Prenatal inflammation exacerbates hyperoxia-induced functional and structural changes in adult mice
Maternally derived inflammatory mediators, such as IL-6 and IL-8, contribute to preterm delivery, low birth weight, and respiratory insufficiency, which are routinely treated with oxygen. Premature infants are at risk for developing adult-onset cardiac, metabolic, and pulmonary diseases. Long-term pulmonary consequences of perinatal inflammation are unclear. We tested the hypothesis that a hostile perinatal environment induces profibrotic pathways resulting in pulmonary fibrosis, including persistently altered lung structure and function. Pregnant C3H/HeN mice injected with LPS or saline on embryonic day 16. Offspring were placed in room air (RA) or 85% O(2) for 14 days and then returned to RA. Pulmonary function tests, microCTs, molecular and histological analyses were performed between embryonic day 18 and 8 wk. Alveolarization was most compromised in LPS/O(2)-exposed offspring. Collagen staining and protein levels were increased, and static compliance was decreased only in LPS/O(2)-exposed mice. Three-dimensional microCT reconstruction and quantification revealed increased tissue densities only in LPS/O(2) mice. Diffuse interstitial fibrosis was associated with decreased micro-RNA-29, increased transforming growth factor-β expression, and phosphorylation of Smad2 during embryonic or early fetal lung development. Systemic maternal LPS administration in combination with neonatal hyperoxic exposure induces activation of profibrotic pathways, impaired alveolarization, and diminished lung function that are associated with prenatal and postnatal suppression of miR-29 expression.
- [Show abstract] [Hide abstract] ABSTRACT: Supraphysiological O2 concentrations, mechanical ventilation, and inflammation significantly contribute to the development of bronchopulmonary dysplasia (BPD). Exposure of newborn mice to hyperoxia causes inflammation and impaired alveolarization similar to that seen in infants with BPD. Previously, we demonstrated that pulmonary cyclooxygenase-2 (COX-2) protein expression is increased in hyperoxia-exposed newborn mice. The present studies were designed to define the role of COX-2 in newborn hyperoxic lung injury. We tested the hypothesis that attenuation of COX-2 activity would reduce hyperoxia-induced inflammation and improve alveolarization. Newborn C3H/HeN mice were injected daily with vehicle, aspirin (non-selective COX-2 inhibitor), or celecoxib (selective COX-2 inhibitor) for the first 7 days of life. Additional studies utilized wild type (C57Bl/6, COX-2(+/+)), heterozygous (COX-2(+/-)), and homozygous (COX-2(-/-)) transgenic mice. Mice were exposed to room air (21% O2) or hyperoxia (85% O2) for 14 days. Aspirin-injected and COX-2(-/-) pups had reduced levels of monocyte chemoattractant protein (MCP-1) in bronchoalveolar lavage fluid (BAL). Both aspirin and celecoxib treatment reduced macrophage numbers in the alveolar walls and airspaces. Aspirin and celecoxib treatment attenuated hyperoxia-induced COX activity, including altered levels of prostaglandin (PG)D2 metabolites. Decreased COX activity, however, did not prevent hyperoxia-induced lung developmental deficits. Our data suggests that increased COX-2 activity may contribute to pro-inflammatory responses, including macrophage chemotaxis, during exposure to hyperoxia. Modulation of COX-2 activity may be a useful therapeutic target to limit hyperoxia-induced inflammation in preterm infants at risk of developing BPD.0Comments 6Citations
- [Show abstract] [Hide abstract] ABSTRACT: Wheezing and asthma are significant clinical problems for infants and young children, particularly following premature birth. Recurrent wheezing in infants can progress to persistent asthma. As in adults, altered airway structure (remodeling) and function (increased bronchoconstriction) are also important in neonatal and pediatric airway diseases. Accumulating evidence suggests that airway disease in children is influenced by perinatal factors including perturbations in normal fetal lung development, postnatal interventions in the intensive care unit (ICU) and environmental and other insults in the neonatal period. Here, in addition to genetics, maternal health, environmental processes, innate immunity and impaired lung development/function can all influence pathogenesis of airway disease in children. We summarize current understanding of how prenatal and postnatal factors can contribute to development of airway diseases in neonates and children. Understanding these mechanisms will help identify and develop novel therapies for childhood airway diseases.0Comments 5Citations
- [Show abstract] [Hide abstract] ABSTRACT: In contrast to early lung development, a process exemplified by the branching of the developing airways, the later development of the immature lung remains very poorly understood. A key event in late lung development is secondary septation, in which secondary septa arise from primary septa, creating a greater number of alveoli of a smaller size, which dramatically expands the surface area over which gas exchange can take place. Secondary septation, together with architectural changes to the vascular structure of the lung which minimize the distance between the inspired air and the blood, are the objectives of late lung development. The process of late lung development is disturbed in bronchopulmonary dysplasia (BPD), a disease of prematurely-born infants in which the structural development of the alveoli is blunted as a consequence of inflammation, volutrauma, and oxygen toxicity. This review aims to highlight notable recent developments in our understanding of late lung development and the pathogenesis of BPD.0Comments 46Citations