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Pathophysiological characterization of the townes mouse model for sickle cell disease

Published:October 30, 2022DOI:https://doi.org/10.1016/j.trsl.2022.10.007

      Abstract

      A deeper pathophysiologic understanding of available mouse models of sickle cell disease (SCD), such as the Townes model, will help improve preclinical studies. We evaluated groups of Townes mice expressing either normal adult human hemoglobin (HbA), sickle cell trait (HbAS), or SCD (HbS), comparing younger versus older adults, and females versus males. We obtained hematologic parameters in steady-state and hypoxic conditions and evaluated metabolic markers and cytokines from serum. Kidney function was evaluated by measuring the urine protein/creatinine ratio and urine osmolality. In vivo studies included von Frey assay, non-invasive plethysmography, and echocardiography. Histopathological evaluations were performed in lung, liver, spleen, and kidney tissues. HbS mice displayed elevated hemolysis markers and white blood cell counts, with some increases more pronounced in older adults. After extended in vivo hypoxia, hemoglobin, platelet counts, and white blood cell counts decreased significantly in HbS mice, whereas they remained stable in HbA mice. Cytokine analyses showed increased TNF-alpha in HbS mice. Kidney function assays revealed worsened kidney function in HbS mice. The von Frey assay showed a lower threshold to response in the HbS mice than controls, with more noticeable differences in males. Echocardiography in HbS mice suggested left ventricular hypertrophy and dilatation. Plethysmography suggested obstructive lung disease and inflammatory changes in HbS mice. Histopathological studies showed vascular congestion, increased iron deposition, and disruption of normal tissue architecture in HbS mice. These data correlate with clinical manifestations in SCD patients and highlight analyses and groups to be included in preclinical therapeutic studies.

      Abbreviations:

      ALP (alkaline phosphatase), ALT (alanine-aminotransferase), AST (aspartate-aminotransferase), BL/6 (C57BL/6), BUN (blood-urea nitrogen), CO (cardiac output), DBIL (direct bilirubin), EDTA (ethylenediaminetetraacetic acid), EDV (end-diastolic volume), EEP (end-expiratory pause), EIP (end-inspiratory pause), ESV (end-systolic volume), GGT (gamma-glutamyl transferase), H&E (hematoxylin and eosin stain), Hb (hemoglobin), HbA (adult hemoglobin), HbF (fetal hemoglobin), HbS (sickle hemoglobin), HR (heart rate), IBIL (indirect bilirubin), IL (interleukin), IVSs (interventricular septum thickness in systole), LDH (lactate dehydrogenase), LLoQ (lower limit of quantification), LV (left ventricle), LVEF (left ventricle ejection fraction), LVFS (left ventricle fractional shortening), LVIDd/s (left ventricle internal diameter in diastole/systole), LVPWd/s (left ventricle posterior wall thickness in diastole/systole), MCV (mean corpuscular volume), MCW (Medical College of Wisconsin), MV (minute ventilation), PEF (peak-expiratory flow), PIF (peak-inspiratory flow), Plt (platelets), Rpef (ratio of time to peak expiratory flow over total expiratory time), QC (quality control), RF (frequency), SCD (sickle cell disease), TBIL (total bilirubin), Te (time of expiration), Ti (time of inspiration), TNF (tumor necrosis factor), TV (tidal volume), WBC (white blood cell count)
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