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Updated: Aug 26, 2025
Mouse Pneumonectomy Model of Compensatory Lung Growth
Published on: December 17, 2014
Effects of systemic anticoagulation in a murine model of compensatory lung growth
Lumeng J Yu1,2, Victoria H Ko1,2, Savas T Tsikis1,2
1Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Insights
Unfractionated heparin and low molecular weight heparin impair lung growth and exercise tolerance in mice. Bivalirudin, an alternative anticoagulant, preserves lung development and function, suggesting its potential for neonates with pulmonary hypoplasia.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Pharmacology
Background:
- Neonates with congenital diaphragmatic hernia (CDH) often develop pulmonary hypoplasia (PH) and require anticoagulation.
- Unfractionated heparin (UFH) is commonly used but may interfere with vascular endothelial growth factor (VEGF), crucial for lung development.
Purpose of the Study:
- To investigate the impact of unfractionated heparin (UFH), low molecular weight heparin (LMWH), and bivalirudin (BV) on compensatory lung growth (CLG) in a murine model.
- To assess the effects of these anticoagulants on lung development, function, and exercise tolerance.
Main Methods:
- Assessed proliferation and apoptosis in lung endothelial cells treated with anticoagulants.
- Utilized a murine model of left pneumonectomy followed by anticoagulation with UFH, LMWH, BV, or saline control.
- Evaluated lung volume, pulmonary function, morphometrics, exercise tolerance, and protein expression.
Main Results:
- UFH and LMWH inhibited endothelial cell proliferation and reduced lung volume, alveolarization, and exercise tolerance.
- Bivalirudin (BV) promoted proliferation, decreased apoptosis, and did not negatively impact lung measures or exercise capacity.
- BV preserved lung volume, alveolarization, and exercise tolerance in the murine CLG model.
Conclusions:
- UFH and LMWH negatively affect compensatory lung growth, alveolarization, and exercise tolerance.
- Bivalirudin demonstrates a potential to improve functional outcomes by preserving lung development and function.
- Alternative anticoagulants like bivalirudin warrant further investigation for neonates with PH to optimize lung development and clinical outcomes.
Background:
Neonates with congenital diaphragmatic hernia (CDH) suffer from pulmonary hypoplasia (PH) and may require extracorporeal membrane oxygenation (ECMO) and anticoagulation, often with unfractionated heparin (UFH). UFH interacts with vascular endothelial growth factor (VEGF), a factor important in lung development. We investigated the effects of UFH, low molecular weight heparin (LMWH), and bivalirudin (BV) on a murine model of compensatory lung growth (CLG).
Methods:
Proliferation and apoptosis were assessed in microvascular lung endothelial cells (HMVEC-L) treated with anticoagulants. Eight-week-old C57Bl/6J mice underwent left pneumonectomy and anticoagulation with low- or high-dose UFH, LMWH, BV, or saline control. Lung volume, pulmonary function tests, morphometrics, treadmill exercise tolerance, and pulmonary protein expression were examined.
Results:
UFH and LMWH inhibited HMVEC-L proliferation. BV promoted proliferation and decreased apoptosis. UFH and LMWH-treated mice had reduced lung volume, total lung capacity, alveolar volume, and septal surface area compared to controls, while BV did not affect these measures. UFH and LMWH-treated mice had lower exercise tolerance compared to controls.
Conclusions:
UFH and LMWH impair pulmonary growth, alveolarization, and exercise tolerance, while BV does not. Alternative anticoagulants to heparin may be considered to improve functional outcomes for neonates with CDH and pulmonary hypoplasia.
Impact:
Unfractionated heparin and low molecular weight heparin may modify compensatory lung growth by reducing microvascular lung endothelial cell proliferation and affecting pulmonary angiogenic signaling. Functional effects of unfractionated heparin and low molecular weight heparin on murine compensatory lung growth include reduction in exercise tolerance. Bivalirudin, a direct thrombin inhibitor, may increase microvascular lung endothelial cell proliferation and preserves lung volume, alveolarization, and exercise tolerance in a murine compensatory lung growth model. Anticoagulants alternative to heparin should be further investigated for use in neonates with pulmonary hypoplastic diseases to optimize lung growth and development and improve outcomes.
