Cytoprotective Mechanisms of the Lung in Sickle Cell Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1538-1538
Author(s):  
Samit Ghosh ◽  
Fang Tan ◽  
Mario Monsunjac ◽  
Solomon F Ofori-Acquah
Keyword(s):  
Sickle Cell Disease ◽  
Lung Disease ◽  
Sickle Cell ◽  
Chronic Lung Disease ◽  
Mrna Level ◽  
Normal Lung ◽  
Mononuclear Leukocytes ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
Cytoprotective Enzymes

Abstract Abstract 1538 Poster Board I-561 Circulating plasma hemoglobin contributes to major vasculopathies including pulmonary hypertension in patients who have sickle cell disease (SCD). There is an emerging concept that such vasculopathies are relatively mild because of activation of several cytoprotective pathways in SCD. The biochemical profile of plasma and the transcriptome of peripheral blood cells in patients who have SCD offer indirect support for this concept. Indeed, heme oxygenase-1 (HO-1), an acute phase enzyme that degrades heme into intermediates and byproducts with vasculoprotective properties is markedly elevated in mononuclear leukocytes of patients who have SCD. Nonetheless, the scope of the cytoprotective mechanisms of the lung and other organs impacted directly by sickle vasculopathies remain poorly appreciated. We previously identified an array of cytoprotective enzymes in lung endothelial cells chronically exposed to non-toxic concentrations of hemin in vitro. In this study, we examined the expression of NAD(P)H oxidase and candidate cytoprotective enzymes in two models of transgenic mice with SCD, and examined HO-1 expression in sickle chronic lung disease. Although NAD(P)H oxidase catalyzes reactive oxygen species generation by heme and is responsible for increased adhesion of leukocytes to the endothelium in SCD mice, there was no elevation of any of its subunits (gp91Phox and p22Phox, p47Phox, p67Phox and p40 Phox) in sickle mice lungs compared to hemizygote control mice lungs. Quantitative RT-PCR analysis revealed unexpectedly no difference in HO-1 mRNA level in sickle and non-sickle control lungs. On the contrary, analysis of the same tissues showed significantly higher NAD(P)H quinone oxidoreductase-1 (NQO1) mRNA level in both Berkeley and Townes knock-in sickle mice compared to controls (p<0.001). Enhanced expression of NQO1 but not HO-1 in sickle mice lungs was confirmed at the protein level by western blot analysis and by immunohistochemistry. Finally, we studied cases of sickle chronic lung disease (n=17) and discovered that NQO1 is expressed in the pulmonary endothelium at significantly higher levels than in normal lung tissues (p<0.002). In agreement with the data in mice, we found no difference in HO-1 staining in sickle human lung and normal lung tissues. Our findings indicate that despite its established role in acute elimination of excess heme, HO-1 is not elevated in sickle lungs. This study highlights the importance of dissecting the cytoprotective phenotype of individual organs impacted by SCD towards a rationale approach to developing efficacious antioxidant therapy for this disorder. Disclosures No relevant conflicts of interest to declare.

Clinicopathological Correlations in Chronic Sickle Cell Lung Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1667-1667 ◽  
Author(s):  
Elizabeth A. Manci
Keyword(s):  
Sickle Cell Disease ◽  
Lung Disease ◽  
Sickle Cell ◽  
Chronic Lung Disease ◽  
Interstitial Fibrosis ◽  
Clinical Stage ◽  
Cell Disease ◽  
Diffusion Capacity ◽  
Histopathologic Findings ◽  
Tortuosity Of Capillaries

