Regulation of the Sodium Pump in Hyperoxic Lung Injury

  • David H. Ingbar
  • Joseph M. Lasnier
  • O. Douglas Wangensteen
  • Christine H. Wendt
Part of the NATO ASI Series book series (NSSA, volume 297)


A major component of the early lesion in the adult respiratory distress syndrome (ARDS) is alveolar edema. Considerable data suggests that decreasing alveolar flooding improves the outcome from acute lung injury (ALI). Studies in humans with ARDS demonstrate that prognosis correlates with the capacity to resorb fluid (Matthay 1990). Retrospective studies indicate that patients with fluid balance out>in, lesser weight gain, lower pulmonary capillary wedge pressures or diuretic treatment have greater survival rates. It is not surprising that decreasing the degree of early alveolar flood could decrease the subsequent need for high pressure ventilation or high levels of oxygen — thus avoiding amplification of the injury.


Acute Lung Injury Alveolar Epithelial Cell Adult Respiratory Distress Syndrome Alveolar Type Keratinocyte Growth Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ahmad M, RM Medford. Evidence for the regulation of Na,K-ATPase α-1 gene expression through the interaction of aldosterone and cAMP-inducible transcriptional factors. Steroids 60:147–152, 1995.PubMedCrossRefGoogle Scholar
  2. Beggah AT, P Jaunin, K Geering. Role of glycosylation and disulfide bond formation in the β subunit in the folding and functional expression of Na,K-ATPase. J Biol Chem 272:10318–10326, 1997.PubMedCrossRefGoogle Scholar
  3. Beguin P, A Beggah, S Cotecchia, K Geering. Adrenergic, dopaminergic and muscarininc receptor stimulation leads to PKA phophorylation of Na,K-ATPase. Am J Physiol 270:C131–C1347, 1996.PubMedGoogle Scholar
  4. Bertorello AM, AI Katz. Regulation of Na-K pump activity: pathways between receptors and effectors. NIPS 10:253–259, 1995.Google Scholar
  5. Bertorello AM, Katz AI. Short-term regulation of renal Na,K-ATPase activity: physiological relevance and cellular mechanisms. Am J Physiol 265:F743–55, 1995Google Scholar
  6. Berthiaume Y: Effects of exogenous cAMP and aminophylline on alveolar and lung liquid clearance in anesthetized sheep. J Appl Physiol 70:2490–2497, 1991.PubMedGoogle Scholar
  7. Boldyrev A, E Kurella: Mechanism of oxidative damage of dog kidney Na/K-ATPase. Biochem Biophys Res Comm 222:483–487, 1996.PubMedCrossRefGoogle Scholar
  8. Borok Z, Hami A, Danto SI, Lubman RL, Kim KJ, Crandall ED: Effects of EGF on alveolar epithelial junctional permeability and active sodium transport. Am J Physiol 270:L559–565, 1996.PubMedGoogle Scholar
  9. Caplan MJ, B Forbush, GE Palade, JD Jamieson. Biosynthesis of the Na,K-ATPase in MDCK cells: activation and cell surface delivery. J Biol Chem 265:3528–2534, 1990.PubMedGoogle Scholar
  10. Carter EP, Duvick SE, Wendt CH, Dunitz J, Nici L, Wangensteen OD, Ingbar DH. Hyperoxia increases active alveolar Na+ resorption in vivo and type II cell Na,K-ATPase in vitro. Chest 105:75S–78S, 1994.PubMedGoogle Scholar
  11. Carter, E.P., Wangensteen, O.D., O’Grady, S.M. and Ingbar, D.H., Effects of hyperoxia on type II cell Na-K-ATPase function and expression. Am. J. Physiol. (Lung) 272:L542–L551, 1997a.Google Scholar
  12. Carter E, Wangensteen OD, Carter EP, Dunitz J, Ingbar DH: Hyperoxic effects on alveolar sodium resorption and lung Na,K-ATPase. Am. J. Physiol. 273:L1191–L1202, 1997b.PubMedGoogle Scholar
  13. Chambers SK, Gilmore-Hebert M, Kacinski BM, Benz EJ: Changes in Na,K-ATPase gene expression during granulocytic differentiation of HL60 cells. Blood 80:1559–1564, 1992PubMedGoogle Scholar
