Newborn Lung Injury Research Articles

TGF-β-neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung

Pulmonary injury is associated with the disruption of alveologenesis in the developing lung and causes bronchopulmonary dysplasia (BPD) in prematurely born infants. Transforming growth factor (TGF)-beta is an important regulator of cellular differentiation and early lung development, and its levels are increased in newborn lung injury. Although overexpression of TGF-beta in the lungs of newborn animals causes pathological features that are consistent with BPD, the role of endogenous TGF-beta in the inhibition of the terminal stage of lung development is incompletely understood. In this investigation, the hypothesis that O(2)-induced injury of the maturing lung is associated with TGF-beta-mediated disruption of alveologenesis and microvascular development was tested using a murine model of BPD. Here we report that treatment of developing mouse lungs with TGF-beta-neutralizing antibodies attenuates the increase in pulmonary cell phospho-Smad2 nuclear localization, which is indicative of augmented TGF-beta signaling, associated with pulmonary injury induced by chronic inhalation of 85% oxygen. Importantly, the neutralization of the abnormal TGF-beta activity improves quantitative morphometric indicators of alveologenesis, extracellular matrix assembly, and microvascular development in the injured developing lung. Furthermore, exposure to anti-TGF-beta antibodies is associated with improved somatic growth in hyperoxic mouse pups and not with an increase in pulmonary inflammation. These studies indicate that excessive pulmonary TGF-beta signaling in the injured newborn lung has an important role in the disruption of the terminal stage of lung development. In addition, they suggest that anti-TGF-beta antibodies may be an effective therapy for preventing some important developmental diseases of the newborn lung.

Pulmonary Vascular Endothelial Growth Factor-C in Development and Lung Injury in Preterm Infants

In mice, vascular endothelial growth factor-C (VEGF-C) plays an important role in development of the lymphatic system and in pathogenesis of pulmonary inflammation. Its role in development of the lymphatic system in human lung and in lung injury in newborns remains unclear. We studied the role of VEGF-C in developing human lung, and in acute and chronic lung injury in preterm infants. Included in the immunohistochemistry study were 10 fetuses, 15 control neonates without primary lung disease, 15 preterm infants with respiratory distress syndrome, and 8 infants with bronchopulmonary dysplasia. Tracheal aspirate fluid samples of intubated very-low-birth-weight infants during Postnatal Weeks 1-5 were analyzed with ELISA. Bronchiolar staining for VEGF-C was observed in all 48 samples. Alveolar epithelial staining was seen in most fetuses (8/10). In addition, staining was observed in alveolar macrophages in bronchopulmonary dysplasia (4/8), and late respiratory distress syndrome (2/7). VEGF receptor-3 (VEGFR-3) staining was observed in lymphatic endothelium adjacent to vascular endothelium. VEGF-C was expressed consistently in tracheal aspirate fluid, being highest during the first 2 postnatal days. Antenatal administration of glucocorticoids was associated with higher VEGF-C in tracheal aspirate fluid. The pattern of pulmonary VEGF-C and VEGFR-3 protein expression and consistent VEGF-C protein appearance in tracheal aspirate fluid in human preterm infants indicate a role for VEGF-C in the physiologic development of the lymphatic system of the lung.

The role of group B streptococci beta-hemolysin expression in newborn lung injury.

There is a direct correlation between the level of GBS beta-hemolysin expression and the ability of GBS to injury lung epithelial cells. Electron microscopy suggest the hemolysin acts as a pore-forming cytolysin. beta-hemolysin-associated lung epithelial cell injury is inhibited by surfactant phospholipid, a substance in which high-risk premature infants are deficient. We have now shown that loss of GBS hemolysin activity is associated with decreased animal virulence following intrathoracic inoculation of the organism. Further, a knockout of a putative GBS beta-hemolysin gene from the literature suggests it is not the major GBS hemolysin determinant. Cloning and sequencing analysis of the Tn916 (or Tn916DE) insertions in three of our nonhemolytic GBS mutants show identical integration sites in a distinct chromosomal locus. Finally, a putative 11-kd hemolysin species is identified by comparative analysis of protein extracts from isogenic hemolysin mutants.

Full-tidal liquid ventilation with perfluorocarbon for prevention of lung injury in newborn non-human primates.

Hyaline membrane disease (HMD), the most common life-threatening respiratory disorder of newborns, is associated with lung injury manifested by alveolar proteinaceous edema. The cause of the disease is thought to be elevated alveolar surface tension due to surfactant deficiency at birth. Treatment with exogenous surfactant may be unsuccessful due to problems in distribution of the surfactant, or inhibition of the surfactant by alveolar proteinaceous edema. Liquid ventilation with oxygen-saturated perfluorocarbon liquid has been proposed as a method to eliminate alveolar surface tension; little is known about the interfacial tension between perfluorocarbon liquids and the lung lining layer. Premature and term newborn monkeys were treated from birth with a pressure-limited, time-cycled liquid ventilator using oxygenated perfluorocarbon liquids (APF-145 and perflubron). Adequate gas exchange was achieved, and pilot experiments suggest long-term survival without adverse sequelae. Although many questions remain, liquid ventilation is a promising tool for the prevention and treatment of lung injury in newborns.

Hyperoxia Induces Interstitial (Type I) and Increases Type IV Collagenase mRNA Expression and Increases Type I and IV Collagenolytic Activity in Newborn Rat Lung

Oxygen toxicity is attributed to the reaction of oxygen metabolites with cellular components leading to cell destruction. Activation of latent human neutrophil interstitial collagenase by reactive oxygen species has been demonstrated. The potential role of collagenases in hyperoxic lung injury has not been investigated. We studied the effect of hyperoxia on newborn rat lung water content, morphology and ultrastructure, interstitial (type I) and type IV collagenase gene expression and type I and IV collagenolytic activity. We observed that hyperoxia causes pulmonary edema, alters newborn rat lung morphology in a sequential manner and produces ultrastructural alterations, induces type I and increases type IV collagenase mRNA expression, and increases type I and IV collagenolytic activity. A role for type I and IV collagenase in hyperoxic newborn lung injury or in the recovery following the injury is proposed.