Despite its potentially adverse effects on lung development and function, supplemental oxygen is often used to treat premature infants in respiratory distress. To understand how neonatal hyperoxia can permanently disrupt lung development, we previously reported increased lung compliance, greater alveolar simplification, and disrupted epithelial development in adult mice exposed to 100% inspired oxygen fraction between postnatal days 1 and 4. Here, we investigate whether oxygen-induced changes in lung function are attributable to defects in surfactant composition and activity, structural changes in alveolar development, or both. Newborn mice were exposed to room air or 40%, 60%, 80%, or 100% oxygen between postnatal days 1 and 4 and allowed to recover in room air until 8 wk of age. Lung compliance and alveolar size increased, and airway resistance, airway elastance, tissue elastance, and tissue damping decreased, in mice exposed to 60 -80% oxygen; changes were even greater in mice exposed to 100% oxygen. These alterations in lung function were not associated with changes in total protein content or surfactant phospholipid composition in bronchoalveolar lavage. Moreover, surface activity and total and hydrophobic protein content were unchanged in large surfactant aggregates centrifuged from bronchoalveolar lavage compared with control. Instead, the number of type II cells progressively declined in 60 -100% oxygen, whereas levels of T1␣, a protein expressed by type I cells, were comparably increased in mice exposed to 40 -100% oxygen. Thickened bundles of elastin fibers were also detected in alveolar walls of mice exposed to Ն60% oxygen. These findings support the hypothesis that changes in lung development, rather than surfactant activity, are the primary causes of oxygen-altered lung function in children who were exposed to oxygen as neonates. Furthermore, the disruptive effects of oxygen on epithelial development and lung mechanics are not equivalently dose dependent. bronchopulmonary dysplasia; epithelium; hyperoxia; type II cells BRONCHOPULMONARY DYSPLASIA (BPD) is a chronic lung disease often seen in premature infants with very low birth weight (21). At autopsy, lungs of infants who die from BPD are less vascularized, with fewer and larger alveoli (7). Although the pathophysiology of BPD is complex and related in part to gestational age, neonatal hyperoxia is recognized as an important contributing factor to this disease in many infants (see Refs. 3,12,17, 37 for review). Premature infants with BPD have low plasma levels of glutathione (59), and hyperoxia in the context of an immature antioxidant defense increases the potential for oxidative stress injury. The use of exogenous surfactant, antenatal steroids, and milder ventilation strategies has markedly increased survival and other improved outcomes for premature infants over the past two decades. However, many patients continue to show decreased lung capacity, even as young adolescents (19,20,55). Moreover, these children are often rehospitalized following r...

Although the endothelial cell is the most abundant cell type in the differentiated lung, little is known about regulation of lung developmental vasculogenesis. Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and angiogenic factor that has putative roles in vascular development. Mitogenic actions of VEGF are mediated by the tyrosine kinase receptor KDR/murine homologue fetal liver kinase Flk-1. HLF (hypoxia-inducible factor-like factor) is a transcription factor that increases VEGF gene transcription. Dexamethasone augments lung maturation in fetal and postnatal animals. However, in vitro studies suggest that dexamethasone blocks induction of VEGF. The objectives for the current study were to measure VEGF mRNA and Flk-1 mRNA in developing mouse lung and to measure the effects of dexamethasone treatment in vivo on VEGF and Flk-1 in newborn mouse lung. Our results show that VEGF and Flk-1 messages increase in parallel during normal lung development (d 13 embryonic to adult) and that the distal epithelium expresses VEGF mRNA at all ages examined. Dexamethasone (0.1-5.0 mg x kg(-1) x d(-1)) treatment of 6-d-old mice resulted in significantly increased VEGF, HLF, and Flk-1 mRNA. Dexamethasone did not affect cell-specific expression of VEGF, VEGF protein, or proportions of VEGF mRNA splice variants. These data suggest that the developing alveolar epithelium has an important role in regulating alveolar capillary development. In addition, unlike effects on cultured cells, dexamethasone, even in relatively high doses, did not adversely affect VEGF expression in vivo. The relatively high levels of VEGF and Flk-1 mRNA in adult lung imply a role for pulmonary VEGF in endothelial cell maintenance or capillary permeability.

CD8+ T cells contribute to the pathophysiology of Pneumocystis pneumonia (PcP) in a murine model of AIDS-related disease. The present studies were undertaken to more precisely define the mechanisms by which these immune cells mediate the inflammatory response that leads to lung injury. Experimental mice were depleted of either CD4+ T cells or both CD4+ and CD8+ T cells and then infected with Pneumocystis. The CD4+-depleted mice had significantly greater pulmonary TNF-α levels than mice depleted of both CD4+ and CD8+ T cells. Elevated TNF-α levels were associated with increased lung concentrations of the chemokines RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant. To determine whether TNFR signaling was involved in the CD8+ T cell-dependent chemokine response, TNFRI- and II-deficient mice were CD4+ depleted and infected with Pneumocystis. TNFR-deficient mice had significantly reduced pulmonary RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant responses, reduced inflammatory cell recruitment to the alveoli, and reduced histological evidence of PcP-related alveolitis as compared with infected wild-type mice. Diminished pulmonary inflammation correlated with improved surfactant activity and improved pulmonary function in the TNFR-deficient mice. These data indicate that TNFR signaling is required for maximal CD8+ T cell-dependent pulmonary inflammation and lung injury during PcP and also demonstrate that CD8+ T cells can use TNFR signaling pathways to respond to an extracellular fungal pathogen.

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