A Mouse Model of Neonatal Continuous Positive Airway Pressure Administration and the Precision Lung Slice Method for Measuring Airway Contractility

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Abstract
Mechanical forces associated with positive-pressure respiratory support used in the intensive care of preterm infants can have both positive and inadvertent consequences for lung development. Positive pressure support improves pulmonary gas exchange, limits atelectasis, and improves systemic oxygenation, but the injurious effects of invasive modalities, such as mechanical ventilation, on lung development are also well known. However, there are major gaps in our understanding of the adverse effects of less invasive forms of ventilation. Here, continuous positive airway pressure (CPAP) is one of the most common respiratory support modalities, representing the least invasive of the positive pressure spectrum. A major limitation in studying human airway development is the lack of age-appropriate models and the ability to administer CPAP to small neonatal animals. We resolved this problem by developing a mouse model of neonatal CPAP delivered daily to awake, un-anesthetized newborn mice -- a model that utilizes clinically relevant CPAP levels at a stage of mouse lung development that corresponds with preterm infants when they are likely to receive CPAP in the ICU. Here, we demonstrate our CPAP model, which includes a convenient, custom-designed system that can deliver CPAP non-invasively to the un-anesthetized newborn with easily adjustable levels. We also provide a demonstration of the precision cut lung slice method for the measurement of airway hyperreactivity ex vivo. The PCLS is described here because it provides a convenient functional readout of the pulmonary system, which can be technically challenging in small (neonatal) animal models, and also has wide applicability to other models unrelated to CPAP. We show data demonstrating that CPAP elicits airway hyperreactivity, which may have important clinical implications for the choice of respiratory support modality in the intensive care of preterm infants.

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