Animal Models, Learning Lessons to Prevent and Treat Neonatal Chronic Lung Disease

Abstract

Bronchopulmonary dysplasia (BPD) is a unique injury syndrome caused by prolonged injury and repair imposed on an immature and developing lung. The decreased septation and decreased microvascular development phenotype of BPD can be reproduced in newborn rodents with increased chronic oxygen exposure and in premature primates and sheep with oxygen and/or mechanical ventilation. The inflammation caused by oxidants, inflammatory agonists, and/or stretch injury from mechanical ventilation seems to promote the anatomic abnormalities. Multiple interventions targeted to specific inflammatory cells or pathways or targeted to decreasing ventilation-mediated injury can substantially prevent the anatomic changes associated with BPD in term rodents and in preterm sheep or primate models. Most of the anti-inflammatory therapies with benefit in animal models have not been tested clinically. None of the interventions that have been tested clinically are as effective as anticipated from the animal models. These inconsistencies in responses likely are explained by the antenatal differences in lung exposures of the developing animals relative to very preterm humans. The animals generally have normal lungs while the lungs of preterm infants are exposed variably to intrauterine inflammation, growth abnormalities, antenatal corticosteroids, and poorly understood effects from the causes of preterm delivery. The animal models have been essential for the definition of the mediators that can cause a BPD phenotype. These models will be necessary to develop and test future-targeted interventions to prevent and treat BPD.

Bronchopulmonary Dysplasia: 50 Years after the Original Description

“…Multiple interventions acting on different pathways leading to BPD, such as blocking inflammatory response, preventing oxidative injury, or providing growth factors, have been evaluated in various animal models of BPD with great success. Most of these interventions have either not transitioned to clinical practice or had limited effect on the incidence of BPD [53]. Whether it is due to oversimplification of BPD in animal models or limitation of clinical definition of BPD needs to be further evaluated.…”

Can We Understand the Pathobiology of Bronchopulmonary Dysplasia?

“…Currently, there is little standardization across studies, regarding both the animals, and the injurious stimuli employed. BPD may be modeled in mice 172 , rats 173 , rabbits 174 , lambs 175 , pigs 176, 177 , and non-human primates 178 , and these models have proved highly valuable in studies on pathobiology 179 and therapy development 180 . Recent reports have documented no less than 40 different hyperoxia exposure protocols used in a two-year period – in mice alone – to study BPD 181, 182 .…”

Bronchopulmonary dysplasia: A review of pathogenesis and pathophysiology

“…Bronchopulmonary dysplasia (BPD) is a chronic lung disease of primarily premature infants that results from an imbalance between lung injury and repair in the developing immature lung 1 . Alveolar simplification and dysmorphic pulmonary vascularization are histopathological features of the majority of infants with current BPD 2,3 .…”