Export file:

Format

  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text

Content

  • Citation Only
  • Citation and Abstract

Nadph oxidase and epithelial sodium channels regulate neonatal mouse lung development

1 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA
2 Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA

Background: Epithelial sodium channels (ENaC) play critically important roles in lung fluid clearance at birth. We have previously shown that Nadph oxidase (NOX)-derived reactive oxygen species signaling activates ENaC and promotes alveolar fluid clearance. In this study, we examined a new physiological role for NOX-mediated ENaC activity in mouse lung development. Methods: NOX isoform and ENaC subunit mRNA levels were evaluated in preterm and neonatal C57Bl6 mouse lung using real-time PCR analysis. Newborn mice were intra-nasally treated with 1 mM amiloride, 100 mM NSC 23766, or 300 mM apocynin during postnatal days 1–15 to study development. Lung development was assessed using hematoxylin and eosin (H&E) staining, coupled with radial alveolar counts (RAC) and mean linear intercept (MLI) measurements. Results: ENaC subunits and NOX1-4 mRNA were detected in mouse lung during late gestation, birth, and postnatally. Inhibition of Rac-1-mediated-NOX signaling indicates functional (Rac-dependent) NOX1-3 isoforms in newborn lung, determined by dihydroethidium (DHE) detection of reactive oxygen species production in postnatal (PN) day 7 mouse lung. Amiloride inhibition of ENaC activity, NSC 23766 inhibition of Rac1, and apocynin inhibition of pan NOX activity attenuated normal alveolar development in mouse lung. Conclusion: NOX and ENaC play important roles in mouse lung development.
  Figure/Table
  Supplementary
  Article Metrics

References

1. Eaton DC, Helms MN, Koval M, et al. (2009) The Contribution of Epithelial Sodium Channels to Alveolar Function in Health and Disease. Annu Rev Physiol 71: 403-423.    

2. Liggins GC, Howie RN (1972) A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50: 515-525.

3. Otulakowski G, Rafii B, Harris M, et al. (2006) Oxygen and glucocorticoids modulate alphaENaC mRNA translation in fetal distal lung epithelium. Am J Respir Cell Mol Biol 34: 204-212.    

4. Otulakowski G, Duan W, Gandhi S, et al. (2007) Steroid and oxygen effects on eIF4F complex, mTOR, and ENaC translation in fetal lung epithelia. Am J Respir Cell Mol Biol 37: 457-466.    

5. Bland RD, Albertine KH, Carlton DP, et al. (2000) Chronic Lung Injury in Preterm Lambs: Abnormalities of the Pulmonary Circulation and Lung Fluid Balance. Pediatr Res 48: 64-74.    

6. Helve O, Pitkanen OM, Andersson S, et al. (2004) Low expression of human epithelial sodium channel in airway epithelium of preterm infants with respiratory distress. Pediatrics 113: 1267-1272.    

7. Helve O, Janer C, Pitkanen O, et al. (2007) Expression of the epithelial sodium channel in airway epithelium of newborn infants depends on gestational age. Pediatrics 120: 1311-1316.    

8. Blackburn S (2012) Respiratory Systems, Maternal, Fetal, & Neonatal Physiology. 4 ed. Marlyand Heights, MO, Elsevier and Saunders, Chapt 10.

9. Jackson RM (1985) Pulmonary oxygen toxicity. Chest 88: 900-905.    

10. Jenkinson SG (1982) Pulmonary oxygen toxicity. Clin Chest Med 3: 109-119.

11. Jobe AH, Kallapur SG (2010) Long term consequences of oxygen therapy in the neonatal period. Semin Fetal Neonatal Med 15: 230-235.    

12. Northway WH, Rosan RC, Porter DY (1967) Pulmonary disease following respirator therapy of hyaline membrane disease. Bronchopulmonary dysplasia. N Engl J Med 276: 357-368.    

13. Goodson P, Kumar A, Jain L, et al. (2012) Nadph oxidase regulates alveolar epithelial sodium channel activity and lung fluid balance in vivo via O(-)(2) signaling. Am J Physiol Lung Cell Mol Physiol 302: L410-L419.    

14. Trac D, Liu B, Pao AC, et al. (2013) Fulvene-5 inhibition of Nadph oxidases attenuates activation of epithelial sodium channels in A6 distal nephron cells. Am J Physiol Renal Physiol 305: F995-F1005.    

15. Emery JL, Mithal A (1960) The number of alveoli in the terminal respiratory unit of man during late intrauterine life and childhood. Arch Dis Child 35: 544-547.    

16. Dunnill MS (1962) Quantitative methods in the study of pulmonary pathology. Thorax 17: 320-328.    

17. Fukuda N, Folkesson HG, Matthay MA (2000) Relationship of interstitial fluid volume to alveolar fluid clearance in mice: ventilated vs. in situ studies. J Appl Physiol 89: 672-679.

