Chronic Lung Injury in Preterm Lambs

Abstract

The cause of chronic lung disease of early infancy, often called bronchopulmonary dysplasia (BPD), remains unclear, partly because large-animal models that reliably reproduce BPD have not been available. We developed a model of BPD in lambs that are delivered prematurely and ventilated for 3 to 4 wk after birth to determine whether the histopathology of chronic lung injury in premature lambs mimics that which occurs in preterm infants who die with BPD, and to compare two ventilation strategies to test the hypothesis that differences in tidal volume (VT) influence histopathologic outcome. The two ventilation strategies were slow, deep ventilation (20 breaths/min, 15 +/- 2 ml/kg body weight VT; n = 5) or rapid, shallow ventilation (60 breaths/min, 6 +/- 1 ml/kg body weight VT; n = 5). Lambs were delivered at 125 +/- 4 d gestation (term = 147 d), treated with surfactant, and mechanically ventilated with sufficient supplemental oxygen to maintain normal arterial oxygenation (60 to 90 mm Hg). Quantitative histologic analysis revealed lung structural abnormalities for both groups of experimental lambs compared with lungs of control term lambs that were < 1 d old (matched for developmental age; n = 5) or 3 to 4 wk old (matched for postnatal age; n = 5). Compared with control lambs, chronically ventilated preterm lambs had pulmonary histopathology characterized by nonuniform inflation patterns, impaired alveolar formation, abnormal abundance of elastin, increased muscularization of terminal bronchioles, and inflammation and edema. Slow, deep ventilation was associated with less atelectasis, less alveolar formation, and more elastin when compared with rapid, shallow ventilation. We conclude that prolonged mechanical ventilation of preterm lambs disrupts lung development and produces pulmonary histopathologic changes that are very similar to those that are seen in the lungs of preterm infants who die with BPD. This chronic lung disease is not prevented by surfactant replacement at birth, does not appear to require arterial hyperoxia, and is influenced by VT.

Short-Term Mechanical Ventilation Increases Airway Reactivity in Rat Pups

“…van Heeckeren et al (10) demonstrated lower measurable lung volumes to inflation and an increased number of neutrophils in alveolar washes of preterm lambs after ventilation with a moderate amount of oxygen for a 2-h period compared with no ventilation or CPAP for 2 h. Ventilation for 30 min after birth with high compared with low tidal volumes leads to persistently decreased lung compliance in preterm lambs (15). In preterm lambs, a 3-4 wk period of mechanical ventilation has been shown to disrupt lung development and produce histopathologic changes including greater smooth muscle thickness around terminal bronchioles similar to lungs of preterm infants dying of BPD (16). After several weeks of mechanical ventilation in the preterm baboon, decreased alveolarization is observed (17).…”

Postnatal Lung Inflammation Increased by Ventilation of Preterm Lambs Exposed Antenatally to Escherichia coli Endotoxin

“…In recent pathologic reports, BPD is characterized by decreased alveolar development resulting in large saccular airspaces (1)(2)(3) that are thought to result from the superposition of injury on the developing lung (4). Similar morphologic alterations with alveolar hypoplasia, variable amounts of saccular wall fibrosis, and dysmorphic capillary development occur in oxygen-exposed newborn mice and ventilated preterm baboons and sheep (5)(6)(7). Although there are differences in the histopathology of BPD before the era of surfactant treatment and newer approaches to more gentle ventilation of preterm infants and more recent descriptions of BPD (1,3), inflammation appears to be a common factor (8).…”

Strategies to minimize lung injury in extremely low birth weight infants

“…Estudos experimentais demonstraram que a ventilação mecânica e o oxigênio podem interferir no desenvolvimento alveolar e vascular de animais prematuros [16][17][18] . Em prematuros, a atividade das enzimas antioxidantes, como a super-óxido desmutase, a catalase e a peroxidase, é relativamente deficiente, tornando-os mais vulnerá-veis à toxicidade ao oxigênio 19 .…”