Effect of the NADPH oxidase inhibitor apocynin on ischemia-reperfusion lung injury

2000 ◽  
Vol 279 (1) ◽  
pp. H303-H312 ◽  
Author(s):  
Jeffrey M. Dodd-O ◽  
David B. Pearse
Keyword(s):  
Lung Injury ◽  
Nadph Oxidase ◽  
Vascular Permeability ◽  
Ischemia Reperfusion ◽  
Pulmonary Artery Hypertension ◽  
Oxidase Inhibitor ◽  
Oxidase Inhibition ◽  
Pmn Leukocyte ◽  
Protein Permeability

Apocynin (4-hydroxy-3-methoxy-acetophenone) inhibits NADPH oxidase in activated polymorphonuclear (PMN) leukocytes, preventing the generation of reactive oxygen species. To determine if apocynin attenuates ischemia-reperfusion lung injury, we examined the effects of apocynin (0.03, 0.3, and 3 mM) in isolated in situ sheep lungs. In diluent-treated lungs, reperfusion with blood (180 min) after 30 min of ischemia (ventilation 28% O2, 5% CO2) caused leukocyte sequestration in the lung and increased vascular permeability [reflection coefficient for albumin (ςalb) 0.47 ± 0.10, filtration coefficient ( Kf) 0.14 ± 0.03 g · min−1· mmHg−1· 100 g−1] compared with nonreperfused lungs (ςalb0.77 ± 0.03, Kf0.03 ± 0.01 g · min−1· mmHg−1· 100 g−1; P < 0.05). Apocynin attenuated the increased protein permeability at 0.3 and 3 mM (ςalb0.69 ± 0.05 and 0.91 ± 0.03, respectively, P < 0.05); Kfwas decreased by 3 mM apocynin (0.05 ± 0.01 g · min−1· mmHg−1· 100 g−1, P < 0.05). Diphenyleneiodonium (DPI, 5 μM), a structurally unrelated inhibitor of NADPH oxidase, worsened injury ( Kf0.32 ± 0.07 g · min−1· mmHg−1· 100 g−1, P < 0.05). Neither apocynin nor DPI affected leukocyte sequestration. Apocynin and DPI inhibited whole blood chemiluminescence and isolated PMN leukocyte-induced resazurin reduction, confirming NADPH oxidase inhibition. Apocynin inhibited pulmonary artery hypertension and perfusate concentrations of cyclooxygenase metabolites, including thromboxane B2. The cyclooxygenase inhibitor indomethacin had no effect on the increased vascular permeability, suggesting that cyclooxygenase inhibition was not the explanation for the apocynin results. Apocynin prevented ischemia-reperfusion lung injury, but the mechanism of protection remains unclear.

scholarly journals Strain-specific differences in sensitivity to ischemia-reperfusion lung injury in mice

2006 ◽  
Vol 100 (5) ◽  
pp. 1590-1595 ◽  
Author(s):  
Jeffrey M. Dodd-o ◽  
Maria L. Hristopoulos ◽  
Laura E. Welsh-Servinsky ◽  
Clarke G. Tankersley ◽  
David B. Pearse
Keyword(s):  
Lung Injury ◽  
Nadph Oxidase ◽  
Evans Blue ◽  
Ischemia Reperfusion ◽  
Left Lung ◽  
Blue Dye ◽  
Related Factor ◽  
Ros Production ◽  
Evans Blue Dye ◽  
Intermediate Phenotypes

Ischemia-reperfusion (I/R) lung injury is characterized by increased pulmonary endothelial permeability and edema, but the genetic basis for this injury is unknown. We utilized an in vivo mouse preparation of unilateral lung I/R to evaluate the genetic determinants of I/R lung injury. An index of pulmonary vascular protein permeability was measured by the ratio of left-to-right lung Evans blue dye of eight inbred mouse strains after 30 min of left lung ischemia and 150 min of reperfusion. The order of strain-specific sensitivity to I/R lung injury was BALB/c < SJL/J < CBA/J < C57BL/6J < 129/J < A/J < C3H/H3J < SWR/J. The reciprocal F1 offspring of the BALB/c and SWR/J progenitor strains had intermediate phenotypes but a differing variance. A similar pattern of right lung Evans blue dye content suggested the presence of contralateral injury because baseline vascular permeability was not different. Lung I/R injury was attenuated by NADPH oxidase inhibition, indicating a role for NADPH oxidase-derived reactive oxygen species (ROS). There was no strain-dependent difference in lung NADPH oxidase expression. Strain-related differences in zymosan-stimulated neutrophil ROS production did not correlate with I/R lung injury in that neutrophil ROS production in SWR/J mice was greater than C57BL/6J but not different from BALB/c mice. These data indicate the presence of a genetic sensitivity to lung I/R injury that involves multiple genes including a maternal-related factor. Although neutrophil-derived ROS production is also modulated by genetic factors, the pattern did not explain the genetic sensitivity to lung I/R injury.

