Modelling Bronchopulmonary Dysplasia in Animals: Arguments for the Preterm Rabbit Model

Abstract

Bronchopulmonary dysplasia (BPD) remains a frequent and disabling consequence of preterm birth, despite the recent advances in neonatal intensive care. There is a need to further improve outcomes and many novel therapeutic or preventive strategies are therefore investigated in animal models. We discuss in this review the aspects of human BPD pathophysiology and phenotype, which ideally should be mimicked by an animal model for this disease. Prematurity remains the common denominator in the heterogeneous spectrum of human BPD, and preterm animal models thus have a clear translational advantage. Additional factors, like excessive oxygen, mechanical ventilation and infection, which frequently have been studied in animal models, can contribute to preterm lung injury however are not indispensable to develop BPD. The phenotype of human BPD is characterized by alveolar developmental arrest with extracellular matrix remodeling, signs of obstructive airway disease and pulmonary vascular disease. Many animal models mimic this phenotype and have their place in BPD research, but results should be interpreted bearing in mind the specific advantages and disadvantages of the model. Term mice and rats are well suited for basic explorative research on specific disease mechanisms, essential for the generation of new hypotheses, while the larger ventilated preterm baboons and lambs provide a good platform for the ultimate translation of these strategies towards clinical application. The preterm rabbit model seems a promising model as it the smallest model that includes a factor of prematurity and has a unique position between the small and large animal models.

Preterm birth impairs postnatal lung development in the neonatal rabbit model

“…In general, pre-and postnatal factors (e.g. infection, oxygen, volutrauma) can contribute to the development of post-prematurity respiratory disease or BPD, however the one common denominator is preterm birth itself [8,9]. The findings in this study support the idea that preterm birth alone, even in the absence of any other pre-and postnatal injury, affects lung development.…”

“…Large animal models such as preterm lambs and baboons mimic the structural and functional immaturity of an extremely preterm neonate, however practical and ethical constraints limit extensive use [12,13]. The preterm rabbit model could be an elegant compromise between the presence of prematurity and ease of experimentation [8,14]. Our finding that preterm birth alone affects developing lungs, supports the use of structurally and functionally preterm animal models for the study of BPD, such as rabbits born on day 28 of gestation.…”

“…Postnatal care (e.g. hyperoxia or mechanical ventilation) can influence respiratory outcome, but the common factor contributing to all BPD cases is prematurity [8,9]. Nevertheless, most preclinical research on BPD is performed in term neonatal rodents exposed to excessive hyperoxia or aggressive mechanical ventilation [10,11].…”

“…Large animal models like preterm baboons and lambs on the other hand can be used to mimic intensive neonatal care with invasive ventilation or even non-invasive pressure support, but impose significant costs [12,13]. The preterm rabbit model could be an intermediate that combines prematurity and the possibility of perinatal manipulations with relative low cost [8,14]. Surprisingly, little animal experimental data is available on the persistent effects of a preterm transition to postnatal life, in the absence of any other noxiae, on lung structure and function.…”

An Innovative Model of Bronchopulmonary Dysplasia in Premature Infants

“…In the study of BPD, the establishment of animal models is essential. The more commonly used animal models are mice, rats, rabbits, sheep, and baboons (4)(5)(6)(7)(8). At present, most people think that oxidative stress of lung tissue caused by hyperoxia exposure is an important reason for the occurrence and development of BPD (9), and preterm is an important risk factor for the occurrence of BPD (10).…”