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.

Keywords: inflammation; lung injury; oxidant injury; prematurity.

Figure 1

Overview of “big events” in pathophysiology of BPD. The three major programs that are active during the course of BPD are lung development, injury, and repair. The major injuries are from oxygen and ventilation-associated inflammation. The time line for the fetus and infant occurs over months to years, which contrasts to studies in term rodent models.

Figure 2

High tidal volumes inure the preterm lung. Six large tidal volumes given by hand at delivery injure the preterm lamb lung and prevent a response to surfactant given at 30 min of age. Redrawn from data in Ref. (31). B. An initial tidal volume of 20 ml/kg results in a high compliance in preterm lambs relative to a low tidal volume of 5 ml/kg, but at 30 min of age, the surfactant response is lost with the high tidal volume. The low tidal volume to 30 min of age allows the lungs to respond to surfactant. Redrawn from data in Ref. (32).

Figure 3

Cytokines are persistently elevated in airway samples from ventilated preterm baboons. IL-6 and IL-8 were increased from day 1 to week 4 in preterm baboons progressing to BPD. Data redrawn from Coalson et al. (48).