TGF-β impairs renal autoregulation via generation of ROS

2005 ◽  
Vol 288 (5) ◽  
pp. F1069-F1077 ◽  
Author(s):  
Kumar Sharma ◽  
Anthony Cook ◽  
Matt Smith ◽  
Cathryn Valancius ◽  
Edward W. Inscho
Keyword(s):  
Nadph Oxidase ◽  
Transforming Growth Factor ◽  
Oxidase Inhibitor ◽  
Glomerular Injury ◽  
Renal Autoregulation ◽  
Renal Vessel ◽  
Ros Scavenger ◽  
Afferent Arterioles

Impaired autoregulation in chronic kidney disease can result in elevation of glomerular capillary pressure and progressive glomerular damage; however, the factors linking chronic glomerular disorders to impaired autoregulation have not been identified. We tested the hypothesis that the cytokine most closely associated with progressive glomerular disease, transforming growth factor (TGF)-β, may also attenuate autoregulation. Kidneys from normal rats were prepared for videomicroscopy, using the blood-perfused juxtamedullary nephron technique. Autoregulatory responses were measured under control conditions and during superfusion with TGF-β1 (10 ng/ml). Control afferent arteriolar diameter averaged 18.4 ± 1 μm and significantly decreased to 16.3 ± 0.9 and 13.2 ± 0.8 μm at perfusion pressures of 130 and 160 mmHg, respectively. In the presence of TGF-β1, autoregulatory responses were completely blocked. In similar experiments performed using PDGF-BB (10 ng/ml) and HGF (25 ng/ml), the normal autoregulatory response was not affected. In vitro studies, using isolated preglomerular vascular smooth muscle cells, revealed that exposure to TGF-β1 stimulated a rapid increase in reactive oxygen species (ROS) that was inhibited by NADPH oxidase inhibitors. In situ studies, with dihydroethidium staining, revealed a marked increase in renal vessel ROS production on exposure to TGF-β1. Pretreatment of the juxtamedullary afferent arterioles with tempol, a ROS scavenger, or with apocynin, a NADPH oxidase inhibitor, prevented the impaired autoregulation induced by TGF-β1. These data reveal a novel hemodynamic pathway by which TGF-β could lead to progressive glomerular injury by impairing normal renal microvascular function.

Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury

2004 ◽  
Vol 287 (2) ◽  
pp. H927-H936 ◽  
Author(s):  
Jeffrey M. Dodd-o ◽  
Laura E. Welsh ◽  
Jorge D. Salazar ◽  
Peter L. Walinsky ◽  
Eric A. Peck ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Lung Injury ◽  
Nadph Oxidase ◽  
Oxidase Inhibition ◽  
Nadph Oxidase Inhibition

Role of xanthine oxidase in postischemic microvascular injury in skeletal muscle

1989 ◽  
Vol 257 (6) ◽  
pp. H1782-H1789 ◽  
Author(s):  
J. K. Smith ◽  
D. L. Carden ◽  
R. J. Korthuis
Keyword(s):  
Skeletal Muscle ◽  
Xanthine Oxidase ◽  
Vascular Permeability ◽  
Oxidase Activity ◽  
Ischemia Reperfusion ◽  
Oxidase Inhibitor ◽  
Xanthine Oxidase Inhibitor ◽  
Microvascular Injury ◽  
Xanthine Oxidase Activity

Previous reports indicate that allopurinol, a xanthine oxidase inhibitor, attenuates the microvascular injury produced by reperfusion of ischemic skeletal muscle. To further assess the role of xanthine oxidase in ischemia/reperfusion (I/R) injury, we examined the effect of xanthine oxidase depletion or inhibition on the increase in microvascular permeability produced by I/R. Changes in vascular permeability were assessed by measurement of the solvent drag reflection coefficient for total plasma proteins (sigma) in rat hindquarters subjected to 2 h of ischemia and 30 min of reperfusion in xanthine oxidase-replete and -depleted animals and in animals pretreated with the xanthine oxidase inhibitor oxypurinol. Xanthine oxidase depletion was accomplished by administration of a tungsten-supplemented (0.7 g/kg diet), molybdenum-deficient diet. In animals fed the tungsten diet, muscle total xanthine dehydrogenase plus xanthine oxidase activity was decreased to less than 10% of control values. Estimates of sigma averaged 0.85 +/- 0.04 in nonischemic (continuous perfusion for 2.5 h) hindquarters, whereas muscle xanthine oxidase activity averaged 3.3 +/- 0.4 mU/g wet wt. I/R was associated with a marked decrease in sigma (0.54 +/- 0.02), whereas xanthine oxidase activity was increased to 5.8 +/- 0.5 mU/g wet wt. These results indicate that I/R produced a dramatic increase in vascular permeability coincident with an increase in muscle xanthine oxidase activity. Xanthine oxidase depletion with the tungsten diet or pretreatment with oxypurinol attenuated this permeability increase (sigma = 0.72 +/- 0.03 and 0.77 +/- 0.7, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Synergistic Effects of EMPs and PMPs on Pulmonary Vascular Leakage and Lung Injury After Ischemia/Reperfusion

