Acute hydroxyurea treatment reduces tubular damage following bilateral ischemia-reperfusion injury in a mouse model of sickle cell disease

2019 ◽  
Vol 515 (1) ◽  
pp. 72-76 ◽  
Author(s):  
Frank Park ◽  
Hitesh Soni ◽  
Jeffrey D. Pressly ◽  
Adebowale Adebiyi
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Reperfusion Injury ◽  
Sickle Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tubular Damage ◽  
Cell Disease ◽  
Hydroxyurea Treatment

scholarly journals New insights into the pathophysiology and development of novel therapies for sickle cell disease

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 493-506 ◽  
Author(s):  
Scott Moerdler ◽  
Deepa Manwani
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Disease ◽  
Oxidant Damage ◽  
Emerging Treatments ◽  
Heterotypic Interactions ◽  
Abnormal Hemoglobin ◽  
Selection Of

Abstract Although the seminal event in sickle cell disease is the polymerization of abnormal hemoglobin, the downstream pathophysiology of vasoocclusion results from heterotypic interactions between the altered, adhesive sickle cell red blood cells, neutrophils, endothelium, and platelets. Ischemia reperfusion injury, hemolysis, and oxidant damage all contribute to heightened inflammation and activation of the hemostatic system. These various pathways are the focus of emerging treatments with potential to ameliorate disease manifestations. This review summarizes the considerable progress in development of these agents despite challenges in selection of study end points and complex pathophysiology.

scholarly journals Pathophysiology of Sickle Cell Disease

2019 ◽  
Vol 14 (1) ◽  
pp. 263-292 ◽  
Author(s):  
Prithu Sundd ◽  
Mark T. Gladwin ◽  
Enrico M. Novelli
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Sterile Inflammation ◽  
Organ Injury ◽  
Single Amino Acid ◽  
Current Evidence ◽  
Cell Disease ◽  
Hemoglobin S

Since the discovery of sickle cell disease (SCD) in 1910, enormous strides have been made in the elucidation of the pathogenesis of its protean complications, which has inspired recent advances in targeted molecular therapies. In SCD, a single amino acid substitution in the β-globin chain leads to polymerization of mutant hemoglobin S, impairing erythrocyte rheology and survival. Clinically, erythrocyte abnormalities in SCD manifest in hemolytic anemia and cycles of microvascular vaso-occlusion leading to end-organ ischemia-reperfusion injury and infarction. Vaso-occlusive events and intravascular hemolysis promote inflammation and redox instability that lead to progressive small- and large-vessel vasculopathy. Based on current evidence, the pathobiology of SCD is considered to be a vicious cycle of four major processes, all the subject of active study and novel therapeutic targeting: ( a) hemoglobin S polymerization, ( b) impaired biorheology and increased adhesion-mediated vaso-occlusion, ( c) hemolysis-mediated endothelial dysfunction, and ( d) concerted activation of sterile inflammation (Toll-like receptor 4– and inflammasome-dependent innate immune pathways). These molecular, cellular, and biophysical processes synergize to promote acute and chronic pain and end-organ injury and failure in SCD. This review provides an exhaustive overview of the current understanding of the molecular pathophysiology of SCD, how this pathophysiology contributes to complications of the central nervous and cardiopulmonary systems, and how this knowledge is being harnessed to develop current and potential therapies.

scholarly journals Targeting novel mechanisms of pain in sickle cell disease

Blood ◽  
2017 ◽  
Vol 130 (22) ◽  
pp. 2377-2385 ◽  
Author(s):  
Huy Tran ◽  
Mihir Gupta ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Acute Pain ◽  
Pain Perception ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Poor Quality ◽  
Current Treatment ◽  
Future Research ◽  
Cell Disease