Abstract Chronic lung injury is a major cause of morbidity and mortality in sickle cell disease. Although this pulmonary injury appears to be progressive and the etiology is multifactorial, the pathogenesis is incompletely understood. Study of the histopathologic changes can be useful as evidence of the underlying pathophysiology, especially if correlated with the clinical stage of the disease. HYPOTHESIS: The histopathology of the lung in sickle cell disease varies with the clinical stage of chronic lung disease. METHODS: Medical records and autopsy reports from 324 archived autopsies of homozygous sickle cell disease were reviewed and each case was assigned a clinical severity score that ranged from 0 (no pulmonary dysfunction) to 3 (severe pulmonary dysfunction). Histologic sections from these cases were then studied in a masked manner and findings were subjectively graded on a scale of 0 (absent) to 4+ (severe). The histopathologic findings were then correlated with the clinical stage of the lung disease, using Pearson’s correlation coefficients and coefficient of determinations. RESULTS: The frequency of some histopathologic findings showed a positive correlation with the increasing severity of the clinical stage of the disease, including age (r = 0.92; R2 = 0.85), vascular intimal hyperplasia (r = 0.74; R2 = 0.55), vascular medial hyperplasia (r = 0.87; R2 = 0.76), dilation of capillary plexi (r = 0.98; R2 = 0.96) and interstitial fibrosis (r = 0.78; R2 = 0.61). Scoring of the severity of the histopathologic findings suggested a pattern of progression of the morphologic injury. The earliest evidence of injury seen during infancy consisted of focal disruption of alveolar septae with hemorrhages and interstitial fibrosis (1+). These findings were more pronounced during childhood (2+) when asymptomatic restrictive defects were reported, but capillary diffusion capacity remained normal. During adolescence, these findings were well defined (3+) along with increased tortuosity of capillaries, dilation of capillary plexi and intimal hyperplasia of medium-size vessels. In adulthood, these findings were most pronounced (4+) and were accompanied by episodic dyspnea. Obliterative vasculopathy was seen almost exclusively in cases with clinical pulmonary hypertension. At end stage there appeared to be less intra-alveolar hemorrhage and edema. DISCUSSION: These findings strongly suggest that the earliest evidence of chronic sickle lung disease is injury to capillaries and to pre- and post-capillary vessels. This early injury appears to be followed by increased tortuosity of capillaries, dilation of collateral vessels and then changes in larger arterial vessels. Interstitial fibrosis was seen in cases with restrictive defects. Increased capillary surface area secondary to tortuosity of capillaries probably accounts for the clinical evidence of normal diffusion capacity. These findings support the clinical evidence that sickle cell chronic lung disease is progressive. Furthermoore, this study strongly suggests that sickle chronic lung disease follows a pattern of injury and remains asymptomatic until the pulmonary architecture has undergone considerable remodeling. These findings help explain the stealthy way in which sickle cell disease steals the pulmonary reserve.

scholarly journals Heterogeneity of respiratory disease in children and young adults with sickle cell disease

Thorax ◽  
2017 ◽  
Vol 73 (6) ◽  
pp. 575-577 ◽  
Author(s):  
Alan Lunt ◽  
Lucy Mortimer ◽  
David Rees ◽  
Sue Height ◽  
Swee Lay Thein ◽  
...  
Keyword(s):  
Young Adults ◽  
Sickle Cell Disease ◽  
Lung Disease ◽  
Respiratory Disease ◽  
Sickle Cell ◽  
Elevated Serum ◽  
Serum Lactate Dehydrogenase ◽  
Cell Disease ◽  
Restrictive Lung Disease ◽  
Children And Young Adults

To detect and characterise different phenotypes of respiratory disease in children and young adults with sickle cell disease (SCD), 11 lung function and haematological biomarkers were analysed using k-means cluster analysis in a cohort of 114 subjects with SCD aged between 5 and 27 years. Three clusters were detected: cluster 1 had elevated pulmonary capillary blood volume, mixed obstructive/restrictive lung disease, hypoxia and moderately severe anaemia; cluster 2 were older patients with restrictive lung disease; and cluster 3 were younger patients with obstructive lung disease, elevated serum lactate dehydrogenase and bronchodilator reversibility. These results may inform more personalised management strategies to improve outcomes.

scholarly journals Role of heme oxygenase 1 in cardiac ferroptosis in sickle cell disease

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Archita Venugopal Menon ◽  
Hanting Tsai ◽  
Seungjeong Yang ◽  
Jonghan Kim
Keyword(s):  
Sickle Cell Disease ◽  
Heme Oxygenase ◽  
Sickle Cell ◽  
Heme Oxygenase 1 ◽  
Cell Disease

scholarly journals Hemolysis Inhibits Humoral B Cell Responses and Modulates Alloimmunization Risk in Patients with Sickle Cell Disease

Blood ◽  
2020 ◽  
Author(s):  
Mouli Pal ◽  
Weili Bao ◽  
Rikang Wang ◽  
Yunfeng Liu ◽  
Xiuli An ◽  
...  
Keyword(s):  
B Cells ◽  
Sickle Cell Disease ◽  
B Cell ◽  
Sickle Cell ◽  
Cell Response ◽  
Cell Activity ◽  
Immunomodulatory Activity ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
B Cell Response

Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely unknown. Intravascular hemolysis, a hallmark of SCD, results in the release of heme with potent immunomodulatory activity, although its effect on SCD humoral response, specifically alloimmunization, remains unclear. Here, we found that cell-free heme suppresses human B cell plasmablast/plasma cell differentiation by inhibiting the DOCK8/STAT3 signaling pathway, which is critical for B cell activation, as well as by upregulating heme oxygenase 1 (HO-1) through its enzymatic byproducts, carbon monoxide and biliverdin. Whereas non-alloimmunized SCD B cells were inhibited by exogenous heme, B cells from the alloimmunized group were non-responsive to heme inhibition and readily differentiated into plasma cells. Consistent with a differential B cell response to hemolysis, we found elevated B cell basal levels of DOCK8 and higher HO-1-mediated inhibition of activated B cells in non-alloimmunized compared to alloimmunized SCD patients. To overcome the alloimmunized B cell heme insensitivity, we screened several heme-binding molecules and identified quinine as a potent inhibitor of B cell activity, reversing the resistance to heme suppression in alloimmunized patients. B cell inhibition by quinine only occurred in the presence of heme and through HO-1 induction. Altogether, these data suggest that hemolysis can dampen the humoral B cell response and that B cell heme responsiveness maybe a determinant of alloimmunization risk in SCD. Quinine by restoring B cell heme sensitivity may have therapeutic potential to prevent and inhibit alloimmunization in SCD patients.

scholarly journals Impairment of neutrophil oxidative burst in children with sickle cell disease is associated with heme oxygenase-1

Haematologica ◽  
2015 ◽  
Vol 100 (12) ◽  
pp. 1508-1516 ◽  
Author(s):  
C. Evans ◽  
K. Orf ◽  
E. Horvath ◽  
M. Levin ◽  
J. De La Fuente ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Heme Oxygenase ◽  
Sickle Cell ◽  
Oxidative Burst ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
Neutrophil Oxidative Burst

Arterial Hypoxemia Syndrome in Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3801-3801
Author(s):  
Patricia Adams-Graves ◽  
M. Muthiah ◽  
G. Presbury ◽  
G. Somes ◽  
K. Lamar
Keyword(s):  
Mechanical Ventilation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Normal Lung ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
X Ray ◽  
Arterial Hypoxemia ◽  
Arterial Blood ◽  
Chest X Ray

Abstract Acute chest syndrome (ACS) is the most common cause of death during hospitalization of adults with sickle cell disease (SCD). ACS includes symptoms referable to the chest and a new infiltrate on chest X-ray. Adults over age 20 years have more symptoms of the disease and are at increased risk of early death compared to children. ACS may be the presenting diagnosis for a patient with SCD, but equally as often, develops while the patient has a painful vascular occlusive crisis. Notably, 35% of SCD patients have a normal lung exam upon presentation to the hospital. Previous research studies indicate that nearly three-fourths of SCD patients who die present during painful crises in an extremity, and about 50% conclusively by autopsy died of massive fat embolism syndrome (FES). Unfortunately, definitive diagnostic tests with rapid turn-around for FES and other acute vascular occlusive lung events do not exist. Earlier identification of the danger that this event may be evolving can be life saving. Clinicians who adhere to the strict definition of ACS may prematurely dismiss the likelihood of a subsequent fatal event. This alarming rate of adverse events may represent a “pre-chest syndrome” prodromal phase of ACS. Arterial hypoxemia syndrome (AHS) or pre-chest syndrome is defined as any sign or symptom referable to the chest, an oxygen saturation (Sp02) of &lt;94% by direct pulse oximeter or a Pa02 &lt;80% by arterial blood gas on room air plus a clear chest X-ray with or without fever. AHS may be a warning sign of an ultimately fatal event if earlier interventions are not done in a timely manner. A secondary data analysis was performed utilizing 500 health records of SCD patients from 1960 to 2004. Prior to 2003, we averaged 2 to 3 ICU admissions per month for ACS with about 20% requiring mechanical ventilation. This study sought to gain insight on 45 years of experience in the treatment of SCD, particularly “pre-chest syndrome.” The primary aims of the study were to devise treatment protocols to reduce ICU admissions and the need for mechanical ventilation in SCD patients presenting with AHS. Retrospective analysis suggests that earlier blood exchanges for patients with SCD may substantially reduce ICU admissions and the need for mechanical ventilation in patients presenting with AHS, compared with patients receiving standard supportive care. Examination of computerized hospital records of 437 sickle cell hospital admissions from January 2003 to March 2005 revealed 3 ICU and 2 step-down unit admissions. During this time period, there were 101 chest syndrome occurrences, of which 2 died. Both patients required mechanical ventilation and underwent red cell apheresis to reduce hemoglobin S to &lt;30%. One patient was admitted due to major trauma from a motor vehicle accident. Death was due to multi-organ failure. The medical condition of the second patient improved. This patient was discharged home in stable condition but died, unexpectedly, 48 hours at home of a massive pulmonary embolus. A protocol has been developed to prospectively evaluate our aims.

