Assessment of pulmonary function in a mouse model of bronchopulmonary dysplasia by unrestrained whole body plethysmography and the forced oscillation technique.

Abstract

Animal models of bronchopulmonary dysplasia (BPD) have allowed the discovery of pathological and disease-management pathways. The laboratory mouse is the go-to model for first-step experimental in vivo studies. BPD encompasses disturbances to lung structure and function, including breathing patterns and gas exchange. Despite advances in quantitative assessment of lung structure in mice, most mouse modeling studies continue to use disordered lung structure as the primary experimental endpoint. Technical challenges associated with lung function studies in neonatal mice have limited enthusiasm for drawing correlations between lung structure and lung function. As this represents a key limitation of mouse BPD models, methodologies were developed here to adapt two established techniques: unrestrained whole body plethysmography (WBP) and the forced oscillation technique (FOT), enabling reliable conscious and anesthetized assessments of lung function in mouse pups. Diseased mice presented with alveolar simplification as well as a reduced tidal volume and breathing frequency, as assessed by WBP. Changes in respiratory mechanics, namely reduced tissue damping and tissue elastance, were revealed by FOT. Alterations to pressure/volume loops suggested an obstructive pattern of disease. In a clinical cohort of 65 patients with BPD, decreased tidal volume but unchanged breathing frequency was noted. Thus, with some exceptions, disturbances to lung function in experimentally modeled elements of BPD in mice paralleled those of infants with BPD. This report serves the dual function of reporting an innovative methodology, describing protocols for using WBP and FOT in neonatal mice, while reporting functional respiratory mechanics outcomes in mice in which BPD was experimentally modeled.Clinically, respiratory disease in newborns is diagnosed and managed using lung function tests; while in animal models of newborn lung disease, lung structure is the primary experimental endpoint. Here, a comprehensive experimental protocol for assessing lung function in newborn mice is provided. Observed disturbances in lung function were discussed in the context of parallel structural changes to the lung architecture, and comparisons were drawn with clinical lung function studies in infants with BPD.