  14. Charles A, Dawicki DD, Oldmixon E, Kuhn C, Cutaia M, Rounds S. Studies on the mechanism of short-term regulation of pulmonary artery endothelial cell Na/K pump activity. J Lab Clin Med 130:157–168, 1997.PubMedCrossRefGoogle Scholar
  15. Clerch LB, Massoro D. Oxidation-reduction-sensitive binding of lung protein to rat mRNA. J Biol Chem 267:2853–2855, 1992PubMedGoogle Scholar
  16. Clerici C, Friedlander G, Amiel C: Impairment of sodium-coupled uptakes by hydrogen peroxide in alveolar type II cells: protective effect of a-Tocopherol. Am J Physiol 262:L542–548, 1992PubMedGoogle Scholar
  17. Compeau CG, OD Rotstein, H Tohda, Y Marunaka, B Rafii, AS Slutsky, H O’Brodovich: Endotoxin-stimulated alveolar macrophages impair lung epithelial Na transport by an L-Argdependent mechanism. Am J Physiol 266:C1330–C1341, 1994.PubMedGoogle Scholar
  18. Crapo JD: Morphologic changes in pulmonary oxygen toxicity. Ann Rev Physiol 48:721–731, 1986.CrossRefGoogle Scholar
  19. Davies KJA, ME Delsignore, SW Lin: Protein damage and degradation by oxygen radicals, I. General aspects & II. Modification of amino acids J Biol Chem 262:9895–9901; 9902-9907, 1987.PubMedGoogle Scholar
  20. Devarajan P, Gilmore-Hebert M, Benz EJ: Differential translation of the Na,K-ATPase subunit mRNAs. J. Biol. Chem. 267:22435–22439, 1992.PubMedGoogle Scholar
  21. Dreher D, Rochat T. Hyperoxia induces alkalinization and dome formation in MDCK epithelial cells. Am J Physiol 262:C358–364, 1992.PubMedGoogle Scholar
  22. Elliot SJ, Schilling WP. Oxidant stress alters Na+ pump and Na+-K+-CI cotransporter activities in vascular endothelial cells. Am J Physiol 263:H96–H102, 1992.Google Scholar
  23. Elmoselhi AB, Butcher A, Samson SE, and Grover AK. Free radicals uncouple the sodium pump in pig coronary artery. Am J Physiol 266:C720–C728, 1994.PubMedGoogle Scholar
  24. Ewart HS, A Klip. Hormonal regulation of the Na-KATPase: mechanisms underlying rapid and sustained changes in pump activity. Am J Physiol 269:C295–311, 1995.PubMedGoogle Scholar
  25. Fanburg BL, Massaro DJ, Cerutti PA, Gail DB, Berberich MA. Regulation of gene expression by 02 tension. Am J Physiol 263:L235–L241, 1992.Google Scholar
  26. Feng J, Orlowski J, Lingrel JB: Identification of a functional thyroid hormone response element in the upstream flanking region of the human Na,K-ATPase α-1 gene. Nucl. Acids Res. 21:2619–2626, 1993.PubMedCrossRefGoogle Scholar
  27. Feschenko MS, KJ Sweadner: Conformation-dependent phosphorylation of Na,K-ATPase by protein kinase A and protein kinase C. J Biol Chem 269:30436–30444, 1994.PubMedGoogle Scholar
  28. Garat C, M Meignan, MA Matthay, DF Luo, C Jayr: Alveolar epithelial fluid clearance mechanisms are intact after moderate hyperoxic lung injury in rats. Chest 111:1381–88, 1997.PubMedCrossRefGoogle Scholar
  29. Geering K. Subunit assembly and posttranslational processing of Na+-pumps. Acta Physiol Scand 146:177–181, 1992.CrossRefGoogle Scholar
  30. Gevondyan NM, VS Gevondyan, NN Modyanov: Location of disulfide bonds in the Na,K-ATPase α subunit. Biochem Molecul Biol Intl 30:347–355, 1993.Google Scholar
  31. Gick GG, Ismail-Beigi F, Edelman IS. Thyroidal regulation of rat renal and hepatic Na,K-ATPase gene expression. J Biol Chem 263:16610–16618, 1988.PubMedGoogle Scholar
  32. Gonzalez-Flecha B, Evelson P, Ridge K, Sznajder JI. Hydrogen peroxide increases Na / K ATPase function in alveolar type II cells. Biochim Biophys Acta 1290:46–52, 1996.PubMedGoogle Scholar
  33. Haddock, PS, MJ Shattock, DJ Hearse. Modulation of cardiac Na-K pump current: role of protein and nonprotein sulfhydryl redox status. Am J Physiol 269:H297–H307, 1995.PubMedGoogle Scholar