Abstract Patients with sickle cell disease (SCD) suffer from intense pain that can start during infancy and increase in severity throughout life, leading to hospitalization and poor quality of life. A unique feature of SCD is vaso-occlusive crises (VOCs) characterized by episodic, recurrent, and unpredictable episodes of acute pain. Microvascular obstruction during a VOC leads to impaired oxygen supply to the periphery and ischemia reperfusion injury, inflammation, oxidative stress, and endothelial dysfunction, all of which may perpetuate a noxious microenvironment leading to pain. In addition to episodic acute pain, patients with SCD also report chronic pain. Current treatment of moderate to severe pain in SCD is mostly reliant upon opioids; however, long-term use of opioids is associated with multiple side effects. This review presents up-to-date developments in our understanding of the pathobiology of pain in SCD. To help focus future research efforts, major gaps in knowledge are identified regarding how sickle pathobiology evokes pain, pathways specific to chronic and acute sickle pain, perception-based targets of “top-down” mechanisms originating from the brain and neuromodulation, and how pain affects the sickle microenvironment and pathophysiology. This review also describes mechanism-based targets that may help develop novel therapeutic and/or preventive strategies to ameliorate pain in SCD.

scholarly journals Targeting novel mechanisms of pain in sickle cell disease

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 546-555 ◽  
Author(s):  
Huy Tran ◽  
Mihir Gupta ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Acute Pain ◽  
Pain Perception ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Poor Quality ◽  
Current Treatment ◽  
Future Research ◽  
Cell Disease

Abstract Patients with sickle cell disease (SCD) suffer from intense pain that can start during infancy and increase in severity throughout life, leading to hospitalization and poor quality of life. A unique feature of SCD is vaso-occlusive crises (VOCs) characterized by episodic, recurrent, and unpredictable episodes of acute pain. Microvascular obstruction during a VOC leads to impaired oxygen supply to the periphery and ischemia reperfusion injury, inflammation, oxidative stress, and endothelial dysfunction, all of which may perpetuate a noxious microenvironment leading to pain. In addition to episodic acute pain, patients with SCD also report chronic pain. Current treatment of moderate to severe pain in SCD is mostly reliant upon opioids; however, long-term use of opioids is associated with multiple side effects. This review presents up-to-date developments in our understanding of the pathobiology of pain in SCD. To help focus future research efforts, major gaps in knowledge are identified regarding how sickle pathobiology evokes pain, pathways specific to chronic and acute sickle pain, perception-based targets of “top-down” mechanisms originating from the brain and neuromodulation, and how pain affects the sickle microenvironment and pathophysiology. This review also describes mechanism-based targets that may help develop novel therapeutic and/or preventive strategies to ameliorate pain in SCD.

scholarly journals Hyper-Interleukin-6 Protects Against Renal Ischemic-Reperfusion Injury—A Mouse Model

2021 ◽  
Vol 8 ◽  
Author(s):  
Mohammad Zuaiter ◽  
Jonathan H. Axelrod ◽  
Galina Pizov ◽  
Ofer N. Gofrit
Keyword(s):  
Mouse Model ◽  
Reperfusion Injury ◽  
Interleukin 6 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Tubular Damage ◽  
Architectural Distortion ◽  
Inflammatory Infiltration

Background: Most of the ischemia-reperfusion injury (IR-I) occurs during reperfusion and is mediated by the immune system. In this study we determined whether immunomodulation with hyper-Interleukin-6 (a recombinant designer cytokine composed of interleukin-6 linked to its soluble receptor) is protective against IR-I in mice kidneys.Methods: Hyper-Interleukin-6 (HIL-6) was administered by in vivo plasmid DNA transfection to 10 male mice. Twenty-four hours later, unilateral nephrectomy was done. IR-I immediately followed by closure of the remaining kidney vascular pedicle for 40 min. Seven mice transfected with non-coding control plasmid served as the control group. The functional and morphological effects of IR-I and its effect on mice longevity were explored. This was done by serial blood tests and by histopathology done upon sacrifice of the animals at post-operative day 7.Findings: Mice pretreated with HIL-6 had a mean creatinine level at post-operative day 1 of 35.45 ± 4.03 μmol/l and mean Urea level was 14.18 ± 2.69 mmol/l, whereas mean creatinine was 89.33 ± 69.27 μmol/l (P = 0.025), and mean urea was 38.17 ± 20.77 mmol/l (P = 0.0024) in the control group. Histological changes in the control group included inflammatory infiltration, tubular damage, and architectural distortion. These were not seen in the treatment group. Seven days post-operatively the survival rate of treated mice was 100% compared to 50% in the control group (P = 0.015).Interpretation: In this single kidney mouse model, pretreatment with HIL-6 administration effectively protected against IR-I both morphologically and functionally. Further studies are needed to better understand the mechanism and feasibility of using this immunomodulator.

