Respiratory distress syndrome is a common problem in preterm infants and the etiology is multifactorial. Lung underdevelopment, lung hypoplasia, abnormal lung water metabolism, inflammation, and pulmonary surfactant deficiency or disfunction play a variable role in the pathogenesis of respiratory distress syndrome. High-quality exogenous surfactant replacement studies and studies on surfactant metabolism are available; however, the contribution of surfactant deficiency, alteration or dysfunction in selected neonatal lung conditions is not fully understood. In this article, we describe a series of studies made by applying stable isotope tracers to the study of surfactant metabolism and lung water. In a first set of studies, which we call ‘endogenous studies', using stable isotope-labelled intravenous surfactant precursors, we showed the feasibility of measuring surfactant synthesis and kinetics in infants using several metabolic precursors including plasma glucose, plasma fatty acids and body water. In a second set of studies, named ‘exogenous studies', using stable isotope-labelled phosphatidylcholine tracer given endotracheally, we could estimate surfactant disaturated phosphatidylcholine pool size and half-life. Very recent studies are focusing on lung water and on the endogenous biosynthesis of the surfactant-specific proteins. Information obtained from these studies in infants will help to better tailor exogenous surfactant treatment in neonatal lung diseases.

1.
Phelps DS: Surfactant regulation of host defense function in the lung: a question of balance. Pediatr Pathol Mol Med 2001;20:269-292.
2.
Hunt AN, Kelly FJ, Postle AD: Developmental variation in whole human lung phosphatidylcholine molecular species: a comparison with guinea pig and rat. Early Hum Dev 1991;25:157-171.
3.
Haagsman HP, Diemel RV: Surfactant-associated proteins: functions and structural variation. Comp Biochem Physiol A Mol Integr Physiol 2001;129:91-108.
4.
Korfhagen TR, Bruno MD, Ross GF, Huelsman KM, Ikegami M, Jobe AH, Wert SE, Stripp BR, Morris RE, Glasser SW, Bachurski CJ, Iwamoto HS, Whitsett JA: Altered surfactant function and structure in SP-A gene targeted mice. Proc Natl Acad Sci USA 1996;93:9594-9599.
5.
Crouch EC: Collectins and pulmonary host defense. Am J Respir Cell Mol Biol 1998;19:177-201.
6.
Botas C, Poulain F, Akiyama J, Brown C, Allen L, Goerke J, Clements J, Carlson E, Gillespie AM, Epstein C, Hawgood S: Altered surfactant homeostasis and alveolar type II cell morphology in mice lacking surfactant protein D. Proc Natl Acad Sci USA 1998;95:11869-11874.
7.
Nogee LM, de Mello DE, Dehner LP, Colten HR: Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med 1993;328:406-410.
8.
deMello DE, Heyman S, Phelps DS, Hamvas A, Nogee L, Cole S, Colten HR: Ultrastructure of lung in surfactant protein B deficiency. Am J Respir Cell Mol Biol 1994;11:230-239.
9.
Glasser SW, Burhans MS, Korfhagen TR, Na CL, Sly PD, Ross GF, Ikegami M, Whitsett JA: Altered stability of pulmonary surfactant in SP-C-deficient mice. Proc Natl Acad Sci USA 2001;98:6366-6371.
10.
Rebello CM, Jobe AH, Eisele JW, Ikegami M: Alveolar and tissue surfactant pool sizes in humans. Am J Respir Crit Care Med 1996;154:625-628.
11.
Jobe A, Ikegami M: Movement of fluid and particles between the airspaces and pulmonary interstitium protein permeability abnormalities in the preterm; in Effros R, Chang H (eds): Fluid and Solute Transport in the Airspaces of the Lungs (Lung Biology in Health and Disease). New York, Marcel Dekker, 1994, pp 335-355.
12.
Batenburg JJ: Surfactant phospholipids: synthesis and storage. Am J Physiol 1992;262:L367-L385.
13.
Jacobs H, Jobe A, Ikegami M, Conaway D: The significance of reutilization of surfactant phosphatidylcholine. J Biol Chem 1983;258:4156-4165.
14.
Wright JR, Dobbs LG: Regulation of pulmonary surfactant secretion and clearance. Annu Rev Physiol 1991;53:395-414.
15.
Martini WZ, Chinkes DL, Barrow RE, Murphey ED, Wolfe RR: Lung surfactant kinetics in conscious pigs. Am J Physiol 1999;277:E187-E195.
16.
Jacobs HC, Ikegami M, Jobe AH, Berry DD, Jones S: Reutilization of surfactant phosphatidylcholine in adult rabbits. Biochim Biophys Acta 1985;837:77-84.
