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 Inhibition of NADPH Oxidase is Neuroprotective after Ischemia—Reperfusion

2009 ◽  
Vol 29 (7) ◽  
pp. 1262-1272 ◽  
Author(s):  
Hai Chen ◽  
Yun Seon Song ◽  
Pak H Chan
Keyword(s):  
Brain Injury ◽  
Nadph Oxidase ◽  
Ischemia Reperfusion ◽  
Brain Infarction ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Neutrophil Infiltration ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Copper Zinc Superoxide Dismutase ◽  
Oxidase Inhibition

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is well known as a major source for superoxide radical generation in leukocytes. Superoxide radicals play a significant role in brain ischemia–reperfusion (I/R) injury. Recent data have also shown expression of NOX in the brain. However, the manner by which NOX is involved in pathologic processes after cerebral ischemia remains unknown. Therefore, we subjected mice deficient in the NOX subunit, gp91phox (gp91phox-/-), those treated with the NOX inhibitor, apocynin, and wild-type (WT) mice to 75 mins of focal ischemia followed by reperfusion. At 24 h of reperfusion, the gp91phox-/- and apocynin-treated mice showed 50% less brain infarction and 70% less cleaved spectrin compared with WT mice. The levels of 4-hydroxy-2-nonenal, malondialdehyde, and 8-hydroxy-2‘-deoxyguanosine increased significantly after I/R, indicating oxidative brain injury. NADPH oxidase inhibition reduced biomarker generation. Furthermore, NOX was involved in postischemic inflammation in the brains, as less intercellular adhesion molecule-1 upregulation and less neutrophil infiltration were found in the NOX-inhibited mice after I/R. Moreover, gp91phox expression increased after ischemia, and was further aggravated by genetic copper/zinc-superoxide dismutase (SOD1) ablation, but ameliorated in SOD1-overexpressing mice. This study suggests that NOX plays a role in oxidative stress and inflammation, thus contributing to ischemic brain injury.

Mac-1 (CD11b/CD18) and intercellular adhesion molecule-1 in ischemia-reperfusion injury of rat liver

2001 ◽  
Vol 281 (2) ◽  
pp. G577-G585 ◽  
Author(s):  
Akira Kobayashi ◽  
Hiroshi Imamura ◽  
Mitsuaki Isobe ◽  
Yutaka Matsuyama ◽  
Junpei Soeda ◽  
...  
Keyword(s):  
Liver Injury ◽  
Rat Liver ◽  
Adhesion Molecule ◽  
Liver Damage ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Hepatocyte Apoptosis ◽  
Intercellular Adhesion Molecule 1

The chronological expression (over 24 h) of two adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) and CD11b/CD18 (Mac-1)] and the extent of liver damage, including injury to sinusoidal endothelial cells (SECs) and hepatocyte apoptosis, were investigated under two conditions of rat liver ischemia-reperfusion (I/R) injury: reversible (30 min) and fatal I/R (60 min). The chronological profiles of upregulation of ICAM-1 on hepatocytes and Mac-1 showed changes in parallel with the other liver damage parameters, and the extent of upregulation and various parameters of liver injury were more advanced in the 60-min I/R group. Paradoxically, the degree of ICAM-1 upregulation of SECs decreased significantly in the 60-min I/R group vs. the 30-min I/R group. Repression of hepatocyte apoptosis by administration of the caspase inhibitor ZVAD-fmk resulted in attenuation of neutrophil infiltration and liver injury. These findings indicate that 1) neutrophil infiltration is involved in the development of liver I/R injury; 2) interaction between ICAM-1 on SECs and Mac-1 on neutrophils is not an essential step for neutrophil transmigration through the endothelial layer because SECs, specifically, were impaired in the early stages of liver I/R injury; 3) the role of ICAM-1 and Mac-1 is to adhere neutrophils firmly to hepatocytes and activate neutrophils; and 4) excessive parenchymal apoptosis may be the signal for the neutrophil-induced inflammatory and necrotic reaction.