  34. Harris ZL, Ridge KM, Gonzalez-Flecha B, Gottlieb L, Zucker A, Sznajder JI. Hyperbaric oxygenation upregulates rate lung Na,K-ATPase. Eur Respir J 9:472–477, 1996PubMedCrossRefGoogle Scholar
  35. Heinecke JW, W Li, GA Francis, JA Goldstein: Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins. J Clin Invest 91:2866–2872, 1993.PubMedCrossRefGoogle Scholar
  36. Horisberger, J-D. The Na,K-ATPase: Structure-Function Relationship. R.G. Landes Co., Austin, 1994.Google Scholar
  37. Hu P, Zhu L, Ischiropoulos H, Matalon S. Peroxynitrite inhibition of oxygen consumption and ion transport in alveolar type II cells. Am J Physiol 266:L628–34, 1994.PubMedGoogle Scholar
  38. Huang W-H, Wang Y, Askari A. (Na+ + K+)-ATPase: inactivation and degradation induced by oxygen radicals. Int J Biochem 24:621–626, 1992.PubMedCrossRefGoogle Scholar
  39. Ingbar DH, Duvick S, Burns CA, Jacobsen E, Dowin R, Savik SD, Gilmore-Hebert M, Jamieson JD. Developmental Regulation of Lung Na, K-ATPase. Am. J. Physiol. (Lung) 270:L619–629, 1996.Google Scholar
  40. Ingbar DH, Wendt CH: Oxidant effects on Na,K-ATPase: If only it were so simple. (Editorial) J Lab Clin Med (In Press) 1997.Google Scholar
  41. Ingbar DH, Wendt CH, Crandell EC: Role of Na,K-ATPase in the resolution of pulmonary edema, inGoogle Scholar
  42. Ingbar DH, Matthay MA Eds.: Pulmonary Edema, volume in Lung Biology in Health & Disease, L’Enfant, C, Ed. M. Dekker (In Press) 1998Google Scholar
  43. Jewell EA, Shamraj OI, Lingrel JB. Isoforms of the α subunit of Na, K-ATPase and their significance. Acta Physiol Scand 146:161–169, 1992.Google Scholar
  44. Julin CM, Zimmerman JJ, Sundaram V, and Chobanian MC. Activated neutrophils inhibit Na+-K+-ATPase in canine renal basolateral membrane. Am J Physiol 262:C1364–C1370, 1992.PubMedGoogle Scholar
  45. Kawakami K, Yanagisawa K, Watanabe Y, Tominaga S, Nagano K: Different factors bind to the regulatory region of the Na,K-ATPase α-1 subunit gene during the cell cycle. FEBS Lett 335:251–254, 1993.PubMedCrossRefGoogle Scholar
  46. Kawakami K, K Masuda, K Nagano, Y Ohkuma, RG Roeder. Characterization of the core promoter of the Na/K-ATPase α1 subunit gene: elements required for transcription by RNA polymerase II and III in vitro. Eur J Biochem 237:440–446, 1996PubMedCrossRefGoogle Scholar
  47. Kim KJ, Suh DJ. Asymmetric effects of H202 on alveolar epithelial barrier properties. Am J Physiol 264:L308–315, 1993.PubMedGoogle Scholar
  48. Kobayashi M, Kawakami K. ATF-1CREB heterodimer is involved in constitutive expression of the housekeeping Na,K-ATPase α-1 subunit gene. Nucl Acids Res 23:2848–2855, 1995.PubMedCrossRefGoogle Scholar
  49. Lane LK: Functional expression of rat α1 Na,K-ATPase containing substitutions for cysteines 454, 458, 459, 513 and 551. Biochem Molecul Biol Intl 31:817–822, 1993.Google Scholar
  50. Lasnier J, OD Wangensteen, LS Schmitz, CR Gross, & DH Ingbar. Terbutaline stimulates alveolar fluid reabsorption in hyperoxic lung injury J. Appl Physiol. 81:1723–1729, 1996PubMedGoogle Scholar
  51. Lescale-Matys L, Putnam DS, McDonough AA. Na+-K+-ATPase α1 and β1-subunit degradation: evidence for multiple subunit specific rates. Am J Physiol 264:C583–C590, 1993.PubMedGoogle Scholar
  52. Lingrel JB, Orlowski J, Shull MM, Price EM. Molecular genetics of Na,K-ATPase. Progress in Nucl Acid Res 38:37–89, 1990CrossRefGoogle Scholar
  53. Liu B, Gick G. Characterization of the 5′ flanking region of the rat Na+/K+-ATPase βl subunit gene. Biochim Biophys Acta 1130:336–338, 1992.PubMedGoogle Scholar
