Novel mechanism for synergistic responses to systemic maternal inflammation and neonatal hyperoxia exposure on lung development and therapies to improve pulmonary function and reduce bronchopulmonary dysplaisa (BPD)
Zusammenfassung der Projektergebnisse
The causes and consequences of preterm birth remain poorly understood and present a significant health burden. Epidemiological data indicate that preterm infants surviving to adulthood are at greater risk for the development of chronic health problems. Systemic maternal inflammation is the most common and clinically relevant stress adversely affecting the developing fetus leading to impaired intrauterine growth, preterm birth, and subsequently increased risk for the development of pulmonary disease in the offspring. In the past three decades, advances in neonatal care, including use of antenatal corticosteroids, surfactant therapy, and high-frequency ventilation, have significantly improved survival rates of extremely preterm and low-birth weight infants. However, little is known about the long-term physiological consequences of a hostile perinatal environment. We tested the hypothesis that a hostile perinatal environment induces profibrotic pathways resulting in pulmonary fibrosis, including persistently altered lung structure and function. Docosahexaenoic acid (DHA) has been shown to have antiinflammatory properties in a variety of diseases but the mechanisms responsible are not clearly defined. In a subset of experiments, we tested the hypothesis that this fibrotic phenotype observed in mice exposed to maternal LPS and neonatal hyperoxia is at least partly due to an induction of EMT and that this phenotype can be rescued by dietary administration of DHA to the pregnant and lactating dam. Pregnant C3H/ HeN mice were injected with LPS or saline on embryonic day 16. Offspring were placed in room air (RA) or 85% O2 for 14 days and then returned to RA. Pulmonary function tests, microCTs, and molecular and histological analyses were performed between embryonic day 18 and 8 wk. Alveolarization was most compromised in LPS/O2-exposed offspring. Collagen staining and collagen protein levels were increased, and static compliance was decreased only in LPS/O2-exposed mice. Three-dimensional microCT reconstruction and quantification revealed increased tissue densities only in LPS/O2 mice. Diffuse interstitial fibrosis was associated with decreased micro-RNA-29, increased tumor growth factor-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. Maternal DHA supplementation during late gestation and early life dampens the inflammatory response in fetal lung tissue, prevents decreased birth weight, improves alveolarization and pulmonary mechanics, and abolishes matrix remodeling and collagen deposition We have established a murine model that combines an adverse intrauterine environment with a fetal intervention that recapitulates much of the pathophysiology that is observed in the infants that develop severe BPD. Our data indicated that the morbidities observed in the both lung structure and function at 8 weeks of age in our LPS/O2 treated mice are due to events that occur within the first 2 weeks of life. In addition, we have demonstrated that dampening the inflammatory responses during late gestation and early life by DHA supplementation, improves outcome by lessening the fibrotic responses and improving alveolarization. Although DHA supplementation to pregnant and lactating mothers is currently recommended, the levels of supplementation are below those found to be efficacious in dampening inflammatory responses. More studies are needed in humans to determine optimal DHA supplementation strategies for preterm infants.
Projektbezogene Publikationen (Auswahl)
-
Maternal docosahexaenoic acid supplementation decreases lung inflammation in hyperoxia-exposed newborn mice. J Nutr. 2011 Feb;141(2):214-22
Rogers LK, Valentine CJ, Pennell M, Velten M, Britt RD, Dingess K, Zhao X, Welty SE, Tipple TE
-
Maternal inflammation, growth retardation, and preterm birth: insights into adult cardiovascular disease. Life Sci. 2011 Sep 26;89(13-14):417-21
Rogers LK, Velten M
-
Systemic maternal inflammation and neonatal hyperoxia induces remodeling and left ventricular dysfunction in mice. PLoS One. 2011;6(9):e24544
Velten M, Hutchinson KR, Gorr MW, Wold LE, Lucchesi PA, Rogers LK
-
Prenatal Inflammation Exacerbates Hyperoxia Induced Functional and Structural Changes in Adult Mice. AJP Regulatory. 2012 Aug;303(3):R279-90
Velten M, Britt RD Jr, Heyob KM, Welty SE, Eiberger B, Tipple TE, Rogers LK
