Abstract
BackgroundIntrauterine exposure to amniotic fluid (AF) cytokines is thought to predispose to bronchopulmonary dysplasia (BPD). We evaluated the effects of GBS exposure on RNA expression in fetal lung tissue to determine early molecular pathways associated with fetal lung injury that may progress to BPD.MethodsTen chronically catheterized pregnant monkeys (Macaca nemestrina) at 118–125 days gestation (term = 172 days) received choriodecidual inoculation of either: 1) Group B Streptococcus (n = 5) or 2) saline (n = 5). Cesarean section and fetal necropsy was performed in the first week after GBS or saline inoculation regardless of labor. RNA was extracted from fetal lungs and profiled by microarray. Results were analyzed using single gene, Gene Set, and Ingenuity Pathway Analysis. Validation was by RT-PCR and immunohistochemistry.ResultsDespite uterine quiescence in most cases, fetal lung injury occurred in four GBS cases (intra-alveolar neutrophils, interstitial thickening) and one control (peri-mortem hemorrhage). Significant elevations of AF cytokines (TNF-α, IL-8, IL-1β, IL-6) were detected in GBS versus controls (p<0.05). Lung injury was not directly caused by GBS, because GBS was undetectable by culture and PCR in the AF and fetal lungs. A total of 335 genes were differentially expressed greater than 1.5 fold (p<0.05) with GBS exposure associated with a striking upregulation of genes in innate and adaptive immunity and downregulation of pathways for angiogenesis, morphogenesis, and cellular growth and development.ConclusionsA transient choriodecidual infection may induce fetal lung injury with profound alterations in the genetic program of the fetal lung before signs of preterm labor. Our results provide a window for the first time into early molecular pathways disrupting fetal lung angiogenesis and morphogenesis before preterm labor occurs, which may set the stage for BPD. A strategy to prevent BPD should target the fetus in utero to attenuate alterations in the fetal lung genetic program.
Highlights
Intra-amniotic inflammation is thought to play a major role in the pathogenesis of fetal lung injury, aberrant lung development and the resulting neonatal and adult chronic lung disease. [1,2] Bronchopulmonary dysplasia (BPD) accounts for the vast majority of chronic lung disease in infancy affecting 35% of infants weighing less than 1,500 grams
[10] Despite surfactant therapy and newer modes of mechanical ventilation, the prevalence of bronchopulmonary dysplasia (BPD) has increased, in very immature infants who may have little or no evidence of respiratory distress syndrome after birth. [11,12] Neonatal lung samples to study the early pathologic changes associated with BPD are extremely limited and tend to exist mainly in end-stage BPD leaving a primary role for animal models to explain the mechanisms for alveolar simplification
Possible factors include disrupted signaling between lung mesenchyme derived growth factors and distal airspace epithelium as well as disrupted endothelial–epithelial cross-talk that interferes with normal alveolar and vascular morphogenesis. [7,10] A critical precursor to BPD may be fetal exposure to cytokines in the amniotic fluid inducing lung injury in utero, which evolves into chronic lung injury following preterm delivery and exposure to mechanical ventilation and hyperoxia. [1,2,4,5,13,14]
Summary
Intra-amniotic inflammation is thought to play a major role in the pathogenesis of fetal lung injury, aberrant lung development and the resulting neonatal and adult chronic lung disease. [1,2] Bronchopulmonary dysplasia (BPD) accounts for the vast majority of chronic lung disease in infancy affecting 35% of infants weighing less than 1,500 grams. [3] Studies have linked elevated cytokines in the amniotic fluid with an increase in BPD and neonatal morbidity/mortality. [1,2,4,5] In surfactant-treated patients, BPD is characterized histologically by some degree of alveolar septal fibrosis, arrest in acinar development, and impaired vascular development. [6,7] Current therapies in the postnatal period are only minimally effective for BPD prevention [8,9] and the mechanisms initiating and propagating lung injury in utero remain ill-defined and difficult to study in humans because of confounding clinical variables in the care of preterm infants.The underlying pathogenesis of BPD is thought to be due to disruption of normal growth and vasculogenesis in the saccular stage of lung development (24–38 weeks gestation), resulting in alveolar simplification from a lack of secondary alveolar septation. [10] Despite surfactant therapy and newer modes of mechanical ventilation, the prevalence of BPD has increased, in very immature infants who may have little or no evidence of respiratory distress syndrome after birth. [11,12] Neonatal lung samples to study the early pathologic changes associated with BPD are extremely limited and tend to exist mainly in end-stage BPD leaving a primary role for animal models to explain the mechanisms for alveolar simplification. [7,10] A critical precursor to BPD may be fetal exposure to cytokines in the amniotic fluid inducing lung injury in utero, which evolves into chronic lung injury following preterm delivery and exposure to mechanical ventilation and hyperoxia. [15,16] A comprehensive genomic analysis of the lung injury has not been done in these models or is not yet possible with commercial microarray platforms (e.g. sheep) These models differ slightly from humans in terms of lung developmental stage at the time of insult, which is a possible limitation in their application to the human neonate. [18] the histopathologic features of BPD have been described in animal models and humans, there is limited understanding of the molecular basis of impaired lung alveolarization and vascular development in the saccular stage of lung development and the relative contribution of intrauterine inflammation to the process.
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