This perspective tells the story of the discovery, characterization, and understanding of the surfactant system of the lung; of how investigators from many disciplines studied the system, stimulated by the demonstration of surfactant deficiency in respiratory distress syndrome of the newborn; and of how the resulting knowledge formed a basis for highly successful surfactant substitution treatment for this syndrome. The chapter includes personal reminiscences and reflections of the author and ends with a few thoughts about the present status and future prospects of this field of research.


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Literature Cited

  1. Avery ME, Mead J. 1959. Surface properties in relation to atelectasis and hyaline membrane disease.. Am. J. Dis. Child. 97:517–23 [Google Scholar]
  2. Bangham AD. 1992. “Surface tension” in the lungs [letter].. Nature 359:110 [Google Scholar]
  3. Baritussio AG, Magoon MW, Goerke J, Clements JA. 1981. Precursor-product relationship between rabbit type II cell lamellar bodies and alveolar surface-active material.. Biochim. Biophys. Acta 666:382–93 [Google Scholar]
  4. Batenburg JJ. 1992. Biosynthesis of surfactant lipids.. See Reference 63A 255–81
  5. Benson B, Hawgood S, Schilling J, Clements J, Damm D. et al. 1985. Structure of canine pulmonary surfactant apoprotein: cDNA and complete amino acid sequence.. Proc. Natl. Acad. Sci. USA 82:6379–83 [Google Scholar]
  6. Brown ES. 1956. Lung area from surface tension effects.. Fed. Proc. 15:26 [Google Scholar]
  7. Brown ES. 1964. Isolation and assay of dipalmitoyl lecithin in lung extracts.. Am. J. Physiol. 207:402–6 [Google Scholar]
  8. Brown ES, Johnson RP, Clements JA. 1959. Pulmonary surface tension.. J. Appl. Physiol. 14:717–20 [Google Scholar]
  9. Brumley GW, Chernick V, Hodson WA, Normand C, Fenner A, Avery ME. 1967. Correlations of mechanical stability, morphology, pulmonary surfactant, and phospholipid content in the developing lamb lung.. J. Clin. Invest. 46:863–73 [Google Scholar]
  10. Buckingham S. 1961. Studies on the identification of an antiatelectasis factor in normal sheep lung.. Am. J. Dis. Child. 102:521–22 [Google Scholar]
  11. Buckingham S, Avery ME. 1962. Time of appearance of lung surfactant in the foetal mouse.. Nature 193:688–89 [Google Scholar]
  12. Chevalier G, Collet AJ. 1972. In vivo incorporation of choline-3H, leucine-3H and galactose-3H in alveolar type II pneumocytes in relation to surfactant synthesis. A quantitative radioautographic study in mouse by electron microscopy.. Anat. Rec. 174:289–310 [Google Scholar]
  13. Chu J, Clements JA, Cotton EK, Klaus MH, Sweet AY. et al. 1967. Neonatal pulmonary ischemia. I. Clinical and physiological studies.. Pediatrics 40:709–82 [Google Scholar]
  14. Clark JC, Wert SE, Bachurski CJ, Stahlman MT, Stripp BR. et al. 1995. Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice.. Proc. Natl. Acad. Sci. USA 92:7794–98 [Google Scholar]
  15. Clements JA. 1956. Dependence of pressure-volume characteristics of lungs on intrinsic surface-active material.. Am. J. Physiol. 187:592–92 [Google Scholar]
  16. Clements JA. 1957. Surface tension of lung extracts.. Proc. Soc. Exp. Biol. Med. 95:170–72 [Google Scholar]
  17. Clements JA. 1977. Functions of the alveolar lining.. Am Rev Respir Dis 115:67–71 [Google Scholar]
  18. Clements J. 1996. Lung surface tension and surfactant: the early years.. In History of Respiratory Physiology, ed. J West, New York: Oxford Univ. Press 208–29
  19. Cochrane CG, Revak SD. 1991. Pulmonary surfactant protein B (SP-B): structure-function relationships.. Science 254:566–68 [Google Scholar]
