Pathophysiologic, Morphometric, and Biochemical Studies of the Premature Baboon with Bronchopulmonary Dysplasia

Abstract

Pathophysiologic, morphometric, and biochemical (surfactant and coagulation-fibrinolytic parameters) features were studied in premature baboons with and without bronchopulmonary dysplasia (BPD). A total of 22 baboons were delivered by hysterotomy at 75% of gestation and randomized into two groups. Group 1 (PRN) animals were ventilated with high-frequency oscillation for 48 to 72 h and then changed to positive-pressure ventilation (PPV) while maintained on clinically appropriate oxygen for the 21-day experimental period. Group 2 (BPD) animals were ventilated with PPV and 1.0 FlO2 for 7 days followed by 0.8 FlO2 for 14 days. Group 3 (control) animals were delivered and immediately killed at 140 days gestation. Group 1 animals showed no significant airway or saccular lesions, and alveolarization of the saccules was present. Group 2 animals showed metaplastic or hyperplastic epithelial lesions in airways and an alternating pattern of atelectatic but more normal appearing saccules and alveoli interposed between foci of thickened overexpanded saccular walls with no alveolarization. Differences within and between the three study groups were analyzed morphometrically. When numerical densities were examined by comparing control, PRN, BPD-atelectatic areas, and BPD-overexpanded areas. Type II cells were significantly increased in the BPD-overexpanded sites above those of control and PRN values. The interstitial cells were significantly more numerous in the BPD-atelectatic blocks compared with control and BPD-overexpanded blocks. Endothelial cell numerical densities were significantly decreased in the overexpanded sites of the BPD animals compared with the control, PRN, and BPD-atelectatic values. Volume density data showed that the interstitial compartment of the BPD group was significantly larger than those of the control and PRN groups. This was seen as significant increases in the cellular, noncellular, and connective tissue fiber components. Vascular endothelium or lumen volume densities were not different between the BPD and PRN animals, but did differ from those of the 140-day gestation controls. Comparable levels of lavage plasminogen-dependent fibrinolytic activity, were detectable at the 21-day study interval. The phospholipid composition of pulmonary surfactant, including disaturated PC and total PG, was similar between BPD and PRN groups at 21 days. The pathologic, morphometric, and biochemical patterns in this study probably represent those seen in human neonates with mild to moderate clinical BPD who survive. At this time, it is not known if the destructive endothelial lesion and the lack of alveolarization in the overexpanded and fibrotic lesions will resolve over time in long-term BPD survivors.

Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

“…125-day PRN (BPD animals): These were delivered at 125 days' gestation, given intratracheal beractant (Survanta; Ross Laboratories, Seattle, WA) (100 mg/kg), intravenous saline (vehicle control), and ventilated for 14 to 21 days to maintain Pa O 2 saturation of approximately 90%, as described (19,34).…”

“…Paraformaldehyde-fixed tissues were processed into paraffin as described (34). Immunostaining was performed using our own rabbit anti-bombesin antisera (22) and monoclonal antibodies for SMA (1:100; Sigma) and CD31 (1:100; PharMingen, San Diego, CA) (35).…”

Neonatal Hyperoxia Stimulates the Expansion of Alveolar Epithelial Type II Cells

“…Although the use of milder ventilation strategies, exogenous surfactant, and antenatal steroids has reduced the incidence of airway inflammation and fibrosis, infants dying from BPD have simplified alveoli that are less vascularized (2). Likewise, alveolar simplification and disorganized vasculature is seen in preterm baboons (3,4) and in term rodents exposed to hyperoxia at birth (5,6). Oxidative stress caused by high oxygen exposure or by the inflammatory response to oxygen-induced cell injury promotes alveolar simplification by suppressing expression of angiogenic factors such as vascular endothelial cell growth factor (VEGF) (for review, see Ref.…”

Animal models of bronchopulmonary dysplasia. The preterm baboon models

“…Surviving animals manifested histological evidence for alternating areas of atelectasis/emphysema, bronchiolar necrosis, early alveolar wall and peribronchial fibrosis, and squamous metaplasia of the airways, all classic findings of old BPD (19). deLemos and colleagues (20,24,28) further refined this model. They showed that a pro re nata (PRN) approach to oxygen therapy at 140 days of gestation (a relatively more mature preterm infant) allowed for complete recovery from HMD and was not accompanied by clinical, radiographic, and pathological manifestations of BPD.…”