Congenital diaphragmatic hernia prevents absorption of distal air space fluid in late-gestation rat fetuses

2006 ◽  
Vol 290 (3) ◽  
pp. L478-L484 ◽  
Author(s):  
Hans G. Folkesson ◽  
Cheryl J. Chapin ◽  
LaMonta L. Beard ◽  
Robert Ertsey ◽  
Michael A. Matthay ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Fluid Secretion ◽  
Alveolar Epithelial Cells ◽  
Normal Lung ◽  
Albumin Concentration ◽  
Fluid Absorption ◽  
Lung Maturation ◽  
Lung Fluid ◽  
Air Space

We hypothesized that congenital diaphragmatic hernia (CDH) may decrease distal air space fluid absorption due to immaturity of alveolar epithelial cells from a loss of the normal epithelial Na+ transport, as assessed by amiloride and epithelial Na+ channel (ENaC) and Na-K-ATPase expression, as well as failure to respond to endogenous epinephrine as assessed by propranolol. Timed-pregnant dams were gavage fed 100 mg of nitrofen at 9.5-day gestation to induce CDH in the fetuses, and distal air space fluid absorption experiments were carried out on 22-day gestation (term) fetuses. Controls were nitrofen-exposed fetuses without CDH. Absorption of distal air space fluid was measured from the increase in 131I-albumin concentration in an isosmolar, physiological solution instilled into the developing lungs. In controls, distal air space fluid absorption was rapid and mediated by β-adrenoceptors as demonstrated by reversal to fluid secretion after propranolol. Normal lung fluid absorption was also partially inhibited by amiloride. In contrast, CDH fetuses continued to show lung fluid secretion, and this secretion was not affected by either propranolol or amiloride. CDH lungs showed a 67% reduction in α-ENaC and β-ENaC expression, but no change in α1-Na-K-ATPase expression. These studies demonstrate: 1) CDH delays lung maturation with impaired distal air space fluid absorption secondary to inadequate Na+ uptake by the distal lung epithelium that results in fluid-filled lungs at birth with reduced capacity to establish postnatal breathing, and 2) the main stimulus to lung fluid absorption in near-term control fetuses, elevated endogenous epinephrine levels, is not functional in CDH fetuses.

Involvement of αENaC and Nedd4-2 in the conversion from lung fluid secretion to fluid absorption at birth in the rat as assayed by RNA interference analysis

2007 ◽  
Vol 293 (4) ◽  
pp. L1069-L1078 ◽  
Author(s):  
Tianbo Li ◽  
Shyny Koshy ◽  
Hans G. Folkesson
Keyword(s):  
Extravascular Lung Water ◽  
Fluid Secretion ◽  
Alveolar Epithelial Cells ◽  
Na Channel ◽  
Fluid Absorption ◽  
Lung Water ◽  
Fourfold Increase ◽  
Lung Fluid ◽  
Near Term

To explore interactions between the epithelial Na channel (ENaC) and neural precursor expressed, developmentally downregulated protein 4-2 (Nedd4-2) at the conversion of the rat lung from fluid secretion to absorption at birth, we used small-interfering RNA (siRNA) against αENaC and Nedd4-2. siRNA-generating plasmid DNA (pDNA) was administered via trans-thoracic intrapulmonary (ttip) injection 24 h before ENaC and Nedd4-2 expression, extravascular lung water, and mortality were measured. αENaC mRNA and protein were specifically reduced by ∼65% after pSi-4 injection. Nedd4-2 mRNA and protein were reduced by ∼60% after pSi-N1 injection. Interestingly, αENaC and βENaC mRNA and protein expression were increased after Nedd4-2 silencing. Extravascular lung water was significantly increased after αENaC silencing and reduced after Nedd4-2 silencing. αENaC silencing resulted in a fourfold increase in newborn mortality, whereas silencing Nedd4-2 did not affect mortality. We also isolated distal lung epithelial (DLE) cells after in vivo αENaC or Nedd4-2 silencing and measured αENaC or Nedd4-2 expression in freshly isolated DLE cells. In these DLE cells, there were attenuated αENaC or Nedd4-2 mRNA and protein, thus demonstrating that αENaC and Nedd4-2 silencing occurred in alveolar epithelial cells after ttip injection. We also looked for pDNA by PCR to determine pDNA presence in the lungs and found strong evidence for pDNA presence in both lungs. Thus we provide evidence that ENaC and Nedd4-2 are involved in the transition from lung fluid secretion to fluid absorption near term and at birth.