2020 ◽  
Author(s):  
Tao Li ◽  
Jie Zhang ◽  
Yu Zhu ◽  
Yue Wu ◽  
Qing-Guang Yan ◽  
...  
Keyword(s):  
Lung Injury ◽  
Vascular Permeability ◽  
Synergistic Effects ◽  
Ischemia Reperfusion ◽  
Pulmonary Sequestration ◽  
Underlying Mechanism ◽  
Vascular Leakage ◽  
Critical Conditions ◽  
Pulmonary Vascular Permeability ◽  
Related Proteins

Abstract Background Vascular leakage is an important process of critical conditions such as shock and I/R-induced lung injury. Microparticles (MPs), including endothelial cell-derived microparticles (EMPs), platelet-derived microparticles (PMPs) and neutrophil-derived microparticles (NMPs), have been shown to participate in many diseases. Whether these MPs take part in pulmonary vascular leakage and lung injury after ischemia/reperfusion (I/R) and have synergistic and the underlying mechanism are not known.Methods Using hemorrhage/transfusion (Hemo/Trans) and aorta abdominalis occlusion-induced ischemia/reperfusion (I/R) rat models, the role of EMPs, PMPs and NMPs and their relationship and the mechanisms in pulmonary vascular leakage and lung injury were studied.Results The concentrations of EMPs, PMPs and NMPs were significantly increased after I/R. Intravenous administration of EMPs and PMPs but not NMPs induced pulmonary vascular leakage and lung injury. Furthermore, EMPs could induce pulmonary sequestration of platelets and promote more PMP production, and synergistically exacerbate pulmonary vascular leakage. MiR-1, miR-155 and miR-542 in EMP, and miR-126 and miR-29 in PMP, were significantly increased after hypoxia/reoxygenation (H/R). Of which, inhibition of miR-155 in EMPs and miR-126 in PMPs alleviated the detrimental effects of EMPs and PMPs on vascular permeability and lung injury. Overexpression of miR-155 in EMPs down-regulated the expression of ZO-1 and claudin-5, the tight junction related proteins, while overexpression of miR-126 up-regulated the expression of caveolin-1 (Cav-1), the trans-cellular transportation related protein. Inhibiting EMP and PMP production with blebbistatin (BLE) and amitriptyline (AMI) respectively, protected pulmonary vascular permeability and lung injury.Conclusions EMPs and PMPs contribute to the pulmonary vascular leakage and lung injury after I/R. EMPs mediate pulmonary sequestration of platelets, producing more PMPs to play synergistic effect. Mechanically, EMPs carrying miR-155 that targets ZO-1 and claudin-5 and PMPs carrying miR-126 that up-regulates Cav-1, synergistically regulate pulmonary vascular permeability and mediate the lung injury after 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.

scholarly journals Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn

2012 ◽  
Vol 302 (6) ◽  
pp. L616-L626 ◽  
Author(s):  
Stephen Wedgwood ◽  
Satyan Lakshminrusimha ◽  
Kathryn N. Farrow ◽  
Lyubov Czech ◽  
Sylvia F. Gugino ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Nadph Oxidase ◽  
Ductus Arteriosus ◽  
Pulmonary Arteries ◽  
Oxidase Inhibitor ◽  
No Synthase ◽  
Persistent Pulmonary Hypertension ◽  
No Donor ◽  
Oxidase Inhibition ◽  
Endothelial Nitric Oxide

NADPH oxidase is a major source of superoxide anions in the pulmonary arteries (PA). We previously reported that intratracheal SOD improves oxygenation and restores endothelial nitric oxide (NO) synthase (eNOS) function in lambs with persistent pulmonary hypertension of the newborn (PPHN). In this study, we determined the effects of the NADPH oxidase inhibitor apocynin on oxygenation, reactive oxygen species (ROS) levels, and NO signaling in PPHN lambs. PPHN was induced in lambs by antenatal ligation of the ductus arteriosus 9 days prior to delivery. Lambs were treated with vehicle or apocynin (3 mg/kg intratracheally) at birth and then ventilated with 100% O2 for 24 h. A significant improvement in oxygenation was observed in apocynin-treated lambs after 24 h of ventilation. Contractility of isolated fifth-generation PA to norepinephrine was attenuated in apocynin-treated lambs. PA constrictions to NO synthase (NOS) inhibition with N-nitro-l-arginine were blunted in PPHN lambs; apocynin restored contractility to N-nitro-l-arginine, suggesting increased NOS activity. Intratracheal apocynin also enhanced PA relaxations to the eNOS activator A-23187 and to the NO donor S-nitrosyl- N-acetyl-penicillamine. Apocynin decreased the interaction between NADPH oxidase subunits p22phox and p47phox and decreased the expression of Nox2 and p22phox in ventilated PPHN lungs. These findings were associated with decreased superoxide and 3-nitrotyrosine levels in the PA of apocynin-treated PPHN lambs. eNOS protein expression, endothelial NO levels, and tetrahydrobiopterin-to-dihydrobiopterin ratios were significantly increased in PA from apocynin-treated lambs, although cGMP levels did not significantly increase and phosphodiesterase-5 activity did not significantly decrease. NADPH oxidase inhibition with apocynin may improve oxygenation, in part, by attenuating ROS-mediated vasoconstriction and by increasing NOS activity.

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