Ep 4: Fetal Lung Fluid Clearance

Learning Objectives

By the end of this episode, NICU Grads will be able to:
1. Discuss the mechanisms of fetal lung fluid clearance 

Fetal Lung Fluid Clearance

Fetal alveolar fluid

• Essential for maintaining intrapulmonary volume and lung development
• Produced by the fetal lung epithelium as early as week 6 of gestation
• In utero, the lung is a secretory organ, producing fluid at a brisk rate (≥5 mL/kg per hour in late gestation)
• Shortly before birth, this fluid secretion slows

ENaC

• Epithelial sodium channel 
• Located on alveolar type II pneumocytes
• Main function
  • Allows passive transport of sodium into the cell following the gradient created by the ATPase pump
  • Once absorbed by ENaC, the sodium and fluid are cleared through the lymphatic and vascular systems.
• Expression of ENaC increases throughout gestation
  • High concentration of ENaC seen in term infant compared to preterm infants
• Evidence of importance of ENaC in the clearance of fetal lung fluid
  • Seen in mouse models, in which absence of ENaC is lethal shortly after birth due to impaired fetal clearance
• Activated/ stimulated by the following:
  • Maternal hormones:
    • Epinephrine
      • Increased the ENaC activity via the cAMP signaling pathway
    • Glucocorticoids
      • ENaC upregulation
      • Increased the ENaC activity of existing channels by slowing degradation
      • Enhance the responsiveness of lungs to beta-adrenergic agents
    • Thyroid hormone
      • Enhance the responsiveness of lungs to beta-adrenergic agents
  • Presence of an alveolar air interface itself is a strong stimulus for ENaC expression
  • Oxygen + lung expansion facilitates fluid resorption
  • Most of the clearance of fetal lung fluid occurs during inspiration
• Inhibited by:
  • Amiloride
• Measurement of ENaC
  • Nasal potential difference (N-PD)
    • Reliable measure of the electrogenic transport of sodium and chloride ions across an epithelium and can be extrapolated to assess ENaC function
    • Used to prove the importance ENaC 
      • Term infants illustrates high N-PD and has been associated with lung compliance.
      • Preterm infants have been associated with low N-PD and poor lung compliance.
    • Not clinically practical

Na-K-2Cl

• Bumetanide inhibits Na-K-2Cl–> impairing lung fluid clearance/liquid absorption

Na-K ATPase

• Ouabain inhibits Na-K ATPase-> reduces lung fluid clearance/liquid absorption

References: 

1. Guglani L, Lakshminrusimha S, Ryan RM. Transient tachypnea of the newborn. Pediatr Rev. 2008. doi:10.1542/pir.29-11-e59
2. Hagen E, Chu A, Lew C. Transient tachypnea of the newborn. Neoreviews. 2017;18(3):e141-146. doi: http://dx.doi.org/10.1542/neo.18-3-e141
3. Elias N, O’Brodovich H. Clearance of Fluid From Airspaces of Newborns and Infants. Neoreviews. 2006;7(2):e88 LP-e94. doi:10.1542/neo.7-2-e88
4. Tutdibi E, Gries K, Bücheler M, Misselwitz B, Schlosser RL, Gortner L. Impact of Labor on Outcomes in Transient Tachypnea of the Newborn: Population-Based Study. Pediatrics. 2010;125(3):e577 LP-e583. doi:10.1542/peds.2009-0314
5. Barker PM, Gowen CW, Lawson EE, Knowles MR. Decreased sodium ion absorption across nasal epithelium of very premature infants with respiratory distress syndrome. J Pediatr. 1997. doi:10.1016/S0022-3476(97)70198-7
6. Helve O, Janér C, Pitkänen O, Andersson S. Expression of the Epithelial Sodium Channel in Airway Epithelium of Newborn Infants Depends on Gestational Age. Pediatrics. 2007;120(6):1311 LP – 1316. doi:10.1542/peds.2007-0100
7. Helve O, Andersson S, Kirjavainen T, Pitkänen OM. Improvement of lung compliance during postnatal adaptation correlates with airway sodium transport. Am J Respir Crit Care Med. 2006. doi:10.1164/rccm.200501-052OC
8. Richard J. Martin, Avroy A. Fanaroff, Michele C. Walsh. (2015). Fanaroff and Martin’s neonatal-perinatal medicine: diseases of the fetus and infant. Philadelphia, PA: Elsevier/Saunders.
9. Brodsky, Dara, and Camilia Martin. Brodsky and Martin’s Neonatology Review Series. 3rd ed., Lulu, 2020.
10. Brodsky, Dara. Neonatology Review: Q&A. 3rd ed., Lulu, 2016.
11. Chess, Patricia. Avery’s Neonatology Board Review: Certification and Clinical Refresher. 1 ed., Elsevier, 2019.
12. Polin, Richard A., and Mervin C. Yoder. Workbook in Practical Neonatology. 5th ed., Saunders, 2014.

Credits

• Written and Produced by: Neena Jube-Desai MD, MBA FAAP
• Cover Art by: Neena Jube-Desai MD, MBA FAAP
• Infographic by: Piyawat Arichai MD
• Host: Neena Jube-Desai MD, MBA FAAP
• Editor: Neena Jube-Desai MD, MBA FAAP
• Guest: Simranjeet Sran, MD FAAP