17.
Jobe A, Ikegami M, Sarton-Miller I, Barajas L: Surfactant metabolism of newborn lamb lungs in vivo. J Appl Physiol 1980;49:1091-1098.
18.
Jobe A: Metabolism of endogenous surfactant and exogenous surfactant for replacement therapy. Semin Perinatol 1988;12:231-239.
19.
Jobe A, Ikegami M, Glatz T, Yoshida Y, Diakomanolis E, Padbury J: Saturated phosphatidylcholine secretion and the effect of natural surfactant on premature and term lambs ventilated for 2 days. Exp Lung Res 1983;4:259-267.
20.
Bunt JE, Zimmermann LJ, Wattimena JL, van Beek RH, Sauer PJ, Carnielli VP: Endogenous surfactant turnover in preterm infants measured with stable isotopes. Am J Respir Crit Care Med 1998;157:810-814.
21.
Merchak A, Janssen DJ, Bohlin K, Patterson BW, Zimmermann LJ, Carnielli VP, Hamvas A: Endogenous pulmonary surfactant metabolism is not affected by mode of ventilation in premature infants with respiratory distress syndrome. J Pediatr 2002;140:693-698.
22.
Cavicchioli P, Zimmermann LJ, Cogo PE, Badon T, Giordano G, Torresin M, Zacchello F, Carnielli VP: Endogenous surfactant turnover in preterm infants with respiratory distress syndrome studied with stable isotope lipids. Am J Respir Crit Care Med 2001;163:55-60.
23.
Bohlin K, Merchak A, Spence K, Patterson BW, Hamvas A: Endogenous surfactant metabolism in newborn infants with and without respiratory failure. Pediatr Res 2003;54:185-191.
24.
Cogo PE, Zimmermann LJ, Rosso F, Tormena F, Gamba P, Verlato G, Baritussio A, Carnielli VP: Surfactant synthesis and kinetics in infants with congenital diaphragmatic hernia. Am J Respir Crit Care Med 2002;166:154-158.
25.
Janssen DJMT: Surfactant Phosphatidylcholine Metabolism in Severe Neonatal Lung Disease Studied with Stable Isotopes. Rotterdam, Erasmus MC, 2003.
26.
Glatz T, Ikegami M, Jobe A: Metabolism of exogenously administered natural surfactant in the newborn lamb. Pediatr Res 1982;16:711-715.
27.
Seidner SR, Jobe AH, Coalson JJ, Ikegami M: Abnormal surfactant metabolism and function in preterm ventilated baboons. Am J Respir Crit Care Med 1998;158:1982-1989.
28.
Bunt JE, Carnielli VP, Janssen DJ, Wattimena JLD, Hop WC, Sauer PJJ, Zimmermann LJI: Treatment with exogenous surfactant stimulates endogenous surfactant synthesis in premature infants with respiratory distress syndrome. Crit Care Med 2000;28:3383-3388.
29.
Cogo PE, Carnielli VP, Bunt JEH, Badon T, Giordano G, Zacchello F, Sauer PJJ, Zimmermann LJI: Endogenous surfactant metabolism in critically ill infants measured with stable isotopes labeled fatty acids. Pediatr Res 1999;45:242-246.
30.
Gersovitz M, Munro HN, Udall J, Young VR: Albumin synthesis in young and elderly subjects using a new stable isotope methodology: response to level of protein intake. Metabolism 1980;29:1075-1086.
31.
Tessari P, Kiwanuka E, Millioni R, Vettore M, Puricelli L, Zanetti M, Gucciardi A, Tosolini M, Cogo P, Carnielli V, Tiengo A, Barazzoni R: Albumin and fibrinogen synthesis and insulin effect in type 2 diabetic patients with normoalbuminuria. Diabetes Care 2006;29:323-328.
32.
Cogo P, Baritussio A, Rosso F, Gucciardi A, Moretti V, Badon T, Duner E, Zimmernann L, Carnielli VP: Surfactant-associated protein B kinetics in vivo in newborn infants by stable isotopes. Pediatr Res 2005;57:519-522.
33.
Simonato M, Baritussio A, Pioselli B, Ori C, Catinella S, Carnielli VP, Cogo PE: Surfactant protein C metabolism in human infants and adult patients by stable isotope tracer and mass spectrometry. Anal Bioanal Chem 2014;406:6225-6233.
34.
Oulton M, Fraser M, Dolphin M, Yoon R, Faulkner G: Quantification of surfactant pool sizes in rabbit lung during perinatal development. J Lipid Res 1986;27:602-612.
