Cardiorespiratory pathogenesis of sickle cell disease in a mouse model

Area of Science:

• Cardiorespiratory pathophysiology
• Animal models of human disease
• Sickle cell disease research

Background:

• Cardiorespiratory impairments in sickle cell disease (SCD) are not well understood.
• Clinical studies have limitations in investigating SCD pathophysiology from birth to maturity.
• The SAD mouse model offers a platform to study SCD-related cardiorespiratory issues.

Purpose of the Study:

• To characterize cardiorespiratory pathophysiology in the SAD mouse model from birth to adulthood.
• To identify critical phases of respiratory dysfunction in SAD mice.
• To understand the mechanisms underlying cardiorespiratory complications in SCD.

Main Methods:

• Longitudinal characterization of cardiorespiratory function in SAD mice from birth to maturity.
• Assessment of respiratory patterns, lung histology, and response to hypoxia.
• Evaluation of exercise capacity and cardiac function in adult SAD mice.

Main Results:

• Two critical phases of respiratory dysfunction were identified: pre-weaning and adulthood.
• Early-life SAD mice exhibited apneas, anemia, and pulmonary congestion, with high mortality.
• Adult SAD mice showed tachypnea, restrictive lung disease, pulmonary hypertension, cardiac enlargement, and impaired exercise capacity and hypoxic response.

Conclusions:

• The SAD mouse model recapitulates key cardiorespiratory complications seen in human sickle cell disease.
• Distinct subgroups of SAD mice exhibit varying cardiorespiratory phenotypes.
• This model provides valuable insights into the developmental trajectory of cardiorespiratory impairments in SCD.