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Molecular mechanisms of hepatic dysfunction in sickle cell disease: lessons from Townes mouse model
Tirthadipa Pradhan-Sundd1,2, Gregory J Kato3, Enrico M Novelli1,2
1Pittsburgh Heart, Liver and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Insights
Sickle cell disease (SCD) causes liver injury through sickling and inflammation. This review explores SCD liver disease mechanisms and therapies using the Townes mouse model.
Area of Science:
- Genetics and Medicine
- Hematology
- Hepatology
Background:
- Sickle cell disease (SCD) is a prevalent genetic disorder affecting millions globally.
- Liver injury is a common complication in SCD, impacting 10%-40% of patients.
- Current therapeutic strategies for SCD-associated liver injury are limited, and underlying mechanisms are poorly understood.
Purpose of the Study:
- To review the molecular mechanisms of liver injury in SCD.
- To explore potential therapeutic options for SCD-related liver dysfunction.
- To highlight the utility of the Townes mouse model in SCD research.
Main Methods:
- Literature review focusing on SCD pathophysiology and liver disease.
- Analysis of data from the Townes mouse model of SCD.
- Examination of molecular pathways involved in SCD-induced liver damage.
Main Results:
- Key pathophysiological pathways in SCD liver injury include erythrocyte sickling, vaso-occlusion, sterile inflammation, and hemolysis.
- Humanized animal models, such as the Townes mouse, offer valuable insights into SCD-related liver diseases.
- Understanding molecular mechanisms is crucial for developing targeted therapies.
Conclusions:
- The Townes mouse model is instrumental in studying SCD-associated liver dysfunction.
- Further research into molecular mechanisms may reveal novel therapeutic targets.
- Developing effective treatments for SCD liver injury remains a critical unmet need.
Abstract:
Sickle cell disease (SCD) is an autosomal recessive genetic disorder that affects ∼100,000 Americans and millions of people worldwide. Erythrocyte sickling, vaso-occlusion, sterile inflammation, and hemolysis are the major pathophysiological pathways leading to liver injury in SCD. Although hepatic dysfunction affects up to 10%-40% of patients with SCD, therapeutic approaches to prevent liver injury in SCD are not known, and the molecular mechanisms promoting progressive liver injury in SCD remain poorly understood. Animal models have been beneficial in bridging the gap between preclinical and translational research in SCD. Recent advances in methodology have allowed the development of several humanized animal models to address various aspects of SCD-related liver diseases. This review provides an overview of current knowledge of the molecular mechanisms and potential therapeutic options of SCD-associated liver dysfunction using the Townes mouse model.