Differential Effects of Lovastatin and Allopurinol Therapy in a Murine Model of Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2325-2325
Author(s):  
Kirkwood A. Pritchard ◽  
Terri L. Besch ◽  
Jingli Wang ◽  
Hao Xu ◽  
Deron W. Jones ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Reperfusion Injury ◽  
Xanthine Oxidase ◽  
Sickle Cell ◽  
Vascular Function ◽  
Ischemia Reperfusion ◽  
Pleiotropic Effects ◽  
Cell Disease ◽  
And Oxidative Stress

Abstract Sickle cell disease is characterized by a chronic state of inflammation and oxidative stress due to repetitive bouts of ischemia and reperfusion injury. Ischemia-reperfusion injury increases the release of xanthine oxidase, which binds to vascular endothelium at sites distant from the original site of tissue damage where it can generate reactive oxygen species and impair normal vascular function. Lovastatin, an HMG COA reductase inhibitor, is a cholesterol lowering pharmaceutical agent use to treat hypercholesterolemia and prevent the premature development of atherosclerosis. Although lovastatin is used primarily to treat hypercholesterolemia, this agent has beneficial, pleiotropic effects that decrease vascular inflammation and improve vasodilation by increasing endothelial nitric oxide synthase (eNOS) in vascular tissues, a desired end-point in sickle cell disease. To test the hypothesis that xanthine oxidase plays an important role in the mechanisms by which sickle cell disease impairs vasodilation and to determine whether the pleiotropic effects of lovastatin can improve vasodilation, Berkeley transgenic sickle cell disease mice (SCD mice) were treated with either placebo, allopurinol (10 mg/kg/d, ip) or lovastatin (25 mg/kg/d by gavage) for 6–8 weeks. At the end of this treatment period, mice were sacrificed and facialis arteries removed by microdissection from a branch of the carotid artery. The facialis arteries were cannulated, pressurized to 60 mmHg, preconstricted with U46619 (10−8 to 10−7M) and then vasodilation responses to acetylcholine (ACh,10−7 to 10−4M) determined by videomicroscopy. Under these conditions, vasodilation of facialis arteries isolated from untreated SCD mice is completely impaired, with little to no response to ACh. Allopurinol treatment markedly improved ACh-induced vasodilation to nearly 40% at the highest concentration of Ach tested. Pretreatment of the isolated and pressurized vessels with L-NAME reduced vasodilation in the allopurinol-treated SCD mice to 13%, indicating that allopurinol increases eNOS-dependent vasodilation by 27% (40%-13%=27%) compared to 0% in placebo-treated SCD mice. In contrast, lovastatin, which is said to increase vascular function by increasing eNOS activity, increased ACh-induced to only 12%. Pretreatment of isolated and pressurized vessels from lovastatin-treated SCD mice with L-NAME reduced vasodilation to approximately 3%. Thus, lovastatin improved eNOS-dependent vasodilation in the SCD mice by approximately 9% (12%-3%=9%) compared to a 0% change in placebo-treated SCD mice. These data suggest that although lovastatin may protect vascular function in hypercholesterolemia, the inflammation and oxidative stress in sickle cell disease exceeds or prevents lovastatin’s purported pleiotrophic effect on arteriolar vasodilation. Thus in sickle cell disease, any increase in eNOS induced by lovastatin may be prone to dysfunction. In contrast, inhibiting xanthine oxidase released from ischemic tissues using allopurinol markedly increases vasodilation suggesting a dominant role for xanthine oxidase in inducing vascular dysfunction in sickle cell disease.