  20. Curstedt T, Jörnvall H, Robertson B, Bergman T, Berggren P. 1987. Two hydrophobic low-molecular-mass protein fractions of pulmonary surfactant. Characterization and biophysical activity.. Eur. J. Biochem. 168:255–62 [Google Scholar]
  21. Davis PA, Gunther RA, Cross CE. 1987. Clearance of instilled surfactant lipid from the lungs of unanesthetized sheep: lipids are differentially transported by nonlymphatic pathways.. J. Lab. Clin. Med. 109:191–200 [Google Scholar]
  22. Dobbs LG, Mason RJ. 1978. Stimulation of secretion of disaturated phosphatidylcholine from isolated alveolar type II cells by 12-O-tetradecanoyl-13-phorbol acetate.. Am. Rev. Respir. Dis. 118:705–33 [Google Scholar]
  23. Dobbs LG, Wright JR, Hawgood S, Gonzalez R, Venstrom K, Nellenbogen J. 1987. Pulmonary surfactant and its components inhibit secretion of phosphatidylcholine from cultured rat alveolar type II cells.. Proc. Natl. Acad. Sci. USA 84:1010–14 [Google Scholar]
  24. Durand DJ, Clyman RI, Heymann MA, Clements JA, Mauray F. et al. 1985. Effects of a protein-free, synthetic surfactant on survival and pulmonary function in preterm lambs.. J. Pediatr. 107:775–80 [Google Scholar]
  25. Enhorning G, Robertson B. 1972. Lung expansion in the premature rabbit fetus after tracheal deposition of surfactant.. Pediatrics 50:58–66 [Google Scholar]
  26. Froh D, Gonzales LW, Ballard PL. 1993. Secretion of surfactant protein A and phosphatidylcholine from type II cells of human fetal lung.. Am. J. Respir. Cell. Mol. Biol. 8:556–61 [Google Scholar]
  27. Fujiwara T, Maeta H, Chida S, Morita T. 1979. Improved lung-thorax compliance and prevention of neonatal pulmonary lesion in prematurely delivered rabbit neonates subjected to IPPV after tracheal instillation of artificial surfactant.. IRCS Med. Sci. 7:313 [Google Scholar]
  28. Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. 1980. Artificial surfactant therapy in hyaline membrane disease.. Lancet 1:55–59 [Google Scholar]
  29. Gil J, Reiss OK. 1973. Isolation and characterization of lamellar bodies and tubular myelin from rat lung homogenates.. J. Cell Biol. 58:152–71 [Google Scholar]
  30. Gil J, Weibel ER. 1969. Improvement in demonstration of lining layer of lung alveoli by electron microscopy.. Respir. Physiol. 8:13–36 [Google Scholar]
  31. Glasser SW, Korfhagen TR, Perme CM, Pilot MT, Kister SE, Whitsett JA. 1988. Two SP-C genes encoding human pulmonary surfactant proteolipid.. J. Biol. Chem. 263:10326–31 [Google Scholar]
  32. Glasser SW, Korfhagen TR, Weaver T, Pilot-Matias T, Fox JL, Whitsett JA. 1987. cDNA and deduced amino acid sequence of human pulmonary surfactant-associated proteolipid SPL(Phe).. Proc. Natl. Acad. Sci. USA 84:4007–11 [Google Scholar]
  33. Gross NJ, Narine KR. 1989. Surfactant subtypes in mice: metabolic relationships and conversion in vitro.. J. Appl. Physiol. 67:414–21 [Google Scholar]
  34. Hallman M, Epstein BL, Gluck L. 1981. Analysis of labeling and clearance of lung surfactant phospholipids in rabbit. Evidence of bi-directional surfactant flux between lamellar bodies and alveolar lavage.. J. Clin. Invest. 68:742–51 [Google Scholar]
  35. Hawgood S, Benson BJ, Schilling J, Damm D, Clements JA, White RT. 1987. Nucleotide and amino acid sequences of pulmonary surfactant protein SP 18 and evidence for cooperation between SP 18 and SP 28–36 in surfactant lipid adsorption.. Proc. Natl. Acad. Sci. USA 84:66–70 [Google Scholar]
  36. Hills BA. 1981. What is the true role of surfactant in the lung?. Thorax 36:1–4 [Google Scholar]
  37. Jobe AH, Rider ED. 1992. Catabolism and recycling of surfactant.. See Reference 63A 313–37