18. Hummler E, Barker P, Gatzy J, et al. (1996) Early death due to defective neonatal lung liquid clearance in [alpha]-ENaC-deficient mice. Nat Genet 12: 325-328.    

19. Barker PM, Nguyen MS, Gatzy JT, et al. (1998) Role of gamma ENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism. J Clin Invest 102: 1634-1640.

20. Rafii B, Tanswell AK, Otulakowski G, et al. (1998) O2- induced ENaC expression is associated with NF-kappaB activation and blocked by superoxide scavenger. Am J Physiol 275: L764-L770.

21. Rafii B, Coutinho C, Otulakowski G, et al. (2000) Oxygen induction of epithelial Na(+) transport requires heme proteins. Am J Physiol Lung Cell Mol Physiol 278: L399-L406.

22. Pendyala S, Gorshkova IA, Usatyuk PV, et al. (2009) Role of Nox4 and Nox2 in hyperoxia-induced reactive oxygen species generation and migration of human lung endothelial cells. Antioxid Redox Signal 11: 747-764.    

23. Pendyala S, Natarajan V (2010) Redox regulation of Nox proteins. Respir Physiol Neurobiol 174: 265-271.    

24. Dagenais A, Kothary R, Berthiaume Y (1997) The alpha subunit of the epithelial sodium channel in the mouse: developmental regulation of its expression. Pediatr Res 42: 327-334.    

25. Jesse NM, McCartney J, Feng X, et al. (2009) Expression of ENaC subunits, chloride channels, and aquaporins in ovine fetal lung: ontogeny of expression and effects of altered fetal cortisol concentrations. Am J Physiol Regul Integr Comp Physiol 297: R453-R461.    

26. O'Brodovich H, Canessa C, Ueda J, et al. (1993) Expression of the epithelial Na+ channel in the developing rat lung. Am J Physiol 265: C491-C496.

27. Talbot CL, Bosworth DG, Briley EL, et al. (1999) Quantitation and localization of ENaC subunit expression in fetal, newborn, and adult mouse lung. Am J Physiol Lung Cell Mol Physiol 20: 398-406.

28. Hughey RP, Bruns JB, Kinlough CL, et al. (2004) Epithelial sodium channels are activated by furin-dependent proteolysis. J Biol Chem 279: 18111-18114.    

29. Vallet V, Chraibi A, Gaeggeler HP, et al. (1997) An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature 389: 607-610.    

30. O'Brodovich H, Hannam V, Seear M, et al. (1990) Amiloride impairs lung water clearance in newborn guinea pigs. J Appl Physiol (1985) 68: 1758-1762.

31. Olver RE, Ramsden CA, Strang LB, et al. (1986) The role of amiloride-blockable sodium transport in adrenaline-induced lung liquid reabsorption in the fetal lamb. J Physiol 376: 321-340.

32. Ramsden CA, Markiewicz M, Walters DV, et al. (1992) Liquid flow across the epithelium of the artificially perfused lung of fetal and postnatal sheep. J Physiol 448: 579-597.    

33. Song W, Wei S, Zhou Y, et al. (2010) Inhibition of lung fluid clearance and epithelial Na+ channels by chlorine, hypochlorous acid, and chloramines. J Biol Chem 285: 9716-9728.    

34. Elberson VD, Nielsen LC, Wang H, et al. (2015) Effects of intermittent hypoxia and hyperoxia on angiogenesis and lung development in newborn mice. J Neonatal Perinatal Med 8: 313-322.

35. Frank L (1985) Effects of oxygen on the newborn. Fed Proc 44: 2328-2334.

36. Wilborn AM, Evers LB, Canada AT (1996) Oxygen toxicity to the developing lung of the mouse: role of reactive oxygen species. Pediatr Res 40: 225-232.    

37. Bird AD, McDougall AR, Seow B, et al. (2015) Minireview: Glucococrticoid Regulation of Lung Development: lessons learned from conditional GR knockout mice. Mol Endocrinol 29: 158-171.    

38. Saugstad OD (2003) Bronchopulmonary dysplasia-oxidative stress and antioxidants. Semin Neonatol 8: 39-49.    

39. O'Brodovich HM, Mellins RB (1985) Bronchopulmonary dysplasia. Unresolved neonatal acute lung injury. Am Rev Respir Dis 132: 694-709.

40. Bonikos DS, Bensch KG, Northway WHJ, et al. (1976) Bronchopulmonary dysplasia: the pulmonary pathologic sequel of necrotizing bronchiolitis and pulmonary fibrosis. Hum Pathol 7: 643-666.    

41. Ghanta S, Leeman KT, Christou H (2013) An update on pharmacologic approaches to bronchopulmonary dysplasia. Semin Perinatol 37: 115-123.    

Copyright Info: © 2017, My N. Helms, et al., licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved