Inhaled nitric oxide protects transgenic SAD mice from sickle cell disease-specific lung injury induced by hypoxia/reoxygenation

Franceschi, Lucia De; A, Baron; Scarpa, Aldo; Adrie, Christophe; Janin, Anne; Barbi, Stefano; Kister, J.; Rouyer-Fessard, P; Corrocher, Roberto; Leboulch, Philippe; Beuzard, Yves

doi:10.1182/blood-2002-07-2135

Cited by 70 publications

(96 citation statements)

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“…I/R stress induced increased levels of p-NF-κB p65 in WT mice at 4 h of hypoxia reaching a peak at 48 h of hypoxia and becoming undetectable at 168 h of hypoxia ( Figure 1B). In A. Siciliano et al 26 haematologica | 2011; 96(1) Pathological score 0 (6) 0.5 ± 0.02 (6) 1.0 ± 0.04 (6)* 1.6 ± 0.03(7)* 1.4 ± 0.09 (6)^1.2 ± 0.05 (6)^1.7 ± 0.02 (5)^3.2 ± 0.05 (6)*^1.8 ± 0.02 (8)° Inflammatory 0 (6) + (6) + (6) ++ (7) + (6) ++ (6) ++ (5) +++ (6) + (8) cell infiltrate Thrombi, % (n. of 0% (6) 0% (6) 0% (6) 0% (7) 0% (6) 0% (6) 0% (5) 16% (6) 0% (8) SAD mice p-NF-κB was undetectable after 4 and 48 h of hypoxia but present at 168 h of hypoxia at a level lower than that observed at baseline but higher than the level in WT mice exposed to the corresponding period of 168 h of hypoxia ( Figure 1B).…”

Section: Hypoxia/reoxygenation Induced Sickle Cell-related Hepatopathmentioning

confidence: 99%

“…26,27 In brief, WT (n=6) and SAD (n=6) mice were evaluated in ambient air and then after hypoxia (8% O2) maintained for 4 h (WT and SAD, n=6), 48 h (WT and SAD, n=6) or 168 h (WT and SAD, n=8), followed by 2 h of reoxygenation. No major problems in mouse behavior or significant changes in mouse weight occurred during the I/R protocol.…”

Section: Ischemic/reperfusion Protocolmentioning

confidence: 99%

“…Blood sampling and vehicle administration had been previously shown not to affect the blood parameters measured in this study. 26,27 Treatment was started 48 h before hypoxia and maintained during the 168 h of hypoxia. Mice did not show major side effects related to rolipram treatment.…”

Section: Ischemic/reperfusion Protocolmentioning

confidence: 99%

“…26 Total bilirubin was measured using a Quantichrom Bilirubin Assay kit (BioAssay Systems, Hayward, CA, USA) according to the manufacturer's instructions. 28,29 Plasma iron was measured by flame atomic absorption.…”

Section: Ischemic/reperfusion Protocolmentioning

confidence: 99%

“…The animals (female and male, 20-25 g in body weight) were aged between 4 and 6 months and free from infectious liver diseases. 26 The experiments were carried out in accordance with guidelines from the Italian Ministry of Health and the agreement of the local ethics committee for animal studies.…”

Section: Introductionmentioning

confidence: 99%

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Abnormal modulation of cell protective systems in response to ischemic/reperfusion injury is important in the development of mouse sickle cell hepatopathy

