Pathophysiology of Stroke in Sickle Cell Disease

Hillery, Cheryl A.; Panepinto, Julie A.

doi:10.1080/10739680490278600

Cited by 71 publications

(40 citation statements)

References 112 publications

(137 reference statements)

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“…Sickle cell disease (SCD) is due to a point mutation in the beta chain of hemoglobin that causes polymerization of deoxyhemoglobin that distorts the shape of erythrocytes, contributing to vascular obstruction and ischemia of tissues and organs [1]. A hallmark feature of the disease is severe pain that arises during acute sickling events, as well as the recently recognized and less well understood chronic pain syndromes that develop in many of these individuals.…”

Section: Resultsmentioning

confidence: 99%

Sickle Cell Mice Exhibit Mechanical Allodynia and Enhanced Responsiveness in Light Touch Cutaneous Mechanoreceptors

et al. 2012

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BackgroundSickle cell disease (SCD) is associated with both acute vaso-occlusive painful events as well as chronic pain syndromes, including heightened sensitivity to touch. We have previously shown that mice with severe SCD (HbSS mice; express 100% human sickle hemoglobin in red blood cells; RBCs) have sensitized nociceptors, which contribute to increased mechanical sensitivity. Yet, the hypersensitivity in these neural populations alone may not fully explain the mechanical allodynia phenotype in mouse and humans.FindingsUsing the Light Touch Behavioral Assay, we found HbSS mice exhibited increased responses to repeated application of both innocuous punctate and dynamic force compared to control HbAA mice (100% normal human hemoglobin). HbSS mice exhibited a 2-fold increase in percent response to a 0.7mN von Frey monofilament when compared to control HbAA mice. Moreover, HbSS mice exhibited a 1.7-fold increase in percent response to the dynamic light touch “puffed” cotton swab stimulus. We further investigated the mechanisms that drive this behavioral phenotype by focusing on the cutaneous sensory neurons that primarily transduce innocuous, light touch. Low threshold cutaneous afferents from HbSS mice exhibited sensitization to mechanical stimuli that manifested as an increase in the number of evoked action potentials to suprathreshold force. Rapidly adapting (RA) Aβ and Aδ D-hair fibers showed the greatest sensitization, each with a 75% increase in suprathreshold firing compared to controls. Slowly adapting (SA) Aβ afferents had a 25% increase in suprathreshold firing compared to HbAA controls.ConclusionsThese novel findings demonstrate mice with severe SCD exhibit mechanical allodynia to both punctate and dynamic light touch and suggest that this behavioral phenotype may be mediated in part by the sensitization of light touch cutaneous afferent fibers to suprathreshold force. These findings indicate that Aβ fibers can be sensitized to mechanical force and should potentially be examined for sensitization in other tissue injury and disease models.

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Section: Resultsmentioning

confidence: 99%

Sickle Cell Mice Exhibit Mechanical Allodynia and Enhanced Responsiveness in Light Touch Cutaneous Mechanoreceptors

et al. 2012

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“…Such lesions tend to exhibit intimal hypertrophy with proliferative changes and a disrupted internal elastic lamina [3, 7]. Additionally included sometimes in pulmonary vasculopathy are the plexiform endothelial lesions typical of pulmonary hypertension.…”

Section: Sickle Vasculopathymentioning

confidence: 99%

A Systems Biology Consideration of the Vasculopathy of Sickle Cell Anemia: The Need for Multi-Modality Chemo-Prophylaxis

Hebbel

Vercellotti

Nath

2009

CHDDT

110

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Much of the morbidity and mortality of sickle cell anemia is accounted for by a chronic vasculopathy syndrome. There is currently no identified therapy, interventional or prophylactic, for this problem. For two reasons, development of an effective therapeutic approach will require a systems biology level perspective on the vascular pathobiology of sickle disease. In the first place, multiple biological processes contribute to the pathogenesis of vasculopathy: red cell sickling, inflammation and adhesion biology, coagulation activation, stasis, deficient bioavailability and excessive consumption of NO, excessive oxidation, and reperfusion injury physiology. The probable hierarchy of involvement of these disparate sub-biologies places inflammation caused by reperfusion injury physiology as the likely, proximate, linking pathophysiological factor. In the second place, most of these sub-biologies overlap with each other and, in any case, have multiple points of potential interaction and transactivation. Consequently, an approach modeled upon chemotherapy for cancer is needed. This would be a truly multi-modality approach that hopefully could be achieved via employment of relatively few drugs. It is proposed here that the specific combination of a statin with suberoylanilide hydroxamic acid would provide a suitable, broad, multi-modality approach to chemo-prophylaxis for sickle vasculopathy.

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“…Individuals with sickle cell disease (SCD) exhibit increased red blood cell (RBC) rigidity and adhesion, multiorgan and vascular pathology, and complex pain syndromes [2;6;9;10;14;29;31;33;34;50;60]. In addition, there is evidence of activation of the inflammatory and coagulation pathways [3;4;8;17;61–63].…”

Section: Introductionmentioning

confidence: 99%

Dietary supplementation with docosahexanoic acid (DHA) increases red blood cell membrane flexibility in mice with sickle cell disease

Wandersee

Maciaszek

Giger

et al. 2015

Blood Cells, Molecules, and Diseases

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Humans and mice with sickle cell disease (SCD) have rigid red blood cells (RBCs). Omega-3 fatty acids, such as docosahexanoic acid (DHA), may influence RBC deformability via incorporation into the RBC membrane. In this study, sickle cell (SS) mice were fed natural ingredient rodent diets supplemented with 3% DHA (DHA diet) or a control diet matched in total fat (CTRL diet). After 8 weeks of feeding, we examined the RBCs for: 1) stiffness, as measured by atomic force microscopy; 2) deformability, as measured by ektacytometry; and 3) percent irreversibly sickled RBCs on peripheral blood smears. Using atomic force microscopy, stiffness is increased and deformability decreased in RBCs from SS mice fed CTRL diet compared to wild-type mice. In contrast, RBCs from SS mice fed DHA diet had markedly decreased stiffness and increased deformability compared to RBCs from SS mice fed CTRL diet. Furthermore, examination of peripheral blood smears revealed less irreversibly sickled RBCs in SS mice fed DHA diet as compared to CTRL diet. In summary, our findings indicate that DHA supplementation improves RBC flexibility and reduces irreversibly sickled cells by 40% in SS mice. These results point to potential therapeutic benefits of dietary omega-3 fatty acids in SCD.

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Pathophysiology of Stroke in Sickle Cell Disease

Cited by 71 publications

References 112 publications

Sickle Cell Mice Exhibit Mechanical Allodynia and Enhanced Responsiveness in Light Touch Cutaneous Mechanoreceptors

Sickle Cell Mice Exhibit Mechanical Allodynia and Enhanced Responsiveness in Light Touch Cutaneous Mechanoreceptors

A Systems Biology Consideration of the Vasculopathy of Sickle Cell Anemia: The Need for Multi-Modality Chemo-Prophylaxis

Dietary supplementation with docosahexanoic acid (DHA) increases red blood cell membrane flexibility in mice with sickle cell disease

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