Pathophysiology of a Sickle Cell Trait Mouse Model: Human αβS Transgenes with One Mouse β-Globin Allele

Noguchi, Constance Tom; Gladwin, Mark T.; Diwan, Bhalchandra A.; Merciris, Patrick; Smith, Richard; Yu, Xiaobing; Buzard, Gregory S.; Fitzhugh, Anthony L.; Keefer, Larry K.; Schechter, Alan N.; Mohandas, Narla

doi:10.1006/bcmd.2001.0469

Cited by 24 publications

(27 citation statements)

References 24 publications

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“…Consistent with that notion, Noguchi et al 21 observed a peculiarly increased adverse sensitivity to severe hypoxia among hBERK1 animals compared with hBERK2 littermates. Thus, it seems probable that hBERK1 mice may have deficient oxygen loading; arterial hemoglobin oxygen saturation and pO 2 will need to be measured to confirm this.…”

Section: Discussionmentioning

confidence: 55%

“…Thus, it is conceivable that pain characteristics observed in the hBERK1 model may be a consequence of severe inflammation, altered oxygen availability, and organ disease, 18,20,21 which may in turn cause perturbation in the peripheral nerves and spinal activation of pain mediators observed herein. Perhaps these behaviors are further influenced by a different degree or tissue distribution of hypoxia in hBERK1 compared with BERK mice.…”

Section: Discussionmentioning

confidence: 92%

“…hBERK1 mice have abnormal activation of pulmonary vein endothelium, just like BERK, 18 and they have renal histopathologic lesions (including inflammatory ones) that are similar to, but more severe than, hBERK2 littermates that have a higher level of HbS. 21 This has been interpreted as suggesting that the histopathology of hBERK1 is perhaps the result of tissue hypoxia caused by abnormally low oxygen affinity of the hybrid human ␣/mouse ␤ hemoglobin, leading to poor oxygen delivery. Ordinarily, a rightshifted oxygen dissociation curve would be expected to increase …”

Section: Discussionmentioning

confidence: 99%

“…20 hBERK mice express the following globin chains: human ␣, human ␤ S , and murine ␤ (thus, human hemoglobin S and a hybrid human ␣/mouse ␤ hemoglobin). 21 Both BERK and hBERK1 are on the same mixed genetic background and are bred as littermates.…”

Section: Micementioning

confidence: 99%

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Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids

Kohli

Khasabov

et al. 2010

Blood

167

298

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Sickle cell disease causes severe pain. We examined pain-related behaviors, correlative neurochemical changes, and analgesic effects of morphine and cannabinoids in transgenic mice expressing human sickle hemoglobin (HbS). Paw withdrawal threshold and withdrawal latency (to mechanical and thermal stimuli, respectively) and grip force were lower in homozygous and hemizygous Berkley mice (BERK and hBERK1 ,

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Micementioning

confidence: 99%

See 2 more Smart Citations

Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids

Kohli

Khasabov

et al. 2010

Blood

167

298

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“…Additional control animals were hemizygous littermates, which have anemia and increased oxidative stress but no sickle deformation. 23,41 All were males ages 3 to 5 months old, except a series of retired breeder males (13 to 15 months old) to determine the effects of aging. Transgenic mice expressing human blood group antigen Duffy b (Fy b ) were used as blood donors for B6CBA-F1 mice, which lack human Fy b , as a model for red blood cell alloimmunization.…”

mentioning

confidence: 99%

Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability

Hsu

Champion

Campbell‐Lee

et al. 2006

Blood

228

204

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Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction, and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors, and endothelium-dependent vasodilators and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/ emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a nonsickle mouse model of acute alloimmune hemolysis. Although the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO. IntroductionPulmonary hypertension is a highly prevalent complication of sickle cell disease that is associated with early mortality. [1][2][3][4] The putative mechanisms responsible for pulmonary hypertension are the focus of intense current research and remain incompletely defined. 5 One mechanism proposed is that hemolytic anemia and decompartmentalization of erythrocyte hemoglobin and arginase into plasma leads to nitric oxide (NO) scavenging and arginine degradation, limiting the bioavailability of NO. 3,[6][7][8][9][10] This process would ultimately lead to acute changes in pulmonary vascular endothelial and vasomotor function and chronic pathologic intimal and smooth muscle hyperplasia. Alternatively, chronic lung disease caused by recurrent pulmonary infarction, pneumonia, acute chest syndrome, and thromboembolism could lead to chronic hypoxemia, pulmonary fibrosis, thrombotic vascular obliteration, and secondary pulmonary hypertension. [11][12][13][14][15] Pulmonary hypertension could also arise from chronic hypoxia or chronic nocturnal hypoxia. [16][17][18] Additional factors contributing to pulmonary hypertension include right-heart failure secondary to a chronic high cardiac output as compensation for chronic anemia and left ventricular diastolic dysfunction secondary to cardiac tissue microinfarction and/or iron overload. [19][20][21][22] In short, is exposure to hemoglobin S (HbS) erythrocytes sufficient to cause pulmonar...

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Sickle Cell Disease

Kaul

2008

Comprehensive Physiology

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Pathophysiology of a Sickle Cell Trait Mouse Model: Human αβS Transgenes with One Mouse β-Globin Allele

Cited by 24 publications

References 24 publications

Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids

Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids

Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability

Sickle Cell Disease

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