35.
Gluck L, Kulovich MV, Borer RC Jr, Keidel WN: The interpretation and significance of the lecithin-sphingomyelin ratio in amniotic fluid. Am J Obstet Gynecol 1974;120:142-155.
36.
Faridy EE, Thliveris JA: Rate of secretion of lung surfactant before and after birth. Respir Physiol 1987;68:269-277.
37.
Hallman M, Merritt TA, Pohjavuori M, Gluck L: Effect of surfactant substitution on lung effluent phospholipids in respiratory distress syndrome: evaluation of surfactant phospholipid turnover, pool size, and the relationship to severity of respiratory failure. Pediatr Res 1986;20:1228-1235.
38.
Griese M, Dietrich P, Reinhardt D: Pharmacokinetics of bovine surfactant in neonatal respiratory distress syndrome. Am J Respir Crit Care Med 1995;152:1050-1054.
39.
Torresin M, Zimmermann LJ, Cogo PE, Cavicchioli P, Badon T, Giordano G, Zacchello F, Sauer PJ, Carnielli VP: Exogenous surfactant kinetics in infant respiratory distress syndrome: a novel method with stable isotopes. Am J Respir Crit Care Med 2000;161:1584-1589.
40.
Cogo PE, Zimmermann LJ, Meneghini L, Mainini N, Bordignon L, Suma V, Buffo M, Carnielli VP: Pulmonary surfactant disaturated-phosphatidylcholine (DSPC) turnover and pool size in newborn infants with congenital diaphragmatic hernia (CDH). Pediatr Res 2003;54:653-658.
41.
Spragg RG, Li J: Effect of phosphocholine cytidylyltransferase overexpression on phosphatidylcholine synthesis in alveolar type II cells and related cell lines. Am J Respir Cell Mol Biol 2000;22:116-124.
42.
Rooney SA, Gobran LI, Marino PA, Maniscalco WM, Gross I: Effects of betamethasone on phospholipid content, composition and biosynthesis in the fetal rabbit lung. Biochim Biophys Acta 1979;572:64-76.
43.
Ballard PL: Hormonal regulation of pulmonary surfactant. Endocr Rev 1989;10:165-181.
44.
Pope TS, Rooney SA: Effects of glucocorticoid and thyroid hormones on regulatory enzymes of fatty acid synthesis and glycogen metabolism in developing fetal rat lung. Biochim Biophys Acta 1987;918:141-148.
45.
Post M, Barsoumian A, Smith BT: The cellular mechanism of glucocorticoid acceleration of fetal lung maturation. Fibroblast-pneumonocyte factor stimulates choline-phosphate cytidylyltransferase activity. J Biol Chem 1986;261:2179-2184.
46.
Kessler DL, Truog WE, Murphy JH, Palmer S, Standaert TA, Woodrum DE, Hodson WA: Experimental hyaline membrane disease in the premature monkey: effects of antenatal dexamethasone. Am Rev Respir Dis 1982;126:62-69.
47.
Bunt JH, Carnielli VP, Seidner SR, Ikegami M, Wattimena JLD, Sauer PJJ, Jobe AH, Zimmermann LJI: Metabolism of endogenous surfactant in premature baboons and effect of prenatal corticosteroids. Am J Respir Crit Care Med 1999;160:1481-1485.
48.
Bunt JE, Carnielli VP, Wattimena DJL, Hop WC, Sauer PJ, Zimmermann LJ: The effect in premature infants of prenatal corticosteroids on endogenous surfactant synthesis as measured with stable isotopes. Am J Respir Crit Care Med 2000;162:844-849.
49.
Ikegami M, Polk D, Jobe A: Minimum interval from fetal betamethasone treatment to postnatal lung responses in preterm lambs. Am J Obstet Gynecol 1996;174:1408-1413.
50.
Beck JC, Mitzner W, Johnson JW, Hutchins GM, Foidart JM, London WT, Palmer AE, Scott R: Betamethasone and the rhesus fetus: effect on lung morphometry and connective tissue. Pediatr Res 1981;15:235-240.
51.
Walther FJ, Jobe AH, Ikegami M: Repetitive prenatal glucocorticoid therapy reduces oxidative stress in the lungs of preterm lambs. J Appl Physiol 1998;85:273-278.
52.
Walther FJ, Ikegami M, Warburton D, Polk DH: Corticosteroids, thyrotropin-releasing hormone, and antioxidant enzymes in preterm lamb lungs. Pediatr Res 1991;30:518-521.
53.
