Hemopexin dosing improves cardiopulmonary dysfunction in murine sickle cell disease

Buehler, Paul W.; Swindle, Delaney; Pak, David; Ferguson, Scott K.; Majka, Susan M.; Karoor, Vijaya; Moldovan, Radu; Sintas, Chantal; Black, Jennifer Ann; Gentinetta, Thomas; Buzzi, Raphael M; Vallelian, Florence; Wassmer, Andreas; Edler, Monika; Bain, Joseph; Schu, Daniel; Hassell, Kathryn L.; Nuss, Rachelle; Schaer, Dominik J.; Irwin, David

doi:10.1016/j.freeradbiomed.2021.08.238

Cited by 11 publications

(14 citation statements)

References 48 publications

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“…Mice presented no pain or discomfort associated with hypoxia and were alert as well as eating, drinking, and grooming normally while housed. All experimental procedures were conducted under the guidelines recommended by The Journal of Physiology ( Buehler et al, 2021a ), the National Institutes of Health and were approved by the Institutional Animal Care and Use Committee at the University of Colorado, Denver, Anschutz Medical Campus (protocol no. 00218—“Vascular and organ effects of Cell free hemoglobin”).…”

Section: Methodsmentioning

confidence: 99%

“…Unmitigated oxidant stress to the erythrocyte ultimately triggers intravascular ( Kato et al, 2017 ) and extravascular hemolysis through splenic sequestration and erythrophagocytosis by the reticuloendothelial system ( Brousse et al, 2014 ). When chronic, this phenomenon promotes increases in splenic macrophage levels of iron, as well as in circulating levels of iron and heme ( Buehler et al, 2021a ; Buehler et al, 2021b ), all factors mediating cardiovascular ( Kato, 2012 ) and renal effects in the sickle cell population ( Gladwin et al, 2014 ). Low exercise capacity is observed in patients suffering from SCD, as gleaned by a 6 min walk test, a simple cardiopulmonary functional testing modality that allows for a non-specific, integrated assessment of the many systems involved during physical activity ( Matos Casano and Anjum, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Metabolic correlates to critical speed in murine models of sickle cell disease

Cendali

Nemkov²,

Lisk³

et al. 2023

Front. Physiol.

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Introduction: Exercise intolerance is a common clinical manifestation in patients with sickle cell disease (SCD), though the mechanisms are incompletely understood.Methods: Here we leverage a murine mouse model of sickle cell disease, the Berkeley mouse, to characterize response to exercise via determination of critical speed (CS), a functional measurement of mouse running speed upon exerting to exhaustion.Results: Upon observing a wide distribution in critical speed phenotypes, we systematically determined metabolic aberrations in plasma and organs—including heart, kidney, liver, lung, and spleen—from mice ranked based on critical speed performances (top vs. bottom 25%). Results indicated clear signatures of systemic and organ-specific alterations in carboxylic acids, sphingosine 1-phosphate and acylcarnitine metabolism. Metabolites in these pathways showed significant correlations with critical speed across all matrices. Findings from murine models were thus further validated in 433 sickle cell disease patients (SS genotype). Metabolomics analyses of plasma from 281 subjects in this cohort (with HbA < 10% to decrease confounding effects of recent transfusion events) were used to identify metabolic correlates to sub-maximal exercise test performances, as measure by 6 min walking test in this clinical cohort. Results confirmed strong correlation between test performances and dysregulated levels of circulating carboxylic acids (especially succinate) and sphingosine 1-phosphate.Discussion: We identified novel circulating metabolic markers of exercise intolerance in mouse models of sickle cell disease and sickle cell patients.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolic correlates to critical speed in murine models of sickle cell disease

Cendali

Nemkov²,

Lisk³

et al. 2023

Front. Physiol.

