Pathophysiological characterization of the Townes mouse model for sickle cell disease. Transl Res 2023 Apr;254:77-91
Date
11/03/2022Pubmed ID
36323381DOI
10.1016/j.trsl.2022.10.007Scopus ID
2-s2.0-85145313487 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
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.
Author List
Alvarez-Argote J, Dlugi TA, Sundararajan T, Kleynerman A, Faber ML, McKillop WM, Medin JAAuthors
Juliana Alvarez Argote MD Assistant Professor in the Medicine department at Medical College of WisconsinJeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AgedAnemia, Sickle Cell
Animals
Cytokines
Female
Hemoglobin, Sickle
Hemoglobins
Hemolysis
Humans
Liver
Male
Mice
Sickle Cell Trait
