Original articlePolynitroxyl albumin inhibits inflammation and vasoocclusion in transgenic sickle mice
Section snippets
Materials
PNA and control albumin solutions were generous gifts from SynZyme Technologies LLC. All other reagents were purchased from Sigma-Aldrich (St Louis, Mo) unless indicated otherwise.
Mice
All animal experiments were approved by the University of Minnesota’s Institutional Animal Care and Use Committee. We used male and female S+S Antilles transgenic sickle mice as our mouse model for SCD.50 S+S Antilles mice are homozygous for deletion of the mouse β- major globin locus and express human α-, βS-, and β
Results
It has been previously shown that systemic hypoxia followed by reoxygenation causes enhanced ROS production in sickle mice compared with normal mice.16, 17 To examine the effect of HR on the activation of transcription factor NF-κB, we measured NF-κB in lung, liver, and skin from normal C57BL6 mice and transgenic sickle mice exposed to ambient air or HR (Table I). As we have previously published,53 NF-κB activation was increased in the lung (322%, P < .01), liver (582%, P ≤ .001), and skin
Discussion
Patients with SCD exhibit markers of inflammation, including a high white-cell count, increased cytokine levels, and increased concentrations of acute-phase reactants. The exact role played by inflammation in vasoocclusion is unclear. Oxidative stress/ROS may be the driving force behind vasoocclusion. We have hypothesized a vicious circle of oxidative stress, vascular inflammation, and vasoocclusion in SCD (Fig 4). RBC sickling and hemolysis not only generate ROS but also release hemoglobin,
References (55)
- et al.
Transgenic sickle mice have vascular inflammation
Blood
(2003) - et al.
Reperfusion injury pathophysiology in sickle transgenic mice
Blood
(2000) - et al.
Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease
Blood
(2004) - et al.
Oxidative stress and induction of heme oxygenase-1 in the kidney in sickle cell disease
Am J Pathol
(2001) - et al.
Low-density lipoprotein susceptibility to oxidation and cytotoxicity to endothelium in sickle cell anemia
J Lab Clin Med
(1999) - et al.
Free radicals in medicine. II. Involvement in human disease
Mayo Clin Proc
(1988) - et al.
Mechanisms of reperfusion injury
Am J Med Sci
(1994) - et al.
Sickle erythrocytes adhere to polymorphonuclear neutrophils and activate the neutrophil respiratory burst
Blood
(1996) - et al.
Blood polymorphonuclear leukocytes from the majority of sickle cell patients in the crisis phase of the disease show enhanced adhesion to vascular endothelium and increased expression of CD64
Blood
(1998) - et al.
Activated monocytes in sickle cell diseasepotential role in the activation of vascular endothelium and vaso-occlusion
Blood
(2000)
Regulation of the transcription factors NF-kappa B and AP-1 by redox changes
Chem Biol Interact
Alpha 4 beta 1-integrin expression on sickle reticulocytesvascular cell adhesion molecule-1-dependent binding to endothelium
Blood
Vascular cell adhesion molecule-1 is involved in mediating hypoxia-induced sickle red blood cell adherence to endotheliumpotential role in sickle cell disease
Blood
Traffic signals for lymphocyte recirculation and leukocyte emigrationthe multistep paradigm
Cell
P-selectin mediates the adhesion of sickle erythrocytes to the endothelium
Blood
The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo
Blood
Polynitroxylated starch/TPL attenuates cachexia and increased epithelial permeability associated with TNBS colitis
Inflammation
Stimulation by nitroxides of catalase-like activity of hemeproteins. Kinetics and mechanism
J Biol Chem
Inhibition of copper-mediated low density lipoprotein peroxidation by quinoline and indolinone nitroxide radicals
Biochem Pharmacol
Pretreatment with polynitroxyl albumin (PNA) inhibits ischemia-reperfusion induced leukocyte-endothelial cell adhesion
Free Radic Biol Med
Polynitroxyl-albumin (PNA) plus tempol attenuate lung capillary leak elicited by prolonged intestinal ischemia and reperfusion(1)
Free Radic Biol Med
A second generation transgenic mouse model expressing both hemoglobin S (HbS) and HbS-Antilles results in increased phenotypic severity
Blood
Polynitroxyl-albumin (PNA) enhances myocardial infarction therapeutic effect of tempol in rat hearts subjected to regional ischemia-reperfusion
Free Radic Biol Med
Sickle cell anemia, a molecular disease
Science
Pathogenesis and treatment of sickle cell disease
N Engl J Med
Circulating activated endothelial cells in sickle cell anemia
N Engl J Med
Pathogenesis of vasoocclusion
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2010, Translational ResearchCitation Excerpt :Because this observation implicates blood cells as activators of endothelium, we demonstrated that infusion of a preparation of peripheral blood mononuclear cells obtained from post-H/R NY1DD mice, but not from unstressed NY1DD mice, caused significant subsequent enhancement of endothelial TF expression in the recipient naïve NY1DD mice. Because the mononuclear cells were harvested exactly 1 h after the end of hypoxia, we know that the implicated mononuclear-activating event had occurred shortly into the reoxygenation period, which is consistent with previous observations on other biomarkers of the expected inflammatory response to ischemia/reperfusion.4-9 Although the current results cannot exclude some contribution from the many lymphocytes or the few granulocytes contained within the mononuclear cell preparation, this seems unlikely because it is the monocytes and not the lymphocytes that typically generate the known endothelial-activating substances of interest.
Supported by NHLBI grants HL67367 and HL55552.