular adhesion molecule (ICAM)-1 protein expression (immunohistochemistry), ICAM-1 gene activation (Northern blotting), nuclear DNA binding activity of nuclear factor (NF)-κb and AP-1 (electrophoretic mobility shift assays), and neutrophil (PMN) accumulation (myeloperoxidase activity) were assessed in myocardial tissue samples. ICAM-1 protein expression was high in vascular endothelium after ischemia-reperfusion but was markedly reduced by MPG. MPG treatment also markedly decreased expression of ICAM-1 mRNA and tissue PMN accumulation. Nuclear DNA binding activities of NF-κB and AP-1, increased by ischemia-reperfusion, were both markedly decreased by MPG at 1 h of reperfusion. However, by 3 h, AP-1 activity was only modestly reduced by MPG and NF-κB activity was not significantly different from ischemic-reperfused controls. These results suggest that oxygen radicals generated in vivo during reperfusion trigger early activation of NF-κb and AP-1, resulting in upregulation of the ICAM-1 gene in vascular endothelium and subsequent tissue accumulation of activated PMNs.

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