scholarly journals Inhibition of Na+/H+exchanger enhances low pH-induced L-selectin shedding and β2-integrin surface expression in human neutrophils

2008 ◽  
Vol 295 (5) ◽  
pp. C1454-C1463 ◽  
Author(s):  
Nubia K. Kaba ◽  
Joanne Schultz ◽  
Foon-Yee Law ◽  
Craig T. Lefort ◽  
Guadalupe Martel-Gallegos ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Intracellular Signaling ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Complete Removal ◽  
Surface Expression ◽  
P38 Map Kinase ◽  
Low Ph ◽  
Human Neutrophils ◽  
Dimethyl Amiloride

Ischemia-reperfusion injury is a common pathological occurrence causing tissue damage in heart attack and stroke. Entrapment of neutrophils in the vasculature during ischemic events has been implicated in this process. In this study, we examine the effects that lactacidosis and consequent reductions in intracellular pH (pHi) have on surface expression of adhesion molecules on neutrophils. When human neutrophils were exposed to pH 6 lactate, there was a marked decrease in surface L-selectin (CD62L) levels, and the decrease was significantly enhanced by inclusion of Na+/H+exchanger (NHE) inhibitor 5-( N, N-hexamethylene)amiloride (HMA). Similar effects were observed when pHiwas reduced while maintaining normal extracellular pH, by using an NH4Cl prepulse followed by washes and incubation in pH 7.4 buffer containing NHE inhibitors [HMA, cariporide, or 5-( N, N-dimethyl)amiloride (DMA)]. The amount of L-selectin shedding induced by different concentrations of NH4Cl in the prepulse correlated with the level of intracellular acidification with an apparent p K of 6.3. In contrast, β2-integrin (CD11b and CD18) was only slightly upregulated in the low-pHicondition and was enhanced by NHE inhibition to a much lesser extent. L-selectin shedding was prevented by treating human neutrophils with inhibitors of extracellular metalloproteases (RO-31-9790 and KD-IX-73-4) or with inhibitors of intracellular signaling via p38 MAP kinase (SB-203580 and SB-239063), implying a transmembrane effect of pHi. Taken together, these data suggest that the ability of NHE inhibitors such as HMA to reduce ischemia-reperfusion injury may be related to the nearly complete removal of L-selectin from the neutrophil surface.

Protective effects of 5-(N,N-dimethyl)amiloride on ischemia-reperfusion injury in hearts

1990 ◽  
Vol 258 (5) ◽  
pp. H1615-H1619 ◽  
Author(s):  
H. P. Meng ◽  
G. N. Pierce
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Significant Rise ◽  
Similar Degree ◽  
Protective Effects ◽  
Tension Development ◽  
Right Ventricular Wall ◽  
Dimethyl Amiloride

An Na(+)-H+ exchange inhibitor, 5-(N,N-dimethyl)amiloride (DMA), was used to probe the possible role of Na(+)-H+ exchange in ischemia-reperfusion injury in coronary perfused isolated rat right ventricular wall. In DMA-untreated hearts, 60 min of ischemia resulted in a significant rise in testing tension (RT: 174 +/- 8% of preischemic level). Thirty minutes of reperfusion further increased RT (273 +/- 12%) and induced a poor recovery in developed tension (DT: 28 +/- 4%). Both the rate of tension development and relaxation (+dT/dt and -dT/dt) recovered to a similar degree. When 1, 5, or 20 microM DMA was included in the perfusate (3 min before ischemia and in the first 3 min of reperfusion), the maximal postischemic RT of the heart was reduced to 204 +/- 21, 166 +/- 15, and 139 +/- 45% of the preischemic levels (P less than 0.05), respectively, and DT was 39 +/- 3, 63 +/- 10, and 79 +/- 8% of the preischemic levels (P less than 0.05), respectively. Similar qualitative recovery of +/- dT/dt was observed. Recovery was similar if DMA was present only during reperfusion. DMA treatment also significantly protected against creatine phosphokinase release during reperfusion. The results demonstrate that DMA can significantly protect the heart during the initial stages of reperfusion. The data suggest that Na(+)-H+ exchange may play an important role in the development of cardiac dysfunction and damage during the first minutes of reperfusion.