Congenital diaphragmatic hernia: endotracheal fluid phospholipidic profile following tracheal occlusion in an experimental model

2017 ◽  
Vol 45 (2) ◽  
Author(s):  
Gloria Pelizzo ◽  
Maria Chiara Mimmi ◽  
Jose Luis Peiro ◽  
Mario Marotta ◽  
Francesco Amoroso ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Partial Recovery ◽  
Lung Maturation ◽  
Tracheal Occlusion ◽  
Dipalmitoyl Phosphatidylcholine ◽  
Recovery Profile ◽  
Profile Changes ◽  
Lung Maturity

AbstractObjective:To compare endotracheal fluid (EF) and amniotic fluid (AF) phospholipidic profile changes following tracheal occlusion (TO) in the congenital diaphragmatic hernia (CDH) fetal lamb model, in order to support the efficacy of TO on lung maturity.Methods:A diaphragmatic defect was induced at 70 days’ gestation, TO was carried out at day 102 and cesarean section at 136 days’ gestation. EF and AF samples, collected at delivery, were evaluated using mass spectrometry (the analysis focused on palmitoyloleoyl-phosphatidylcholine [POPC, PC(18:1/16:0)], dipalmitoyl-phosphatidylcholine [DPPC, PC(16:0/16:0)] and sphingomyelins [SMs]).Results:The effects of CDH and TO were different on AF and EF. POPC levels were higher than DPPC levels in AF of healthy lambs. Following induction of the diaphragmatic malformation, an evident decrease in POPC was noted, while a substantial return to normal POPC levels and an increased DPPC peak were prompted by the TO. After CDH induction, a decrease in N-palmitoyl-D-sphingomyelin [SM(d18:1/16:0)] was revealed (P<0.01) and an increased peak in SMs in AF was prompted by the TO (P=0.05). While the most represented phosphatidylcholine (PC) species in EF of healthy lambs was DPPC, CDH induced a decrease in the DPPC peak and treatment with TO induced its partial recovery. SMs were detectable only in healthy EF samples.Conclusion:The phospholipid recovery profile following TO suggests the potential role of this therapy in restoring processes involved in surfactant-mediated lung maturation, even though other interactions involved in AF turnover should be considered. Moreover, these metabolites could be used as biomarkers of fetal pulmonary development.

Fetal lung maturation in congenital diaphragmatic hernia

1995 ◽  
Vol 173 (5) ◽  
pp. 1401-1405 ◽  
Author(s):  
Fernando R. Moya ◽  
Vickey L. Thomas ◽  
Josefina Romaguera ◽  
Mohan R. Mysore ◽  
Mark Maberry ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Fetal Lung ◽  
Lung Maturation ◽  
Fetal Lung Maturation

IL-1β-induced cortisol stimulates lung fluid absorption in fetal guinea pigs via SGK-mediated Nedd4-2 inhibition

2009 ◽  
Vol 296 (3) ◽  
pp. L527-L533 ◽  
Author(s):  
Tianbo Li ◽  
Shyny Koshy ◽  
Hans G. Folkesson
Keyword(s):  
Guinea Pigs ◽  
Protein Concentration ◽  
Fetal Lung ◽  
Na Channel ◽  
Fluid Absorption ◽  
Severe Respiratory Distress ◽  
Lung Fluid ◽  
Air Space ◽  
Distal Lung ◽  
Epithelial Na Channel

We tested the hypothesis that interleukin (IL)-1β-induced cortisol synthesis stimulates distal lung fluid absorption in fetal guinea pigs via induction of serum- and glucocorticoid-regulated kinase (SGK) and inhibition of neural precursor cell expressed, developmentally downregulated protein 4-2 (Nedd4-2). IL-1β was subcutaneously administered daily to timed-pregnant guinea pigs over 3 days. Fetuses were obtained by abdominal hysterotomy at gestation day (GD)61 and GD68 and instilled with an isosmolar 5% albumin solution into the lungs. Distal lung fluid movement was measured over 1 h from the change in distal air space protein concentration. Fetal lungs were secreting lung fluid at GD61 while absorbing lung fluid at GD68. Distal lung fluid absorption was induced at GD61 by IL-1β but unaffected at GD68. Plasma cortisol concentrations were increased by IL-1β at GD61 and endogenously at GD68. Distal lung fluid absorption was measured and correlated to SGK and Nedd4-2 expression and to α-epithelial Na channel (ENaC) expression. SGK was increased by IL-1β and late during gestation (GD68), while Nedd4-2 was decreased by IL-1β and late during gestation. α-ENaC was induced by IL-1β at GD61 and increased late during gestation. Thus our study suggests that cortisol-stimulated fetal lung fluid absorption is mediated by increased ENaC expression and may be governed by the SGK/Nedd4-2 pathway. These observations may explain why babies delivered preterm after intrauterine inflammation have a reduced risk of developing severe respiratory distress.