  38. Johansson J, Szyperski T, Wuthrich K. 1995. Pulmonary surfactant-associated polypeptide SP-C in lipid micelles: CD studies of intact SP-C and NMR secondary structure determination of depalmitoyl-SP-C(1–17).. FEBS. Lett 362:261–65 [Google Scholar]
  39. Keough KMW. 1992. Physical chemistry of pulmonary surfactant in the terminal air spaces.. See Reference 63A 109–64
  40. Kikkawa Y, Yoneda K. 1974. The type II epithelial cell of the lung. I. Method of isolation.. Lab. Invest. 30:76–84 [Google Scholar]
  41. King RJ. 1974. The surfactant system of the lung.. Fed. Proc. 33:2238–47 [Google Scholar]
  42. Klaus M, Reiss OK, Tooley WH, Piel C, Clements JA. 1962. Alveolar epithelial cell mitochondria as source of the surface-active lung lining.. Science 137:750–51 [Google Scholar]
  43. Klaus MH, Clements JA, Havel RJ. 1961. Composition of surface-active material isolated from beef lung.. Proc. Natl. Acad. Sci. USA 47:1858–59 [Google Scholar]
  44. Kuroki Y. 1992. Surfactant protein SP-D.. See Reference 63A 77–85
  45. Lau MJ, Keough KMW. 1981. Lipid composition of lung and lung lavage fluid from map turtles maintained at different environmental temperatures.. Can. J. Biochem. 59:208–19 [Google Scholar]
  46. Liggins GC. 1969. Premature delivery of foetal lambs infused with glucocorticoids.. J. Endocrinol. 45:515–23 [Google Scholar]
  47. Liggins GC, Howie RN. 1972. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.. Pediatrics 50:515–25 [Google Scholar]
  48. Long W, Thompson T, Sundell H, Schumacher R, Volberg F, Guthrie R. 1991. Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700- to 1350-gram infants with respiratory distress syndrome. The American Exosurf Neonatal Study Group I.. J. Pediatr. 118:595–605 [Google Scholar]
  49. Magoon MW, Wright JR, Baritussio A, Williams MC, Goerke J. et al. 1983. Subfractionation of lung surfactant. Implications for metabolism and surface activity.. Biochim. Biophys. Acta 750:18–31 [Google Scholar]
  50. Manabe T. 1979. Freeze-fracture study of alveolar lining layer in adult rat lungs.. J. Ultrastruct. Res. 69:86–97 [Google Scholar]
  51. Mason RJ, Williams MC, Greenleaf RD, Clements JA. 1977. Isolation and properties of type II alveolar cells from rat lung.. Am. Rev. Resp. Dis. 115:1015–26 [Google Scholar]
  52. Mead J, Whittenberger JL, Radford EP. 1957. Surface tension as a factor in pulmonary volume-pressure hysteresis.. J. Appl. Physiol. 10:191–96 [Google Scholar]
  53. Nicholas TE, Power J, Barr HA. 1982. Surfactant homeostasis in the rat lung during swimming exercise.. J. Appl. Physiol. 53:1521–28 [Google Scholar]
  54. Nogee LM, de Mello DE, Dehner LP, Colten HR. 1993. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis.. N. Engl. J. Med. 328:406–10 [Google Scholar]
  55. Oyarzun MJ, Clements JA. 1978. Control of lung surfactant by ventilation, adrenergic mediators, and prostaglandins in the rabbit.. Am. Rev. Respir. Dis. 117:879–91 [Google Scholar]
  56. Pattle RE. 1955. Properties, function and origin of the alveolar lining layer.. Nature 175:1125–26 [Google Scholar]
  57. Pattle RE, Thomas LC. 1961. Lipoprotein composition of the film lining of the lung.. Nature 189:844 [Google Scholar]
  58. Persson A, Chang D, Rust K, Moxley M, Longmore W, Crouch E. 1989. Purification and biochemical characterization of CP4 (SP-D), a collagenous surfactant-associated protein.. Biochemistry 28:6361–67 [Google Scholar]
  59. Phibbs RH, Ballard RA, Clements JA, Heilbron DC, Phibbs CS. et al. 1991. Initial clinical trial of EXOSURF, a protein-free synthetic surfactant, for the prophylaxis and early treatment of hyaline membrane disease.. Pediatrics 88:1–9 [Google Scholar]
