Search

Bronchopulmonary dysplasia (BPD) is a common consequence of life-saving interventions for infants born with immature lungs. Resident tissue myeloid cells regulate lung pathology, but their role in BPD is poorly understood. To determine the role of lung interstitial myeloid cells in neonatal responses to lung injury, we exposed newborn mice to hyperoxia, a neonatal mouse lung injury model with features of human BPD. In newborn mice raised in normoxia, we identified a CD45(+) F4/80(+) CD11b(+), Ly6G(lo-int) CD71(+) population of cells in lungs of neonatal mice present in significantly greater percentages than in adult mice. In response to hyperoxia, surface marker and gene expression in whole lung macrophages/monocytes was biased to an alternatively activated phenotype. Partial depletion of these CD11b(+) mononuclear cells using CD11b-diphtheria toxin (DT) receptor transgenic mice resulted in 60% mortality by 40 hours of hyperoxia exposure with more severe lung injury, perivascular edema, and alveolar hemorrhage compared with DT-treated CD11b-DT receptor-negative controls, which displayed no mortality. These results identify an antiinflammatory population of CD11b(+) mononuclear cells that are protective in hyperoxia-induced neonatal lung injury in mice, and suggest that enhancing their beneficial functions may be a treatment strategy in infants at risk for BPD.

Rationale: Lungs of adult mice exposed to hyperoxia as newborns are simplified and exhibit reduced function much like that observed in people who had bronchopulmonary dysplasia (BPD) as infants. Because survivors of BPD also show increased risk for symptomatic respiratory infections, we investigated how neonatal hyperoxia affected the response of adult mice infected with influenza A virus infection., Objectives: To determine whether neonatal hyperoxia increased the severity of influenza A virus infection in adult mice., Methods: Adult female mice exposed to room air or hyperoxia between Postnatal Days 1 and 4 were infected with a sublethal dose of influenza A virus., Measurements and Main Results: The number of macrophages, neutrophils, and lymphocytes observed in airways of infected mice that had been exposed to hyperoxia as neonates was significantly greater than in infected siblings that had been exposed to room air. Enhanced inflammation correlated with increased levels of monocyte chemotactic protein-1 (CCL2) in lavage fluid, whereas infection-associated changes in IFN-gamma, IL-1beta, IL-6, tumor necrosis factor-alpha, KC, granulocyte-macrophage colony-stimulating factor, and macrophage inflammatory protein-1alpha, and production of virus-specific antibodies, were largely unaffected. Increased mortality of mice exposed to neonatal hyperoxia occurred by Day 14 of infection, and was associated with persistent inflammation and fibrosis., Conclusions: These data suggest that the disruptive effect of hyperoxia on neonatal lung development also reprograms key innate immunoregulatory pathways in the lung, which may contribute to exacerbated pathology and poorer resistance to respiratory viral infections typically seen in people who had BPD.