Siciliano¹,

Malpeli²,

Platt³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundSickle cell disease, a genetic red cell disorder inherited in an autosomal recessive manner, occurs throughout the world. Hepatic dysfunction and liver damage may be present in sickle cell disease, but the pathogenesis of these conditions is only partially understood. Design and MethodsTransgenic mice with sickle cell disease (SAD mice) and wild-type mice were exposed to an ischemic/reperfusion stress. The following parameters were evaluated: hematologic profile, transaminase and bilirubin levels, liver histopathology, and mRNA levels of nuclear factor-κB p65, endothelial nitric oxide synthase, inducible nitric oxide synthase, heme oxygenase-1 and phosphodiesterase-1, -2, -3, and -4 genes in hepatocytes obtained by laser-capture microdissection. Immunoblotting was used to analyze the expression of the following proteins: nuclear factor-κB p65 and phospho-nuclear factor-κB p65, heme oxygenase-1, biliverdin reductase, heat shock protein-70, heat shock protein-27 and peroxiredoxin-6. A subgroup of SAD mice was treated with the phosphodiesterase-4 inhibitor rolipram (30 mg/Kg/day by gavage) during the ischemic/reperfusion protocol. ResultsIn SAD mice the ischemic/reperfusion stress induced liver damage compatible with sickle cell disease hepatopathy, which was associated with: (i) lack of hypoxia-induced nuclear factor-κB p65 activation; (ii) imbalance in the endothelial/inducible nitric oxide synthase response to ischemic/reperfusion stress; (iii) lack of hypoxia-induced increased expression of heme oxygenase-1/biliverdin reductase paralleled by a compensatory increased expression of heat shock proteins 70 and 27 and peroxiredoxin-6; and (iv) up-regulation of the phosphodiesterase-1, -2, -3, and -4 genes. In SAD mice the phosphodiesterase-4 inhibitor rolipram attenuated the ischemic/reperfusion-related microcirculatory dysfunction, reduced the inflammatory cell infiltration and induced the heme oxygenase-1/ biliverdin reductase cytoprotective systems. ConclusionsIn SAD mice, sickle cell hepatopathy is associated with perturbed nuclear factor-κB p65 signaling with an imbalance of endothelial/inducible nitric oxide synthase levels, lack of heme oxygenase-1/biliverdin reductase expression and up-regulation of two novel cytoprotective systems: heat shock protein-27 and peroxiredoxin-6.Key words: NF-κB p65, endothelial nitric oxide synthase, inducible nitric oxide synthase, heat shock protein-70, heat shock protein-27, peroxiredoxin-6.

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Section: Hypoxia/reoxygenation Induced Sickle Cell-related Hepatopathmentioning

confidence: 99%

Section: Ischemic/reperfusion Protocolmentioning

confidence: 99%

Section: Ischemic/reperfusion Protocolmentioning

confidence: 99%

Section: Ischemic/reperfusion Protocolmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Abnormal modulation of cell protective systems in response to ischemic/reperfusion injury is important in the development of mouse sickle cell hepatopathy

Siciliano¹,

Malpeli²,

Platt³

et al. 2010

Haematologica

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Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis

Gladwin¹

2011

JAMA

207

139

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Context Inhaled nitric oxide (NO) has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). Objective To determine whether inhaled NO gas reduces the duration of painful crisis in patients with SCD who present to the emergency room or hospital for care. Design, Setting and Participants Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled NO gas versus inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004 and December 22, 2008. The primary endpoint was the time to resolution of painful crisis, defined by: 1) freedom from parenteral opioid use for 5 hours; 2) pain relief as assessed by visual analog pain scale scores ≤ 6 cm; 3) ability to walk; and 4) patient and family’s decision, with physician consensus, that the remaining pain could be managed at home. Intervention Inhaled NO gas versus inhaled nitrogen placebo. Results There was no significant change in the primary endpoint between the NO and the placebo groups, with a median time to resolution of crisis of 73.0 hours (95% CI: 46.0–91.0) and 65.5 hours (95% CI: 48.1–84.0), respectively (P=.87). There were no significant differences in secondary outcome measures, including length of hospitalization, VAS scores, cumulative opioid usage and the rate of acute chest syndrome. Inhaled NO was well tolerated with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed compliance and randomization, but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. Conclusions Among patients with SCD hospitalized with VOC, the use of inhaled NO compared with placebo did not improve time to crisis resolution.

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