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)

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.

Combined inhibition of P-selectin and ICAM-1 reduces myocardial injury following ischemia and reperfusion

1996 ◽  
Vol 271 (6) ◽  
pp. H2421-H2429 ◽  
Author(s):  
D. J. Lefer ◽  
D. M. Flynn ◽  
D. C. Anderson ◽  
A. J. Buda
Keyword(s):  
Blood Flow ◽  
Monoclonal Antibodies ◽  
Myocardial Blood Flow ◽  
Myocardial Protection ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Intercellular Adhesion Molecule ◽  
Myeloperoxidase Activity ◽  
Intercellular Adhesion Molecule 1 ◽  
Neutrophil Accumulation

Neutrophil-endothelial cell interactions are mediated by a number of cell adhesion proteins. We investigated the effects of inhibition of P-selectin and intercellular adhesion molecule-1 (ICAM-1), individually or in combination, in the ischemic-reperfused canine myocardium. Monoclonal antibodies PB1.3 (anti-P-selectin) and CL 18/6 (anti-ICAM-1) were administered to dogs subjected to coronary artery occlusion and reperfusion. After reperfusion, untreated dogs experienced a 61% decline (P < 0.01 vs. baseline) in myocardial blood flow and a ninefold increase in ischemic zone neutrophil accumulation (4.7 +/- 0.9 U/100 mg tissue myeloperoxidase activity). In contrast, PB1.3 and CL 18/6 administered individually preserved myocardial blood flow (11 and 24% decrease from baseline, respectively, both P < 0.01 vs. saline), and significantly attenuated myeloperoxidase activity (1.4 +/- 0.3 and 1.5 +/- 0.26 U/100 mg tissue, respectively, both P < 0.01 vs. saline). PB1.3 and CL 18/6 in combination resulted in significant coronary vascular and myocardial protection that was not superior to treatment with either antibody alone. Thus the coadministration of anti-P-selectin and anti-ICAM-1 monoclonal antibodies does not enhance the degree of myocardial protection in this model of reperfusion injury.

ICAM-1 and VCAM-1 mediate endotoxemic myocardial dysfunction independent of neutrophil accumulation

2002 ◽  
Vol 283 (2) ◽  
pp. R477-R486 ◽  
Author(s):  
Christopher D. Raeburn ◽  
Casey M. Calkins ◽  
Michael A. Zimmerman ◽  
Yong Song ◽  
Lihua Ao ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Cardiac Dysfunction ◽  
Gene Knockout ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Immunofluorescent Staining ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Neutrophil Accumulation

Both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been implicated in neutrophil-mediated lung and liver injury during sepsis. However, the role of these adhesion molecules as well as the contribution of neutrophils in myocardial dysfunction during sepsis remains to be determined. The purpose of this study was to examine the role of ICAM-1, VCAM-1, and neutrophils in lipopolysaccharide (LPS)-induced myocardial dysfunction. Mice were subjected to LPS (0.5 mg/kg ip) or vehicle (normal saline), and left ventricular developed pressure (LVDP) was determined by the Langendorff technique. LVDP was depressed by nearly 40% at 6 h after LPS. Immunofluorescent staining revealed a temporal increase in myocardial ICAM-1/VCAM-1 expression and neutrophils after LPS. Antibody blockade of VCAM-1 reduced myocardial neutrophil accumulation and abrogated LPS-induced cardiac dysfunction. Antibody blockade or absence of ICAM-1 (gene knockout) also abrogated LPS-induced cardiac dysfunction but did not reduce neutrophil accumulation. Neutrophil depletion (vinblastine or antibody) did not protect from LPS-induced myocardial dysfunction. Our results suggest that although endotoxemic myocardial dysfunction requires both ICAM-1 and VCAM-1, it occurs independent of neutrophil accumulation.

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