Rationale: Bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns triggered by oxygen and barotrauma, is characterized by arrested alveolarization. Increased levels of bombesin-like peptides shortly after birth mediate lung injury: anti-bombesin antibody 2A11 protects against BPD in two baboon models. The role of adaptive immunity in BPD has not been explored previously., Objectives: Our goal was to test the hypothesis that thymic architecture and/or T-cell function is altered with BPD, leading to autoimmunity and immunodeficiency., Methods: Thymic structure was analyzed by histopathology of thymic architecture and immunohistochemistry for thymic maturation markers (terminal deoxynucleotidyl transferase, proliferating cell nuclear antigen, CD4, and CD8). Thymic cortical epithelial cells (nurse cells) were studied using HLA-DR and protein gene product 9.5 as markers. Functional analysis was performed with "mixed lymphocyte reaction" of thymocyte or splenocyte responder cells with autologous lung cells as the stimulators., Measurements and Main Results: 2A11 treatment attenuates thymic cortical involution in BPD animals, sustaining terminal deoxynucleotidyl transferase-positive prothymocytes and thymocyte proliferation. BPD animals have increased CD4(+) cells in thymic cortex and lung interstitium, which are reduced by 2A11. Conversely, cortical protein gene product 9.5/HLA-DR-positive thymic nurse cells are depleted in BPD animals, but are preserved by 2A11-treatment. Whereas fetal thymocytes and splenocytes respond to phythemagglutinin/ionomycin and to a lesser extent, to autologous lung, BPD thymocytes and splenocytes are phythemagglutinin/ionomycin-unresponsive, and yet react strongly to autologous lung. The 2A11 normalizes these responses., Conclusions: These observations suggest that bombesin-like peptides mediate premature thymic maturation and thymic nurse-cell depletion, leading to autoreactive T cells that could contribute to lung injury.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, may be associated with long-term airflow limitation. Survivors of BPD may develop asthma-like symptoms in childhood, with a variable response to beta(2)-agonists. However, the pathologic pathways underlying these respiratory manifestations are still unknown. The aim of this study was to measure exhaled nitric oxide (FE(NO)) and lung function in a group of 31 school-age survivors of BPD. They showed variable degrees of airflow obstruction (mean FEV(1) 77.8 +/- 2.3% predicted) unresponsive to beta(2)-agonists in 72% of the subjects. Their FE(NO) values (geometric mean [95% confidence interval]: 7.7 [+/- 1.1] ppb) were significantly lower than in a group of healthy matched control subjects born at term (10.7 [+/- 1.1] ppb, p < 0.05) and a group of preterm children without BPD (9.9 [+/- 1.1] ppb, p < 0.05). The children with BPD were also compared with a group of 31 patients with asthma with a comparable airflow limitation (FEV(1) 80.2 +/- 2.1% predicted) and showed FE(NO) values four times lower than in those with asthma (24.9 [+/- 1.2] ppb, p < 0.001). In conclusion, unlike children with asthma, school-age survivors of BPD have airflow limitation associated with low FE(NO) values and lack of reversibility to beta(2)-agonists, probably as a result of mechanisms related to early life structural changes in the airways.

Intratracheal endotoxin causes acute inflammation in the adult lung, and injurious styles of mechanical ventilation can result in systemic inflammation derived from the lungs. We asked how ventilated premature and near-term lungs responded to intratracheal endotoxin and if systemic inflammation occurred. Lambs delivered at 130 d gestational age (GA) were treated with surfactant or surfactant plus endotoxin (0.1 mg/kg or 10 mg/kg) (Escherichia coli, serotype O55:B5) and were ventilated for 6 h. Both endotoxin doses resulted in impaired gas exchange and systemic inflammation in the preterm lambs. Lambs at 141 d GA (term 146 d) were given either 10 mg/kg intratracheal endotoxin, 10 mg/kg endotoxin plus high tidal volume ventilation for the first 30 min of life, or 5 microg/kg endotoxin given intravenously. Endotoxin alone (10 mg/kg) caused lung inflammation but no systemic effects after 6 h of ventilation. Lambs given 10 mg/kg endotoxin plus high tidal volume ventilation or 5 microg/kg endotoxin intravenously had decreased gas exchange and systemic inflammation. Endotoxin was detected in the plasma of lambs at 130 d GA but not at 141 d GA. Inflammation in the lungs was more severe in preterm animals. Mechanical ventilation of the endotoxin-exposed preterm lung resulted in systemic effects at a low endotoxin dose and without high tidal volume ventilation.

Intraamniotic endotoxin causes chorioamnionitis, which is followed by improved fetal lung function after 4 d in fetal sheep. We evaluated 0.1 mg, 1 mg, 4 mg, and 10 mg endotoxin for inflammation and lung maturation effects after 7 d. Four and 10 mg endotoxin caused similar lung maturation and inflammation in the lung and chorioamnion. The number of neutrophils in cord blood and the inflammatory cells in alveolar lavage and fetal lung tissue increased in a dose-dependent manner. Lower endotoxin doses induced indicators of chorioamnionitis, lung and systemic inflammation without inducing lung maturation. Therefore, some degree of inflammation can occur without subsequent lung maturation. The inflammatory changes caused by 4 mg endotoxin were assessed after 5 h, 24 h, 72 h, and 7 d to discern local versus systemic inflammation after intraamniotic endotoxin. At 5 h active inflammatory cells were in the airways producing hydrogen peroxide, and interleukin-6 and -8 were increased in the cord blood indicating both lung and systemic responses. Cells recruited into the amniotic fluid produced proinflammatory cytokine mRNA for 7 d with no cytokine mRNA in chorioamnion, lung, or spleen after 72 h. The cells in the amniotic fluid may be a source of prolonged fetal exposure to proinflammatory cytokines.