scholarly journals Cord blood-derived endothelial colony-forming cell function is disrupted in congenital diaphragmatic hernia

2016 ◽  
Vol 310 (11) ◽  
pp. L1143-L1154 ◽  
Author(s):  
Hideshi Fujinaga ◽  
Hiroko Fujinaga ◽  
Nobuyuki Watanabe ◽  
Tomoko Kato ◽  
Moe Tamano ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Congenital Diaphragmatic Hernia ◽  
Cord Blood ◽  
Mrna Expression ◽  
Diaphragmatic Hernia ◽  
Cell Function ◽  
De Novo ◽  
Normal Lung ◽  
No Production

Vascular growth is necessary for normal lung development. Although endothelial progenitor cells (EPCs) play an important role in vascularization, little is known about EPC function in congenital diaphragmatic hernia (CDH), a severe neonatal condition that is associated with pulmonary hypoplasia. We hypothesized that the function of endothelial colony-forming cells (ECFCs), a type of EPC, is impaired in CDH. Cord blood (CB) was collected from full-term CDH patients and healthy controls. We assessed CB progenitor cell populations as well as plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1α (SDF1α) levels. CB ECFC clonogenicity; growth kinetics; migration; production of VEGF, SDF1α, and nitric oxide (NO); vasculogenic capacity; and mRNA expression of VEGF-A, fms-related tyrosine kinase 1 (FLT1), kinase insert domain receptor (KDR), nitric oxide synthase (NOS) 1–3, SDF1, and chemokine (C-X-C motif) receptor 4 (CXCR4) were also assessed. Compared with controls, CB ECFCs were decreased in CDH. CDH ECFCs had reduced potential for self-renewal, clonogenicity, proliferation, and migration. Their capacity for NO production was enhanced but their response to VEGF was blunted in CDH ECFCs. In vivo potential for de novo vasculogenesis was reduced in CDH ECFCs. There was no difference in CB plasma VEGF and SDF1α concentrations, VEGF and SDF1α production by ECFCs, and ECFC mRNA expression of VEGF-A, FLT1, KDR, NOS1-3, SDF1, and CXCR4 between CDH and control subjects. In conclusion, CB ECFC function is disrupted in CDH, but these changes may be caused by mechanisms other than alteration of VEGF-NO and SDF1-CXCR4 signaling.

Oxytocin-induced labor augments IL-1β-stimulated lung fluid absorption in fetal guinea pig lungs

2005 ◽  
Vol 289 (6) ◽  
pp. L1029-L1038 ◽  
Author(s):  
Prem K. Nair ◽  
Tianbo Li ◽  
Reshma Bhattacharjee ◽  
Xin Ye ◽  
Hans G. Folkesson
Keyword(s):  
Guinea Pig ◽  
Sodium Channels ◽  
Blood Circulation ◽  
Fetal Lung ◽  
Maternal Blood ◽  
Fluid Absorption ◽  
Lung Maturation ◽  
Induced Labor ◽  
Atpase Subunit ◽  
Lung Fluid

We tested the hypothesis that oxytocin-induced labor augmented IL-1β-induced/-stimulated lung fluid absorption in preterm guinea pig fetuses. IL-1β was administered subcutaneously daily to timed-pregnant guinea pigs for 3 days with and without simultaneous cortisol synthesis inhibition by metyrapone. At day 3, oxytocin was administered, and fetuses were delivered by abdominal hysterotomy at 61 and by oxytocin-induced birth at 68 days gestation. Delivered fetuses were instilled with isosmolar 5% albumin into the lungs, and lung fluid movement was measured over 1 h by mass balance. Lung fluid absorption was induced in 61-day and stimulated in 68-day gestation lungs by IL-1β. Labor induction by oxytocin augmented IL-1β-induced/-stimulated lung fluid absorption. Metyrapone pretreatment did not affect oxytocin-induced/-stimulated lung fluid absorption, while completely blocking IL-1β-induced/-stimulated fluid absorption. Fetal lung fluid absorption, when present, was always propranolol and amiloride sensitive, suggesting that β-adrenoceptor stimulation and amiloride-sensitive sodium channels were critical for fluid absorption. Epithelial sodium channel and Na-K-ATPase subunit expressions were both increased by IL-1β, but not further by oxytocin. Our results indicate that IL-1β release into the maternal blood circulation positively affects lung maturation due to the IL-1β-induced release of cortisol and thus prepares the lungs for the epinephrine surge associated with labor.

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