Ischemia-Reperfusion Lung Injury Is Prevented by Apocynin, a Novel Inhibitor of Leukocyte NADPH Oxidase

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.1.h303 ◽

2000 ◽

Vol 279 (1) ◽

pp. H303-H312 ◽

Cited By ~ 80

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.

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Inducible nitric oxide synthase inhibition attenuates lung injury and decreases NADPH oxidase expression and activation during ischemia‐reperfusion in the ventilated rabbit lung

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.620.2 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Andrew M Roberts ◽

Ewoenam A Akabua ◽

David Lominadze ◽

Evelyne Gozal

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Lung Injury ◽

Nadph Oxidase ◽

Inducible Nitric Oxide Synthase ◽

Ischemia Reperfusion ◽

Rabbit Lung ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Alleviation of remote lung injury following liver ischemia/reperfusion: Possible protective role of vildagliptin

International Immunopharmacology ◽

10.1016/j.intimp.2020.107305 ◽

2021 ◽

Vol 91 ◽

pp. 107305

Author(s):

Iman O. Sherif ◽

Nora H. Al-Shaalan

Keyword(s):

Lung Injury ◽

Ischemia Reperfusion ◽

Protective Role ◽

Liver Ischemia

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Ginsenoside Rb1 Treatment Attenuates Pulmonary Inflammatory Cytokine Release and Tissue Injury following Intestinal Ischemia Reperfusion Injury in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/843721 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 22

Author(s):

Ying Jiang ◽

Zhen Zhou ◽

Qing-tao Meng ◽

Qian Sun ◽

Wating Su ◽

...

Keyword(s):

Lung Injury ◽

Signaling Pathway ◽

Intestinal Ischemia ◽

Ischemia Reperfusion ◽

Critical Role ◽

Weight Ratio ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Ginsenoside Rb1 ◽

Intestinal Ischemia Reperfusion

Objective. Intestinal ischemia reperfusion (II/R) injury plays a critical role in remote organ dysfunction, such as lung injury, which is associated with nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. In the present study, we tested whether ginsenoside Rb1 attenuated II/R induced lung injury by Nrf2/HO-1 pathway.Methods. II/R injury was induced in male C57BL/6J mice by 45 min of superior mesenteric artery (SMA) occlusion followed by 2 hours of reperfusion. Ginsenoside Rb1 was administrated prior to reperfusion with or without ATRA (all-transretinoic acid, the inhibitor of Nrf2/ARE signaling pathway) administration before II/R.Results. II/R induced lung histological injury, which is accompanied with increased levels of malondialdehyde (MDA), interleukin- (IL-) 6, and tumor necrosis factor- (TNF-)αbut decreased levels of superoxide dismutase (SOD) and IL-10 in the lung tissues. Ginsenoside Rb1 reduced lung histological injury and the levels of TNF-αand MDA, as well as wet/dry weight ratio. Interestingly, the increased Nrf2 and HO-1 expression induced by II/R in the lung tissues was promoted by ginsenoside Rb1 treatment. All these changes could be inhibited or prevented by ATRA.Conclusion. Ginsenoside Rb1 is capable of ameliorating II/R induced lung injuries by activating Nrf2/HO-1 pathway.

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Hypoxia compared with normoxia alters the effects of nitric oxide in ischemia-reperfusion lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.273.3.l504 ◽

1997 ◽

Vol 273 (3) ◽

pp. L504-L512 ◽

Cited By ~ 2

Author(s):

Y. C. Huang ◽

P. W. Fisher ◽

E. Nozik-Grayck ◽

C. A. Piantadosi

Keyword(s):

Nitric Oxide ◽

Lung Injury ◽

Average Rate ◽

Ischemia Reperfusion ◽

Oxidant Stress ◽

No Production ◽

Protective Effects ◽

Lung Weight ◽

Edema Formation ◽

No Donors

Because both the biosynthesis of nitric oxide (NO.) and its metabolic fate are related to molecular O2, we hypothesized that hypoxia would alter the effects of NO. during ischemia-reperfusion (IR) in the lung. In this study, buffer-perfused lungs from rabbits underwent either normoxic IR (AI), in which lungs were ventilated with 21% O2 during ischemia and reperfusion, or hypoxic IR (NI), in which lungs were ventilated with 95% N2 during ischemia followed by reoxygenation with 21% O2. Lung weight gain (WG) and pulmonary artery pressure (Ppa) were monitored continuously, and microvascular pressure (Pmv) was measured after reperfusion to calculate pulmonary vascular resistance. We found that both AI and NI produced acute lung injury, as shown by increased WG and Ppa during reperfusion. In AI, where perfusate PO2 was > 100 mmHg, the administration of the NO. synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before ischemia worsened WG and Ppa. Pmv also increased, suggesting a hydrostatic mechanism involved in edema formation. The effects of L-NAME could be attenuated by giving L-arginine and exogenous NO. donors before ischemia or before reperfusion. Partial protection was also provided by superoxide dismutase. In contrast, lung injury in NI at perfusate PO2 of 25-30 mmHg was attenuated by L-NAME; this effect could be reversed by L-arginine. Exogenous NO. donors given either before ischemia or before reperfusion, however, did not increase lung injury. NO. production was measured by quantifying the total nitrogen oxides (NOx) accumulating in the perfusate. The average rate of NOx accumulation was greater in AI than in NI. We conclude that hypoxia prevented the protective effects of NO on AI lung injury. The effects of hypoxia may be related to lower NO. production relative to oxidant stress during IR and/or altered metabolic fates of NO.-mediated production of peroxynitrite by hypoxic ischemia.

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