Verlato G, Cogo PE, Balzani M, Gucciardi A, Burattini I, De Benedictis F, Martiri G, Carnielli VP: Surfactant status in preterm neonates recovering from respiratory distress syndrome. Pediatrics 2008;122:102-108.
54.
Herting E, Gefeller O, Land M, van Sonderen L, Harms K, Robertson B: Surfactant treatment of neonates with respiratory failure and group B streptococcal infection. Members of the Collaborative European Multicenter Study Group. Pediatrics 2000;106:957-964.
55.
Herting E, Moller O, Schiffmann JH, Robertson B: Surfactant improves oxygenation in infants and children with pneumonia and acute respiratory distress syndrome. Acta Paediatr 2002;91:1174-1178.
56.
Finer NN: Surfactant use for neonatal lung injury: beyond respiratory distress syndrome. Paediatr Respir Rev 2004;5(suppl A):S289-S297.
57.
Escande B, Kuhn P, Rivera S, Messer J: Secondary surfactant deficiencies. Arch Pediatr 2004;11:1351-1359.
58.
Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL: Surfactant treatment of full-term newborns with respiratory failure. Pediatrics 1991;87:101-107.
59.
Chinese Collaborative Study Group for Neonatal Respiratory Distress: Treatment of severe meconium aspiration syndrome with porcine surfactant: a multicentre, randomized, controlled trial. Acta Paediatr 2005;94:896-902.
60.
Fetter WP, Baerts W, Bos AP, van Lingen RA: Surfactant replacement therapy in neonates with respiratory failure due to bacterial sepsis. Acta Paediatr 1995;84:14-16.
61.
Hintz SR, Suttner DM, Sheehan AM, Rhine WD, Van Meurs KP: Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): how new treatment modalities have affected ECMO utilization. Pediatrics 2000;106:1339-1343.
62.
Verlato G, Cogo P, Pesavento R, Gomirato S, Benettazzo A, Gucciardi A, Grazzini M, Carnielli V: Surfactant kinetics in newborn infants with pneumonia and respiratory distress syndrome. Ital J Pediatr 2003;29:354-357.
63.
D'Aronco S, Simonato M, Vedovelli L, Baritussio A, Verlato G, Nobile S, Giorgetti C, Nespeca M, Carnielli VP, Cogo PE: Surfactant protein B and A concentrations are increased in neonatal pneumonia. Pediatr Res 2015;78:401-406.
64.
Moses D, Holm BA, Spitale P, Liu MY, Enhorning G: Inhibition of pulmonary surfactant function by meconium. Am J Obstet Gynecol 1991;164:477-481.
65.
Sun B, Curstedt T, Robertson B: Surfactant inhibition in experimental meconium aspiration. Acta Paediatr 1993;82:182-189.
66.
Bae CW, Takahashi A, Chida S, Sasaki M: Morphology and function of pulmonary surfactant inhibited by meconium. Pediatr Res 1998;44:187-191.
67.
Cleary GM, Antunes MJ, Ciesielka DA, Higgins ST, Spitzer AR, Chander A: Exudative lung injury is associated with decreased levels of surfactant proteins in a rat model of meconium aspiration. Pediatrics 1997;100:998-1003.
68.
Dargaville PA, South M, McDougall PN: Surfactant and surfactant inhibitors in meconium aspiration syndrome. J Pediatr 2001;138:113-115.
69.
Lotze A, Whitsett JA, Kammerman LA, Ritter M, Taylor GA, Short BL: Surfactant protein A concentrations in tracheal aspirate fluid from infants requiring extracorporeal membrane oxygenation. J Pediatr 1990;116:435-440.
70.
Lotze A, Knight GR, Martin GR, Bulas DI, Hull WM, O'Donnell RM, Whitsett JA, Short BL: Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation. J Pediatr 1993;122:261-268.
71.
Higgins ST, Wu AM, Sen N, Spitzer AR, Chander A: Meconium increases surfactant secretion in isolated rat alveolar type II cells. Pediatr Res 1996;39:443-447.
72.
Janssen DJ, Tibboel D, Carnielli VP, van Emmen E, Luijendijk IH, Darcos Wattimena JL, Zimmermann LJ: Surfactant phosphatidylcholine pool size in human neonates with congenital diaphragmatic hernia requiring ECMO. J Pediatr 2003;142:247-252.
73.
Sun B, Curstedt T, Robertson B: Exogenous surfactant improves ventilation efficiency and alveolar expansion in rats with meconium aspiration. Am J Respir Crit Care Med 1996;154:764-770.
74.
