Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice

Kaul, Dhananjay K.; Hebbel, Robert P.

doi:10.1172/jci9225

Cited by 369 publications

(351 citation statements)

References 56 publications

(43 reference statements)

Supporting

Mentioning

334

Contrasting

Unclassified

Order By: Relevance

“…The concept that sickle cell disease (SCD) is a state of inflammation has been substantiated by the reports of endothelial injury/activation and excessive generation of ROS in this disease, and enhanced leukocyte-endothelium interactions [3,13,15,31]. The oxidative stress in SCD is likely the result of intravascular sickling and transient vaso-occlusive events.…”

Section: Introductionmentioning

confidence: 99%

“…NO has important salutary physiological properties like vascular tone regulation, quenching reactive oxygen intermediates and inhibiting leukocyte recruitment in the microcirculation [2,15,17,22,27,29]. Depleted NO production in a transgenic-knockout (BERK) model is associated with increased tyrosine nitration [16], suggesting that hemolysis in this model may trigger the reported hemin-mediated nitrotyrosine formation in the presence of nitrite and hydrogen peroxide (H 2 O 2 ) [38].…”

Section: Introductionmentioning

confidence: 99%

“…To test this aspect, we have used transgenic mouse models of mild (NY1DD mice) and severe pathology (BERK mice). Transgenic NY1DD mice show a mild phenotype but develop an inflammatory phenotype after hypoxia/reoxygenation as evident by increased lipid peroxidation and leukocyte recruitment [15,31]. Transgenic-knockout BERK mice express exclusively human hemoglobin S, and recapitulate many features of human sickle cell disease, i.e., hemolytic anemia, reticulocytosis, presence of irreversibly sickled cells (ISCs) and multiple organ damage [33,37].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

Dasgupta

Hebbel

Kaul

2006

Free Radical Biology and Medicine

129

101

View full text Add to dashboard Cite

Sickle cell disease (SCD) is characterized by reperfusion injury and chronic oxidative stress. Oxidative stress and hemolysis in SCD result in inactivation of nitric oxide (NO) and depleted arginine levels. We hypothesized that augmenting NO production by arginine supplementation will reduce oxidative stress in SCD. To this end, we measured the effect of arginine (5% in mouse chow) on NO metabolites (NOx), lipid peroxidation (LPO) and selected antioxidants in transgenic sickle mouse models. Untreated transgenic sickle (NY1DD) mice (expressing ~75% β S -globin of all β-globins; mild pathology) and knockout sickle (BERK) mice (expressing exclusively hemoglobin S; severe pathology) showed reduced NOx levels and significant increases in the liver LPO compared with C57BL mice, with BERK mice showing maximal LPO increase in accordance with the disease severity. This was accompanied by reduced activity of antioxidants (glutathione [GSH], total superoxide dismutase [SOD], catalase and glutathione peroxidase [GPx]). However, GSH levels in BERK were higher than in NY1DD mice indicating a protective response to greater oxidative stress. Importantly, dietary arginine significantly increased NOx levels, reduced LPO and increased antioxidants in both sickle mouse models. In contrast, L-NAME, a potent non-selective NOS inhibitor, worsened the oxidative stress in NY1DD mice. Thus, attenuating effect of arginine on oxidative stress in SCD mice suggests its potential application in the management of this disease.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

Dasgupta

Hebbel

Kaul

2006

Free Radical Biology and Medicine

129

101

View full text Add to dashboard Cite

show abstract

“…The polymerization of deoxygenated sickle hemoglobin is the primary event in the molecular pathogenesis of SCD and is responsible for the vaso-occlusive phenomena that are the hallmarks of the disease [3]. The repetitive vaso-occlusive episodes cause tissue ischemia and reperfusion injury, resulting in endothelial cell activation and inflammation [4,5]. Sickle patients have multiple indicators of an inflammatory response including elevated white counts [6][7][8][9], C-reactive protein levels [10][11][12][13], cytokines [14][15][16][17], as well as activated monocytes [13,18], neutrophils [19][20][21], platelets [18,[22][23][24][25][26][27][28], and endothelial cells [29,30] in circulation.…”

Section: Introductionmentioning

confidence: 99%

Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

et al. 2004

View full text Add to dashboard Cite

Vascular inflammation, secondary to ischemia-reperfusion injury, may play an essential role in vaso-occlusion in sickle cell disease (SCD). To investigate this hypothesis, dorsal skin fold chambers (DSFCs) were implanted on normal and transgenic sickle mice expressing human a and b s /b s-Antilles globin chains. Microvessels in the DSFC were visualized by intravital microscopy at baseline in ambient air and after exposure to hypoxia-reoxygenation. The mean venule diameter decreased 9% (P < 0.01) in sickle mice after hypoxia-reoxygenation but remained constant in normal mice. The mean RBC velocity and wall shear rate decreased 55% (P < 0.001) in sickle but not normal mice after hypoxia-reoxygenation. None of the venules in normal mice became static at any time during hypoxia-reoxygenation; however, after 1 hr of hypoxia and 1 hr of reoxygenation, 11.9% of the venules in sickle mice became static (P < 0.001). After 1 hr of hypoxia and 4 hr of reoxygenation, most of the stasis had resolved; only 3.6% of the subcutaneous venules in sickle mice remained static (P = 0.01). All of the venules were flowing again after 24 hr of reoxygenation. Vascular stasis could not be induced in the subcutaneous venules of sickle mice by tumor necrosis factor alpha (TNF-a). Leukocyte rolling flux and firm adhesion, manifestations of vascular inflammation, were significantly higher at baseline in sickle mice compared to normal (P < 0.01) and increased 3-fold in sickle (P < 0.01), but not in normal mice, after hypoxia-reoxygenation. Plugs of adherent leukocytes were seen at bifurcations at the beginning of static venules. Misshapen RBCs were also seen in subcutaneous venules. Am.

show abstract

“…Separate support for long-term administration an agent that blocks only P-selectin derives from its safety in avoiding the infectious complications likely associated with blocking two or three selectins [24]. While it has been suggested that adhesion of leukocytes to the endothelium and formation of heterocellular platelet aggregates are important to impaired blood flow [9], the evident dependence of these mechanism on P-selectin mediated adhesion [12,25,26] suggests that P-selectin-blocking therapy would surmount vasoocclusive contributions from these pathophysiologies.…”

mentioning

confidence: 99%

A potent oral P‐selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease

et al. 2012

View full text Add to dashboard Cite

Genomic DNA was extracted from 200 mL of whole EDTA blood, either manually or using the DNA Qiacube 1 appliance (Qiagen, Courtaboeuf, France). All SNPs were genotyped by direct sequencing (Applied 3130 XL), except for OPRM1 and COMT (FRET Light Cycler 1 ) [2,22] and for the *5 and dup CYP2D6 alleles (PCR-based methods) [9,23].HWE and allelic frequencies. To check for each SNP the genetic homogeneity of our SCD cohort, we compared by a Chi square test the observed genotypes repartition in wild-type, heterozygous and homozygous with the theoretical one given by the HWE [24]. Thereafter, considering that our SCD cohort was representative of all SCD patients, we determined the 95% confidence intervals (CI95) for the mutant allele frequencies. Calculations were made with the XLSTAT Version 2011.2.04 software and differences were considered as significant when P < 0.05. These intervals were compared with the data previously reported for African-American and Caucasian patients on

show abstract

Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice

Cited by 369 publications

References 56 publications

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

A potent oral P‐selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease

Contact Info

Product

Resources

About