  54. Matalon S: Mechanisms and regulation of ion transport in adult mammaliam alveolar type II pneumocytes. Am J Physiol 261:C727–738, 1991.PubMedGoogle Scholar
  55. Matalon S, DJ Benos, RM Jackson: Biophysical and molecular properties of amiloride-inhibitable Na channels in alveolar epithelial cells. Am J Physiol 271:L1–L22, 1996.PubMedGoogle Scholar
  56. Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am Rev Respir Dis 142:1250–1257, 1990PubMedGoogle Scholar
  57. Matthay MA, Folkesson HG, Verkman AS: Salt and water transport across alveolar and distal airway epithelia in the adult lung. Am J Physiol 270:L487–503, 1996.PubMedGoogle Scholar
  58. McDonough AA, Geering K, Farley RA. The sodium pump needs its β subunit. FASEB J. 4:1598–1605, 1990a.PubMedGoogle Scholar
  59. McDonough AA, Tang M-J, Lescale-Matys L: Ionic regulation of the biosynthesis of Na,K-ATPase subunits. Semin Nephrol 10:400–409, 1990b.PubMedGoogle Scholar
  60. Meharg JV, McGowan-Jordan J, Charles A, Parmelee JT, Cutaia MV, Rounds S. Hydrogen peroxide stimulates sodium-potassium pump activity in cultured pulmonary arterial endothelial cells. Am J Physiol. 265:L613–L621, 1993.PubMedGoogle Scholar
  61. Mircheff AK, Bowen JW, Yiu SC, McDonough AA. Synthesis and translocation of Na+-K+-ATPase α-and β-subunits to plasma membrane in MDCK cells. Am J Physiol 262:C470–C483, 1992.PubMedGoogle Scholar
  62. Mishra OP, M Delivoria-Papadopoulos, G Cahillane, LC Wagerie. Lipid peroxidation as the mechanism of modification of the affinity of the NaK-ATPase active sites for ATP, K, Na and strophanthidin in vitro. Neurochem Res 14:845–851, 1989.PubMedCrossRefGoogle Scholar
  63. Nici L, Dowin R, Jamieson JD, Ingbar DH: Upregulation of rat type II pneumocyte Na,K-ATPase during hyperoxic lung injury. Am J Physiol 26:LL307–314, 1991.Google Scholar
  64. Nomoto M, Gonzales FJ, Mita T, Inoue N, Kawamura M. Analysis of cis-acting regions upstream of the rat Na/K-ATPase α-1 subunit gene by in vivo footprinting. Biochim. Biophys Acta 1264:35–39, 1995.PubMedGoogle Scholar
  65. O’Brodovich H. Epithelial ion transport in the fetal and perinatal lung. Am J Physiol 261:C555–564, 1991.Google Scholar
  66. O’Brodovich HM. The role of active Na transport by lung epithelium in the clearance of airspace fluid. New Horizons 3:240–247, 1995.PubMedGoogle Scholar
  67. Olivera WG, Ridge KM, Sznajder JI. Lung liquid clearance and Na, K-ATPase during acute hyperoxia and recovery in rats. Am J Respir Crit Care Med 152:1229–34, 1995.PubMedGoogle Scholar
  68. Olivera W, Ridge K, Wood LDH, Sznajder JI. Active sodium transport and alveolar epithelial Na-K-ATPase increase during subacute hyperoxia in rats. Am J Physiol. 266:L577–L584, 1994.PubMedGoogle Scholar
  69. Panos R, Bak PM, Simonet WS, Rubin JS, Smith LJ. Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats. J Clin Invest 96:2026–2033, 1995.PubMedCrossRefGoogle Scholar
  70. Planes C, Friedlander G, A Loiseau, C Amiel, C Clerici: Inhibition of Na-K-ATPase activity after prolonged hypoxia in an alveolar epithelial cell line. Am J Physiol 271:L70–L78, 1996.PubMedGoogle Scholar
  71. Ridge KM, Rutschman DH, Factor P, Katz AI, Bertorello AM, Sznajder JI. Differential expression of Na,K-ATPase isoforms in rat alveolar cells. Am J Physiol 273:L246–L255, 1997.PubMedGoogle Scholar
  72. Robison T, Kim KJ. Enhancement of airway epithelial Na,K-ATPase activity by N02 and protective role of nordihydroguaiaretic acid. Am J Physiol (Lung) 270:L266–L272, 1996.Google Scholar
  73. Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element. J Biol Chem 266:11632–11639, 1991.PubMedGoogle Scholar