  60. Phizackerley P, Town MH, Newman GE. 1979. Hydrophobic proteins of lamellated osmiophilic bodies isolated from pig lung.. Biochem. J. 183:731–36 [Google Scholar]
  61. Post M, Smith BT. 1992. Hormonal control of surfactant metabolism.. See Reference 63A 379–424
  62. Poulain FR, Clements JA. 1995. Pulmonary surfactant therapy.. West. J. Med. 162:43–50 [Google Scholar]
  63. Radford EJ. 1954. Method for estimating respiratory surface area of mammalian lungs from their physical characteristics.. Proc. Soc. Exp. Biol. Med. 87:58–61 [Google Scholar]
  64. Robertson B, van Golde LMG, Batenburg JJ. 1992. Pulmonary Surfactant. Amsterdam: Elsevier [Google Scholar]
  65. Scarpelli EM, Mautone AJ. 1995. The surface monolayer theory does not explain surfactant function in vivo [letter].. Pediatr. Pulmonol. 19:198–202 [Google Scholar]
  66. Schürch S, Goerke J, Clements JA. 1976. Direct determination of surface tension in the lung.. Proc. Natl. Acad. Sci. USA 73:4698–702 [Google Scholar]
  67. Schürch S, Possmayer F, Cheng S, Cockshutt AM. 1992. Pulmonary SP-A enhances adsorption and appears to induce surface sorting of lipid extract surfactant.. Am. J. Physiol. 263:L210–18 [Google Scholar]
  68. Suzuki Y, Fujita Y, Kogishi K. 1989. Reconstitution of tubular myelin from synthetic lipids and proteins associated with pig pulmonary surfactant.. Am. Rev. Respir. Dis. 140:75–81 [Google Scholar]
  69. Thet LA, Clerch L, Massaro GD, Massaro D. 1979. Changes in sedimentation of surfactant in ventilated excised rat lungs. Physical alterations in surfactant associated with the development and reversal of atelectasis.. J. Clin. Invest. 64:600–8 [Google Scholar]
  70. Tooley WH, Clements JA, Muramatsu K, Brown CL, Schlueter MA. 1987. Lung function in prematurely delivered rabbits treated with a synthetic surfactant.. Am. Rev. Respir. Dis. 136:651–56 [Google Scholar]
  71. van Iwaarden JF, van Strijp JA, Ebskamp MJ, Welmers AC, Verhoef J, van Golde LM. 1991. Surfactant protein A is opsonin in phagocytosis of herpes simplex virus type 1 by rat alveolar macrophages.. Am. J. Physiol. 261:L204–9 [Google Scholar]
  72. von Neergaard K. 1929. Neue Auffasungen über einen Grundbegriff der Atemmechanik.. Z. Gesamte. Exp. Med. 66:373–94 [Google Scholar]
  73. Weaver TE. 1992. Biosynthesis and intracellular processing of surfactant proteins.. See Reference 63A 283–93
  74. Weibel ER, Kistler GS, Töndury G. 1966. A stereologic electron microscope study of “tubular myelin figures” in alveolar fluids of rat lungs.. Z. Zellforschung. 69:418–27 [Google Scholar]
  75. Whitsett JA, Ohning BL, Ross G, Meuth J, Weaver T. et al. 1986. Hydrophobic surfactant-associated protein in whole lung surfactant and its importance for biophysical activity in lung surfactant extracts used for replacement therapy.. Pediatr. Res. 20:460–67 [Google Scholar]
  76. Williams MC. 1982. Ultrastructure of tubular myelin and lamellar bodies in fast-frozen adult rat lung.. Exp. Lung Res. 4:37–46 [Google Scholar]
  77. Williams MC, Hawgood S, Hamilton RL. 1991. Changes in lipid structure produced by surfactant proteins SP-A, SP-B, and SP-C.. Am. J. Respir. Cell. Mol. Biol. 5:41–50 [Google Scholar]
  78. Wirtz HR, Dobbs LG. 1990. Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells.. Science 250:1266–69 [Google Scholar]
  79. Wright JR, Wager RE, Hawgood S, Dobbs L, Clements JA. 1987. Surfactant apoprotein Mr = 26,000–36,000 enhances uptake of liposomes by type II cells.. J. Biol. Chem. 262:2888–94 [Google Scholar]
  80. Wright JR, Youmans DC. 1993. Pulmonary surfactant protein A stimulates chemotaxis of alveolar macrophage.. Am. J. Physiol. 264:L338–44 [Google Scholar]
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