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“…Indeed, these cellular and molecular mechanisms have informed the current therapeutics usually used in patients with pulmonary hypertension such as endothelin receptor (ETR) antagonists (Bosentan, Ambrisetan), those which prevents the degradation of cyclic guanosine monophosphate (cGMP) (Riociguat and Sildenafil), vasodilators (Epoprostenol) and anticoagulant (warfarin) among others. Clinical trials using hemopexin, a scavenger molecule that removes heme from circulation are underway in humans and have shown promising results in murine models 65 Unfortunately, trials with ETR antagonists 66 , Riociguat 67 , and Sildenafil 68,69 were either limited by small sample size or adverse side effects respectively underscoring the need to better understand the pathology and larger clinical trials researching PH in SCD.…”

Section: Inflammation and Acute Chest Syndromementioning

confidence: 99%

The Role of Inflammation in the Cellular and Molecular Mechanisms of Cardiopulmonary Complications of Sickle Cell Disease

Gbotosho¹,

Gollamudi²,

Hyacinth³

2023

Preprint

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Cardiopulmonary complications remain the major cause of mortality despite newer therapies and improvements in lifespan of patients with sickle cell disease (SCD). Inflammation has been identified as a major risk modifier in the pathogenesis of SCD associated cardiopulmonary complications in recent mechanistic and observational studies. In this review, we discuss recent cellular and molecular mechanisms of cardiopulmonary complications in SCD and summarize the most recent evidence from clinical and laboratory studies. We emphasize the role of inflammation in the onset and progression of these complications to better understand the underlying pathobiological processes. We also discuss future basic and translational research in addressing questions about the complex role of inflammation in the development of SCD cardiopulmonary complications, which may lead to promising therapies and reduce morbidity and mortality in this vulnerable population.

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“…Therefore, no patients with COVID-19 pulmonary infection were included during this study period. Hemopexin (hx) level of pulmonary disease was associated with lung fibroproliferation [41,42], but the study lacked detection of hx.…”

Section: Table 3 Association Between Active CMV Infection and Pulmona...mentioning

confidence: 99%

Association between active cytomegalovirus infection and lung fibroproliferation in adult patients with acute respiratory distress syndrome: a retrospective study

Zhang

Chen

et al. 2022

BMC Infect Dis

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Background Cytomegalovirus (CMV) has high seroprevalence, and its active infection is associated with several adverse prognoses in adult patients with acute respiratory distress syndrome (ARDS). However, the role of active CMV infection in ARDS-associated fibroproliferation is unknown. This study aimed at determining the association between active CMV infection and lung fibroproliferation in adult patients with ARDS. Methods We retrospectively reviewed the medical records of all adult patients with ARDS who were admitted to the intensive care unit (ICU) from January 2018 to December 2020 at a national university-affiliated hospital in China. Study subjects were divided into active and non-active CMV infection groups based on CMV DNAemia within a 28-day ICU hospitalization. Lung fibroproliferation was measured using chest high-resolution computed tomography (HRCT) and N-terminal peptide of serum procollagen III (NT-PCP-III) within the first 28 days of ICU admission. Pulmonary fibrosis, clinical features, laboratory findings, treatment measures, and clinical outcomes were compared between the two groups. Results Among the 87 ARDS patients included in this study, the incidence of active CMV infection was 16.1% within the 28-day ICU admission period. In logistic regression analyze, active CMV infection was found to be associated with higher pulmonary fibrogenesis, pulmonary fibrosis score, and NT-PCP-III level (P < 0.05). The duration of ICU stay in ARDS patients with active CMV infection was significantly higher than in those without active CMV infection (P < 0.05). Conclusions Among adult patients with ARDS, active CMV infection was related to poor clinical outcomes. Active CMV infection was associated with ARDS-associated fibroproliferation. Prophylactic and preemptive use of anti-CMV agents on pulmonary fibrosis should be assessed to determine a consensus therapeutic strategy.

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Hemopexin dosing improves cardiopulmonary dysfunction in murine sickle cell disease

Cited by 11 publications

References 48 publications

Metabolic correlates to critical speed in murine models of sickle cell disease

Metabolic correlates to critical speed in murine models of sickle cell disease

The Role of Inflammation in the Cellular and Molecular Mechanisms of Cardiopulmonary Complications of Sickle Cell Disease

Association between active cytomegalovirus infection and lung fibroproliferation in adult patients with acute respiratory distress syndrome: a retrospective study

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