Neonatal Chronic Lung Disease in Extremely Immature Baboons

Abstract

A borderline viability model of bronchopulmonary dysplasia (BPD)/chronic lung disease of infancy (CLD) with pathophysiologic parameters consistent with those in extremely immature humans with BPD/CLD is described. After prenatal steroid treatment of pregnant dams, 12 premature baboons were delivered by cesarean-section at 125 d (term gestation, 185 d), treated with exogenous surfactant, and maintained on appropriate oxygen and positive pressure ventilation for at least 1 to 2 mo. In spite of appropriate oxygenation (median FI(O(2)) at 28 d = 0.32; range, 0.21 to 0.50) and ventilatory strategies to prevent volutrauma, the baboons exhibited pulmonary pathologic lesions known to occur in extremely immature humans of less than 1,000 g: alveolar hypoplasia, variable saccular wall fibrosis, and minimal, if any, airway disease. The CLD baboon lungs showed significantly decreased alveolization and internal surface area measurements when compared with term and term + 2-mo air-breathing controls. A decrease in capillary vasculature was evident by PECAM staining, accompanied by dysmorphic changes. Significant elevations of TNF-alpha, IL-6, IL-8 levels, but not of IL-1beta and IL-10, in tracheal aspirate fluids were present at various times during the period of ventilatory support, supporting a role for mediator-induced autoinflammation. IL-8 levels were elevated in necropsy lavages of animals with significant lung infection. This model demonstrates that impaired alveolization and capillary development occur in immature lungs, even in the absence of marked hyperoxia and high ventilation settings.

Catch-up Alveolarization in Ex-Preterm Children. Evidence from 3He Magnetic Resonance

“…The consensus from these histologic studies is that there is delay in acinar and alveolar development in preterm survivors up to 3 years of age. Taken together with the theory that human alveolarization is complete at 3 years, it was assumed that deranged alveolar structure would be a lifelong feature in preterm survivors (9,15).…”

“…The preterm baboon model of CLD was designed to resolve this problem. It (9,36) showed that alveolar hypoplasia was the predominant feature of "new CLD" (use of prenatal steroids and postnatal surfactant combined with "gentle ventilation"). Despite this pioneering work, there were no data on long-term survivors, because the maximum survival reported is 8 months, a human developmental equivalent of 3 years.…”

“…Most evidence regarding structure and development of periphery of the lung in preterm infants comes from histologic studies, either from animal models (9,10) or from autopsies of infants who died of CLD (8). However, available histologic data do not extend to children surviving beyond 3 years of age (3,11,12), with a sole exception of an 8 year old described by Husain and coworkers (4).…”

“…The histologic data are necessarily from fatal cases. Animal studies have not assessed preterm survivors beyond a human equivalent of 3 years of age (9). Because human alveolarization was thought to be complete by 3 years of age (13,14), the histologic data were extrapolated to postulate persistence of acinar damage in preterm and CLD survivors (9,15).…”

Postnatal Estradiol Up-regulates Lung Nitric Oxide Synthases and Improves Lung Function in Bronchopulmonary Dysplasia

“…We previously determined whether there are alterations in NOS in proximal lung and accompanying changes in NO production in a model of BPD in baboon fetuses delivered at 125 days of gestation (term 5 185 d) and ventilated for 14 days. This model best exemplifies the current form of BPD observed in extremely preterm human infants (11). In contrast to the normal 73% increase in NOS activity AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Postnatal therapies to prevent bronchopulmonary dysplasia (BPD) in preterm infants are limited.…”