  74. Sakuma T, HG Folkesson, S Suzuki, G Okaniwa, S Fujimura, MA Matthay. Beta-adrenergic agonist stimulated alveolar fluid clearance in ex vivo human and rat lungs. Am J Respir Crit Car Med 155:506–512, 1997Google Scholar
  75. Saumon G, Basset G: Electrolyte and fluid transport across the mature alveolar epithelium. J Appl Physiol 74:1–15, 1993.PubMedCrossRefGoogle Scholar
  76. Schneeberger EE, McCarthy KM: Cytochemical localization of Na-K-ATPase in rat type II pneumocytes. J Appl Physiol 60:1584–1589, 1986.PubMedCrossRefGoogle Scholar
  77. Shull MM, Pugh DG, Lingrel JB. The human Na, K-ATPase al Gene: characterization of the 5’-flanking region and identification of a restriction fragment length polymorphism. Genomics 6:451–460, 1990.PubMedCrossRefGoogle Scholar
  78. Skou JC: Overview: The Na,K-Pump. Meth Enzymol 156:1–25, 1988.PubMedCrossRefGoogle Scholar
  79. Suzuki S, D Zuege, Berthiaume Y. Sodium-independent modulation of Na,K-ATPase activity by β-adrenergic agonist alveolar type II cells. Am J Physiol 268:L983–990, 1995.PubMedGoogle Scholar
  80. Sweadner KJ. Isozymes of the Na,K-ATPase. Biochim Biophys Acta 1989; 988:185-220. Thet LA. Repair of oxygen-induced lung injury in: physiology of oxygen radicals. Am Physiol Soc, 87–107, 1986Google Scholar
  81. Ueno S, M Kusaba, K Takeda, M Maeda, M Futai, F Izumi, M Kawamura. Functional consequences of subustitution of the disulfide-bonded segment, Cysl27-Cysl50, located in the extracellular domain of the Na,K-ATPase β subunit: Arg l48 is essential for the functional expression of Na,K-ATPase. J Biochem 117:591–596, 1995.PubMedGoogle Scholar
  82. Watanable YU, Kawakami K, Hirayama Y, Nagano K: Transcription factors positively and negatively regulating the Na,K-ATPase α-1 subunit gene. J Biochem 114:849–855, 1993.Google Scholar
  83. Wendt CH, H Towle, R Sharma, S Duvick, K Kawakami, G Gick & Ingbar DH. Regulation of Na,KATPase gene expression in hyperoxia Am J Physiol (Cell) (in press) 1997.Google Scholar
  84. Yagawa Y, Kawakami K, Nagano K. Cloning and analysis of the 5′-flanking region of rat Na+K+-ATPase α-1 subunit gene. Biochim Biophys Acta 1049:286–292, 1990.PubMedGoogle Scholar
  85. Yagawa YS, Kawakami K, Nagano K. Housekeeping Na,K-ATPAse α-1 subunit gene promoter is composed of multiple cis elements to which common and cell type-specific factors bind. Molec Cell Biol 12:4046–4055, 1992.Google Scholar
  86. Yue G, Russell WJ, Benos DJ et al. Increased expression and activity of sodium channels in alveolar type II cells of hyperoxic rats. Proc Natl Acad Sci 92(18):8418–22, 1995.PubMedCrossRefGoogle Scholar
  87. Yue G, S Matalon. Mechanisms and sequelae of increased alveolar fluid clearance in hyperoxic rats. Am J Physiol 272:L407–L412, 1997.PubMedGoogle Scholar
  88. Zheng LP, Du RS, Goodman BE. Effects of acute hyperoxic exposure on solute fluxes across the blood-gas barrier in rat lungs. J Appl Physiol 82:240–247, 1997.PubMedGoogle Scholar
  89. Zolotarjova N. Ho C, Mellgren RL, Askari A, Huang Wu-h. Different sensitivities of native and oxidized forms of Na+/ K+-ATPase to intracellular proteinases. Biochim Biophys Acta 1192:125–131, 1994.PubMedCrossRefGoogle Scholar
  90. Zuege D, Suzuki S, Berthiaume Y. Increase of lung sodium-potassium-ATPase activity during recovery from high permeability pulmonary edema. Am J Physiol 271:L896–L909, 1996.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1998

Authors and Affiliations

  • David H. Ingbar
    • 1
  • Joseph M. Lasnier
    • 1
  • O. Douglas Wangensteen
    • 1
  • Christine H. Wendt
    • 1
  1. 1.Departments of Medicine, Physiology and PediatricsUniversity of Minnesota School of MedicineMinneapolisUSA

Personalised recommendations