Protective Effect of Fetal Hemoglobin On Inflammation-Induced Expression of Hypoxia-Inducible Factor-1α (HIF-1α) in Sickle Mice: Microvascular Implications

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3250-3250
Author(s):  
Dhananjay K. Kaul ◽  
Mary E. Fabry ◽  
Sandra M Suzuka ◽  
Janki Shah
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Hypoxia Inducible Factor ◽  
Heme Oxygenase 1 ◽  
No Production ◽  
Cell Disease ◽  
Activation Markers ◽  
No Bioavailability

Abstract Abstract 3250 Chronic inflammation is a salient feature of human sickle cell disease (SCD) and transgenic-knockout sickle (BERK) mouse model. Although tissue ischemia is the primary instigator of hypoxia-inducible factor (HIF) activation, a number of inflammatory factors/pathways and oxidative stress can potentially induce expression of HIF-1α. Increased oxidative stress and inflammation are implicated in the activation of HIF-1α under normoxic conditions. HIF can trigger transcription of genes for vasoactive molecules such as vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1) and endothelin, which are implicated in the pathophysiology of SCD. We hypothesize that, in SCD, inflammation coupled with nitric oxide (NO) depletion will induce expression of HIF-1α. To this end, we have examined the expression of HIF-1α in normoxic BERK mice expressing exclusively human α- and βS- globins, and evaluated the effect of HbF in BERK mice (i.e., <1.0%, 20% and 40% HbF). We have previously shown that HbF exerts anti-sickling and anti-inflammatory effects (Kaul et al. J Clin Invest, 2004; Dasgupta et al. Am J Physiol, 2010). Here, we show that HIF-1α is expressed in BERK mice under normoxic conditions (i.e., normal hemoglobin oxygen saturation levels). In BERK mice expressing HbF, HIF-1α expression decreased concomitantly with increasing HbF, commensurately with increased NO bioavailability, and showed a strong inverse correlation with plasma NO metabolites (NOx) levels. Reduced HIF-1α expression in BERK mice expressing HbF was associated with decreased HO-1 and VEGF expression, and reduced serum endothelin-1 (ET-1) levels, which are among the target vasoactive molecules of HIF-1α. Furthermore, the commensurate decrease in HIF-1α expression with increase in HbF levels in BERK mice was accompanied by a distinct decrease in soluble (s) forms of endothelial activation markers such as sP-selectin and vascular cell adhesion molecule-1 (sVCAM-1). Notably, arteriolar dilation, enhanced volumetric blood flow and low blood pressure in normoxic BERK mice all showed a trend toward normalization with the introduction of HbF. Also, arginine treatment reduced HIF-1α expression as well as ET-1 levels in normoxic BERK mice, supporting a role of decreased NO bioavailability in HIF-1α activation. The present in vivo studies show that reduced inflammation and increased NO production in normoxic BERK mice (expressing HbF or treated with arginine) are distinctly associated with suppression of HIF-1α activation and inhibition of vasodilators, resulting in improved microvascular and hemodynamic parameters in the BERK model of sickle cell disease. The unique feature of inflammation in SCD is that it can be ameliorated by increased HbF, thereby coupling HbS polymerization/sickling to NO depletion, HIF-1α expression and inflammation in this disease. Disclosures: No relevant conflicts of interest to declare.

Induction Of Ferroportin, Erg-1, p21 and IKBα In Sickle Cell Disease May Contribute To HIV-1 Inhibition

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2250-2250
Author(s):  
Sergei A Nekhai ◽  
Namita Kumari ◽  
Denitra Breuer ◽  
Charlee Mclean ◽  
Tatiana Ammosova ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Enzymatic Activity ◽  
Sickle Cell ◽  
Iron Chelators ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
Regulatory Pathways ◽  
Cyclin T1 ◽  
Cellular Iron ◽  
Hiv 1

