STUDYING FLOW-INDUCED PULMONARY HYPERTENSION AND COMPENSATORY LUNG GROWTH: INSIGHTS FROM A NOVEL MURINE MODEL
In the realm of pulmonary research, the search to understand complex lung conditions has led to the development of various animal models. Among these, a new murine model from Tsijis et al (2023) stands out for its potential to investigate flow-induced pulmonary hypertension (PH) and compensatory lung growth (CLG). This blog outlines this innovative model, its significance, and the method of measuring Total Lung Capacity (TLC) using the flexiVent system.
Developmental disorders like congenital diaphragmatic hernia (CDH) and congenital heart disease (CHD) often cause pulmonary complications such as defective alveolarization, pulmonary hypoplasia, and pulmonary arterial hypertension (PAH). These conditions are challenging to treat, highlighting the need for accurate animal models. To address this, researchers developed a murine model called extended pneumonectomy (EP), involving the simultaneous removal of the left lung and right caval lobe. This model reduces compensatory lung growth (CLG) and induces reproducible PH, making it valuable for studying cellular responses and molecular mechanisms in flow-induced PH.
Pulmonary function testing using the flexiVent system is crucial for measuring parameters like total lung capacity (TLC) to gain insights into lung health and compensatory mechanisms post-surgery. The flexiVent system employs a forced oscillation maneuver and a single-compartment model to measure inspiratory capacity and mechanical work of breathing (mWOB). To determine TLC, mice are ventilated with 100% oxygen for five minutes, followed by five minutes of tracheal tube occlusion to allow lung degassing and alveolar collapse. After euthanasia, the lungs are inflated and deflated through three rounds to generate pressure-volume curves, from which TLC is calculated using the Flexiware v8.3 software. The inspiratory capacity and TLC are then normalized to the mouse’s body weight for accurate assessment.
The EP model has demonstrated several advantages over traditional models:
- Efficiency and Reproducibility: The EP procedure is straightforward, does not require additional equipment, and can be completed within 20 minutes. This efficiency, coupled with high survival rates and minimal post-operative complications, underscores its reproducibility and reliability.
- Enhanced Study of PH and CLG: EP results in significant reductions in lung volume, inspiratory capacity, and TLC compared to traditional pneumonectomy (LP) and sham procedures. This persistence of lung disease makes it an excellent model for studying long-term pulmonary complications.
- Physiological Relevance: Increased mWOB and impaired exercise performance in EP mice closely mimic human pulmonary conditions, enhancing the model’s translational potential. Moreover, EP-induced PH is more severe than that observed in LP models, aligning closely with clinical observations.
- Histological Correlates: Morphometric analysis reveals decreased alveolarization and increased vascular remodeling in EP mice, providing a detailed understanding of the structural changes associated with PH and CLG.
The extended pneumonectomy model in mice offers a robust and reproducible method for studying compensatory lung growth and flow-induced pulmonary hypertension. By leveraging advanced tools like the flexiVent system to measure total lung capacity, researchers can gain invaluable insights into the underlying mechanisms of these conditions. This model holds promise for developing new therapeutic strategies for patients suffering from pulmonary hypoplasia and PAH, bridging the gap between preclinical research and clinical applications.
Reference:
A pneumonectomy model to study flow-induced pulmonary hypertension and compensatory lung growth. (2023). Tsijis, S.T. et al. Cell Reports Methods, 3, 100613
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