Neutrophils accentuate ischemia-reperfusion injury in isolated perfused rat kidneys

1988 ◽  
Vol 255 (4) ◽  
pp. F728-F735 ◽  
Author(s):  
S. L. Linas ◽  
P. F. Shanley ◽  
D. Whittenburg ◽  
E. Berger ◽  
J. E. Repine
Keyword(s):  
Reperfusion Injury ◽  
Filtration Rate ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Human Neutrophils ◽  
Sodium Reabsorption ◽  
Vascular Endothelial ◽  
Myristate Acetate ◽  
Dependent Mechanism ◽  
Rat Kidneys

The contribution of neutrophils to reperfusion injury after ischemia is not known. To determine the effect of neutrophils on the function of ischemic kidneys, we added purified human neutrophils during perfusion of isolated ischemic or nonischemic rat kidneys. Reperfusion of ischemic kidneys with neutrophils caused a distinct morphological lesion of vascular endothelial and smooth muscle cells and more functional injury than reperfusion with buffered albumin alone; with neutrophils, glomerular filtration rate (GFR) was 113 +/- 7 microliter.min-1.g-1, tubular sodium reabsorption (TNa) was 72 +/- 2%; without neutrophils, GFR was 222 +/- 18 microliter.min-1.g-1; TNa was 90 +/- 2%; both P less than 0.01 vs. reperfusion with neutrophils. In contrast, addition of neutrophils did not injure control kidneys, unless the neutrophil activator, phorbol myristate acetate, was also added. Two experiments suggested that O2 metabolites contributed to neutrophil-mediated injury to ischemic kidneys. First, reperfusion of ischemic kidneys with O2 metabolite-deficient neutrophils from a patient with chronic granulomatous disease did not cause more injury than reperfusion with buffered albumin alone. Second, simultaneous addition of the O2 metabolite scavenger, catalase, prevented the GFR and TNa decreases caused by neutrophils but did not decrease injury in the absence of neutrophils. We conclude that neutrophils by an O2 metabolite-dependent mechanism contribute to ischemia-reperfusion injury in the isolated perfused kidney.

PREVENTION OF KIDNEY ISCHEMIA-REPERFUSION INJURY: ROLE OF P38 MAP KINASE INHIBITION

2008 ◽  
Vol 86 (Supplement) ◽  
pp. 494
Author(s):  
P Gehwolf ◽  
N Fischler ◽  
R Oberhuber ◽  
C Margreiter ◽  
R Öllinger ◽  
...  
Keyword(s):  
Map Kinase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
P38 Map Kinase ◽  
Kinase Inhibition ◽  
Kidney Ischemia

Tetrahydrobiopterin compounds modulate intracellular signaling and reactive oxygen species levels in an in vitro model of ischemia-reperfusion injury

Pteridines ◽  
2013 ◽  
Vol 24 (3) ◽  
pp. 225-235
Author(s):  
Peter Santer ◽  
Thomas Ratschiller ◽  
Muhammad Imtiaz Ashraf ◽  
Ernst R. Werner ◽  
Gabriele Werner-Felmayer ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reperfusion Injury ◽  
Intracellular Signaling ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Solid Organ ◽  
Oxygen Species ◽  
Prolonged Incubation ◽  
Mitochondrial Ros

AbstractTetrahydrobiopterin (BH4) and 4-amino-tetrahydrobiopterin (ABH4) prevent acute rejection after solid organ transplantation. Moreover, BH4 also attenuates ischemia-reperfusion injury (IRI). The mechanisms underlying these protective effects are poorly defined. Activation of intracellular signaling proteins, including the mitogen-activated protein kinases (MAPKs) ERK, p38, and JNK, and the excessive production of mitochondrial reactive oxygen species (ROS) are observed mainly during early reperfusion. While the role of ROS in the initiation and progression of IRI is well understood, the contribution of individual signaling pathways is less clear. Here, we tested the potential effects of BH4 and ABH4 on MAPK activity and mitochondrial ROS levels. During hypoxia and reoxygenation (H/R), all three MAPKs were activated during early reoxygenation in cardiomyocytes and endothelial cells. p38 and JNK activation were further augmented by BH4 and ABH4, whereas ERK activation was not affected. Pretreatment with BH4 and ABH4 reduced the basal mitochondrial ROS levels as well as the H/R-induced increase in ROS. Prolonged incubation with ABH4, however, showed pro-apoptotic effects in cardiomyocytes. These data suggest that a protective effect of BH4 and ABH4 pretreatment may be attributed mainly to their antioxidant capacity. The effects on intracellular signaling are complex and warrant further investigations.

Role of p38 MAP kinase in postcapillary venule leukocyte adhesion induced by ischemia/reperfusion injury

2005 ◽  
Vol 51 (5) ◽  
pp. 463-471 ◽  
Author(s):  
Douglas G. Johns ◽  
Zhaohui Ao ◽  
Robert N. Willette ◽  
Colin H. Macphee ◽  
Stephen A. Douglas
Keyword(s):  
Map Kinase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
P38 Map Kinase ◽  
Postcapillary Venule

Intracellular Signaling MAPK Pathway After Cerebral Ischemia–Reperfusion Injury

2012 ◽  
Vol 37 (7) ◽  
pp. 1568-1577 ◽  
Author(s):  
Maria Kovalska ◽  
Libusa Kovalska ◽  
Martina Pavlikova ◽  
Maria Janickova ◽  
Katarina Mikuskova ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Intracellular Signaling ◽  
Ischemia Reperfusion Injury ◽  
Mapk Pathway ◽  
Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury
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