Retinal microvascular analysis using Fundus Fluorescein Angiography in Egyptian sickle cell disease patients

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Nayera H El Sherif ◽  
Mahmoud A Kenny ◽  
Waheed S Elhalfawy
Keyword(s):  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Fluorescein Angiography ◽  
Sickle Cell ◽  
Large Sample Size ◽  
Cell Disease ◽  
Fundus Fluorescein Angiography ◽  
Transfusion Therapy ◽  
Hydroxyurea Treatment ◽  
Trans Cranial Doppler

Abstract Background Sickle cell disease can affect retina of eye via vaso-occulsive changes that occur in micro-vessels of retina which could be analysed by using Fundus Fluorescein Angiography. Aim To analyze macular microvascular alternation in patients with SCD by Fundus Fluorescein Angiography (FFA) and to assess the role of potentially contributory Clinico-pathological factors including Trans-Cranial Doppler, genotypes, hydroxyurea, transfusion therapy and finally iron overload state on the development of macular alterations. Method This was across-sectional study which included 30 Sickle cell disease patients randomly recruited from the Paediatric Haematology clinic, children Hospital, Ain Shams University, Cairo, Egypt. Complete blood count (CBC), Trans-Cranial Doppler (TCD) and Fundus Fluorescein Angiography. Results In our study, there were 30 patients with mean age (14.1± 4.02), 5 patients had abnormal/conditional Trans-Cranial, 15 patients had Vaso-occlusive crises, 11 patients were on regular simple blood transfusion; all 30 studied sickle cell disease patients had normal Fundus Fluorescein Angiography and eye examination and only one patient hadabnormal visual acuity;A 29 years oldgirl who had five attacks of cerebral strokes last year, on regular simple blood transfusion and Hydroxyurea treatment with abnormal TCD and recurrent Vaso-occlusive crises in last two years, Although her vision is hand movement yet Fundus Fluorescein Angiography was normal. Conclusion we didn’t find any Retinal microvascular alternation in our studied SCD patients using Fundus Fluorescein Angiography, we related our results to the fact that our studied SCD patients were young and all our studied patients were on hydroxyurea therapy with fair compliance, further studies using large sample size are warranted in order to illustrate the utility of Fundus Fluorescein Angiography (FFA) as a tool for better detection of sickle retinopathy.

scholarly journals Hydroxyurea Treatment for Sickle Cell Disease

2002 ◽  
Vol 2 ◽  
pp. 1706-1728 ◽  
Author(s):  
Martin H. Steinberg
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Pharmacologic Therapy ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Globin Chains ◽  
Hydroxyurea Treatment ◽  
Erythroid Precursors

High fetal hemoglobin (HbF) levels inhibit the polymerization of sickle hemoglobin (HbS) and reduce the complications of sickle cell disease. Pharmacologic agents that can reverse the switch from γ- to β-chain synthesis — γ-globin chains characterize HbF, and sickle β-globin chains are present in HbS — or selectively increase the proportion of adult erythroid precursors that maintain the ability to produce HbF are therapeutically useful. Hydroxyurea promotes HbF production by perturbing the maturation of erythroid precursors. This treatment increases the total hemoglobin concentration, reduces the vaso-occlusive complications of pain and acute chest syndrome, and attenuates mortality in adults. It is a promising beginning for pharmacologic therapy of sickle cell disease. Still, its effects are inconsistent, trials in infants and children are ongoing, and its ultimate value — and peril — when started early in life are still unknown.

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