Sickle Cell Lung Disease and Sudden Death

Jk, Graham; Mosunjac, Mario; Rl, Hanzlick

doi:10.1097/01.paf.0000257397.92466.50

Cited by 98 publications

(22 citation statements)

References 20 publications

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“…This finding has been replicated in a recent study in 1990–2004 at Grady Memorial Hospital (Atlanta, Georgia, USA; ref. 54), reaffirming the role of endothelial barrier dysfunction in the pathobiology of SCD. The adherens junction complex and its major adhesive constituent VE-cadherin is the central component of the endothelial barrier.…”

Section: Discussionmentioning

confidence: 83%

Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice

et al. 2016

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The prevention of organ damage and early death in young adults is a major clinical concern in sickle cell disease (SCD). However, mechanisms that control adult progression of SCD during the transition from adolescence are poorly defined with no cognate prophylaxis. Here, we demonstrate in a longitudinal cohort of homozygous SCD (SS) mice a link between intravascular hemolysis, vascular inflammation, lung injury, and early death. Prophylactic Nrf2 activation in young SS mice stabilized intravascular hemolysis, reversed vascular inflammation, and attenuated lung edema in adulthood. Enhanced Nrf2 activation in endothelial cells in vitro concurred with the dramatic effect on vascular inflammation in the mice. BM chimeric SS mice lacking Nrf2 expression in nonhematopoietic tissues were created to dissect the role of nonerythroid Nrf2 in SCD progression. The SS chimeras developed severe intravascular hemolysis despite having erythroid Nrf2. In addition, they developed premature vascular inflammation and pulmonary edema and died younger than donor littermates with intact nonhematopoietic Nrf2. Our results reveal a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD. Furthermore, we show that prophylactic augmentation of Nrf2-coordinated cytoprotection effectively impedes onset of the severe adult phenotype of SCD in mice.

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Section: Discussionmentioning

confidence: 83%

Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice

et al. 2016

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“…Also pulmonary and splenic arteries are common sites of atherosclerosis in sickle cell disease. One-third of the sickle patients had histological evidence of medial hypertrophy and intimal proliferation in these arteries (de Chadarevian et al, 2001; Graham et al, 2007). …”

Section: Altered Iron Homeostasis and Atherosclerosis: Epidemiologicamentioning

confidence: 99%

Atherogenesis and iron: from epidemiology to cellular level

et al. 2014

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Iron accumulates in human atherosclerotic lesions but whether it is a cause or simply a downstream consequence of the atheroma formation has been an open question for decades. According to the so called “iron hypothesis,” iron is believed to be detrimental for the cardiovascular system, thus promoting atherosclerosis development and progression. Iron, in its catalytically active form, can participate in the generation of reactive oxygen species and induce lipid-peroxidation, triggering endothelial activation, smooth muscle cell proliferation and macrophage activation; all of these processes are considered to be proatherogenic. On the other hand, the observation that hemochromatotic patients, affected by life-long iron overload, do not show any increased incidence of atherosclerosis is perceived as the most convincing evidence against the “iron hypothesis.” Epidemiological studies and data from animal models provided conflicting evidences about the role of iron in atherogenesis. Therefore, more careful studies are needed in which issues like the source and the compartmentalization of iron will be addressed. This review article summarizes what we have learnt about iron and atherosclerosis from epidemiological studies, animal models and cellular systems and highlights the rather contributory than innocent role of iron in atherogenesis.

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“…New and old thrombi in the pulmonary vasculature are prevalent in autopsy series 21,24,25 . The analysis of a large discharge database in the state of Pennsylvania from 2001 to 2006 found that the incidence of pulmonary embolism was 50-fold to 100-fold higher in the SCD population (0.22–0.52%) than in the general Pennsylvania population (0.0039–0.0058%) 26 .…”

Section: Evidence For Increased Thromboembolic Events In Sickle Cell mentioning

confidence: 99%

Role of the Hemostatic System on Sickle Cell Disease Pathophysiology and Potential Therapeutics

Pakbaz

Wun

2014

Hematology/Oncology Clinics of North America

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SynopsisRecent studies suggest that sickle cell disease is a hypercoagulable state contributing to the vasoocclusive events in microcirculation resulting in acute and chronic sickle cell related organ damage. In this article, we will review the existing evidence for contribution of hemostatic system perturbation to sickle cell disease pathophysiology. We will also review the data showing increased risk of thromboembolic events, particularly newer information on the incidence of VTE. Finally, the potential role of platelet inhibitors and anticoagulants in SCD will be briefly reviewed.Keywords sickle cell; thromboembolism; hypercoagulable; anti-platelets; anticoagulants IntroductionSickle cell disease (SCD) is the result of homozygous or compound heterozygous inheritance of mutation in the β-globin gene. The resulting substitution of the hydrophilic amino acid glutamic acid at the sixth position by the hydrophobic amino acid valine, leads to the production of hemoglobin S (HbS). HbS polymerizes when deoxygenated and this polymerization is associated with cell dehydration and increased red cell density [1][2][3] . The dense, rigid and sickling red cells lead to vaso-occlusion and impaired blood flow 2,4 , and is thought to underlie acute (painful episodes, acute chest syndrome) and chronic (avascular necrosis, renal insufficiency) complications of the disease. Also, intracellular polymerization ultimately damages the red cell membrane and leads to chronic and episodic extra-vascular and intravascular hemolytic anemia, hemolysis linked nitric oxide (NO) dysregulation and endothelial dysfunction 5 resulting leg ulcer, pulmonary hypertension (PHTN), priapism and stroke 6 .Corresponding author: Ted Wun, MD. Authors contact information Address/Phone/Fax (for both authors): University of California, Davis Cancer Center, 4501 X St., Ste. 3016, Sacramento, CA 95817, Phone: (916) Fax: (916) 734-7946, zahra.pakbaz@ucdmc.ucdavis.edu, ted.wun@ucdmc.ucdavis.edu ZP has no conflict of interest.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptSeveral investigators have reported increased thromboembolic events and alteration in hemostatic system in SCD both under steady state and during acute events. This suggests that perturbation in hemostatic system may contribute to SCD pathophysiology. Changes that have been described include increased expression of tissue factor on blood monocytes 7-9 and endothelial cells 10,11 , abnormal exposure of phosphatidylserine on the red cell surface 12,13 and i...

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Sickle Cell Lung Disease and Sudden Death

Cited by 98 publications

References 20 publications

Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice

Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice

Atherogenesis and iron: from epidemiology to cellular level

Role of the Hemostatic System on Sickle Cell Disease Pathophysiology and Potential Therapeutics

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