Abstract Background Hypoxia and low iron induce hypoxia-induced factor 1(HIF-1) by stabilizing its alpha subunit and deregulate HIV-1 which transcription and several other steps of life cycle depend on cellular iron [1]. HIV-1 transcription is inhibited at low oxygen levels and reduced cellular iron through deregulation of CDK9/cyclin T1 and CDK2/cyclin E. Sickle cell disease has low odds of ratio for HIV-1 infection [2]. Sickle cell disease (SCD) leads to hemolytic anemia which results in local ischemia and release of heme. Induction of heme oxygenase-1 (HO-1) by hemin was shown to inhibit HIV-1 [1], although the mechanism of the inhibition was not clarified. Iron depletion by iron chelators or through the expression of ferroportin, an iron export protein, inhibits CDK2 and CDK9 activities and blocks HIV-1 transcription [1]. Because neither CDK2 nor CDK9 require iron for the enzymatic activity, we analyzed the expression of hypoxia and iron –dependent factors that may deregulate HIV-1 infection in SCD. Results Expression profiling followed by real-time PCR analysis showed induction of HO-1, p21, Erg-1, IKBα, HIF-1 and ferroportin mRNA and decrease of hepcidin mRNA in PBMCs from SCD patients. HIV-1 replication was reduced in SCD PBMCs comparing to normal controls, and also in THP1 cells treated with hemin. Subsequent treatment with hepcidin restored HIV-1 replication in SCD PBMC and in hemin-treated THP-1 cells, suggesting that ferroportin played a key role in the HIV-1 inhibition in these settings. Stable ferroportin knock down in THP-1 cells led to the inability of hemin to inhibit HIV-1, suggesting that ferroportin played a key role in the heme-meidated HIV-1 inhibition. Stable HIF-1a knockdown in promonocytic THP1 cells increased HIV replication suggesting that HIF1α is a restriction factor for HIV-1. Iron chelators induced the expression of IKBα, an inhibitor of NF-kB and also induced the expression of HIF-1 and p21. Iron chelators also inhibited enzymatic activity of CDK2 and shifted CDK9/cyclin T1 from the large to the small complex making it unavailable for HIV-1 Tat recruitment. Hemin treatment induced expression of HO-1, ferroportin, IkBα, HIF1α and p21 thus mimicking the effect of iron chelators. Conclusions Hemolytic conditions of sickle cell disease upregulate hypoxia and iron regulatory pathways leading to refraction of HIV-1. Targeting cellular iron, ferroportin and HO-1 may lead to novel anti-HIV-1 therapeutics. Acknowledgments This project was supported by NIH Research Grants 1SC1GM082325, 2G12RR003048, and P30HL107253. References 1. Nekhai S, Kumari N, Dhawan S: Role of cellular iron and oxygen in the regulation of HIV-1 infection. Future Virol 2013, 8(3):301-311. 2. Nouraie M, Nekhai S, Gordeuk VR: Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in U.S. hospital discharge records: a cross-sectional study. Sex Transm Infect 2012, 88(7):528-533. Disclosures: No relevant conflicts of interest to declare.

Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2451-2459 ◽  
Author(s):  
John D. Belcher ◽  
Paul H. Marker ◽  
Jill P. Weber ◽  
Robert P. Hebbel ◽  
Gregory M. Vercellotti
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Nuclear Translocation ◽  
Mononuclear Leukocytes ◽  
Cell Contact ◽  
Cell Disease ◽  
Tnf Α ◽  
Activated Monocytes

Sickle cell anemia is characterized by painful vaso-occlusive crises. It is hypothesized that monocytes are activated in sickle cell disease and can enhance vaso-occlusion by activating endothelium. To test this hypothesis, human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (MVEC) with sickle and normal mononuclear leukocytes were incubated, and endothelial activation was measured. Endothelial cells incubated with sickle mononuclear leukocytes were more activated than those incubated with normal mononuclear leukocytes, as judged by the increased endothelial expression of adhesion molecules and tissue factor and the adhesion of polymorphonuclear leukocytes (PMNL). Monocytes, not lymphocytes or platelets, were the mononuclear cells responsible for activating endothelial cells. Sickle monocytes triggered endothelial nuclear factor-kappa B (NF-κB) nuclear translocation. Cell-to-cell contact of monocytes and endothelium enhanced, but was not required for, activation. Antibodies to tumor necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) blocked activation of the endothelium by monocytes. Peripheral blood monocytes from patients with sickle cell disease had 34% more IL-1β (P = .002) and 139% more TNF-α (P = .002) per cell than normal monocytes. Sixty percent of sickle monocytes expressed the adhesion molecule ligand CD11b on their surfaces compared with only 20% of normal monocytes (P = .002). Serum C-reactive protein, a marker of systemic inflammation, was increased 12-fold in sickle serum than in normal serum (P = .003). These results demonstrate that sickle monocytes are activated and can, in turn, activate endothelial cells. It is speculated that vascular inflammation, marked by activated monocytes and endothelium, plays a significant role in the pathophysiology of vaso-occlusion in sickle cell anemia.

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