Halliday HL, Speer CP, Robertson B: Treatment of severe meconium aspiration syndrome with porcine surfactant. Collaborative Surfactant Study Group. Eur J Pediatr 1996;155:1047-1051.
75.
Findlay RD, Taeusch HW, Walther FJ: Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics 1996;97:48-52.
76.
Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH: Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr 1998;132:40-47.
77.
Cochrane CG, Revak SD, Merritt TA, Schraufstatter IU, Hoch RC, Henderson C, Andersson S, Takamori H, Oades ZG: Bronchoalveolar lavage with KL4-surfactant in models of meconium aspiration syndrome. Pediatr Res 1998;44:705-715.
78.
Moller JC, Kohl M, Reiss II, Diederich W, Nitsche EM, Gopel W, Gortner L: Saline lavage with substitution of bovine surfactant in term neonates with meconium aspiration syndrome (MAS) transferred for extracorporeal membrane oxygenation (ECMO): a pilot study. Crit Care 1999;3:19-22.
79.
Wiswell TE, Knight GR, Finer NN, Donn SM, Desai H, Walsh WF, Sekar KC, Bernstein G, Keszler M, Visser VE, Merritt TA, Mannino FL, Mastrioianni L, Marcy B, Revak SD, Tsai H, Cochrane CG: A multicenter, randomized, controlled trial comparing Surfaxin (lucinactant) lavage with standard care for treatment of meconium aspiration syndrome. Pediatrics 2002;109:1081-1087.
80.
Glick PL, Stannard VA, Leach CL, Rossman J, Hosada Y, Morin FC, Cooney DR, Allen JE, Holm B: Pathophysiology of congenital diaphragmatic hernia. II. The fetal lamb CDH model is surfactant deficient. J Pediatr Surg 1992;27:382-387.
81.
Wilcox DT, Glick PL, Karamanoukian HL, Azizkhan RG, Holm BA: Pathophysiology of congenital diaphragmatic hernia. XII. Amniotic fluid lecithin/sphingomyelin ratio and phosphatidylglycerol concentrations do not predict surfactant status in congenital diaphragmatic hernia. J Pediatr Surg 1995;30:410-412.
82.
Sullivan KM, Hawgood S, Flake AW, Harrison MR, Adzick NS: Amniotic fluid phospholipid analysis in the fetus with congenital diaphragmatic hernia. J Pediatr Surg 1994;29:1020-1023.
83.
Moya FR, Thomas VL, Romaguera J, Mysore MR, Maberry M, Bernard A, Freund M: Fetal lung maturation in congenital diaphragmatic hernia. Am J Obstet Gynecol 1995;173:1401-1405.
84.
Minowa H, Takahashi Y, Kawaguchi C, Sadou T, Konishi N, Nishikubo T, Yoshioka A: Expression of intrapulmonary surfactant apoprotein-A in autopsied lungs: comparative study of cases with or without pulmonary hypoplasia. Pediatr Res 2000;48:674-678.
85.
Ijsselstijn I, Zimmermann LJ, Bunt JE, de Jongste JC, Tibboel D: Prospective evaluation of surfactant composition in bronchoalveolar lavage fluid of infants with congenital diaphragmatic hernia and of age-matched controls. Crit Care Med 1998;26:573-580.
86.
Cogo PE, Zimmermann LJ, Verlato G, Midrio P, Gucciardi A, Ori C, Carnielli VP: A dual stable isotope tracer method for the measurement of surfactant disaturated-phosphatidylcholine net synthesis in infants with congenital diaphragmatic hernia. Pediatr Res 2004;56:184-190.
87.
Bos AP, Tibboel D, Hazebroek FW, Molenaar JC, Lachmann B, Gommers D: Surfactant replacement therapy in high-risk congenital diaphragmatic hernia. Lancet 1991;338:1279.
88.
Glick PL, Leach CL, Besner GE, Egan EA, Morin FC, Malanowska-Kantoch A, Robinson LK, et al: Pathophysiology of congenital diaphragmatic hernia. III. Exogenous surfactant therapy for the high-risk neonate with CDH. J Pediatr Surg 1992;27:866-869.
89.
Lotze A, Knight GR, Anderson KD, Hull WM, Whitsett JA, O'Donnell RM, Martin G, Bulas DI, Short BL: Surfactant (beractant) therapy for infants with congenital diaphragmatic hernia on ECMO: evidence of persistent surfactant deficiency. J Pediatr Surg 1994;29:407-412.
90.
Van Meurs K: Is surfactant therapy beneficial in the treatment of the term newborn infant with congenital diaphragmatic hernia? J Pediatr 2004;145:312-316.
91.
Lally KP, Lally PA, Langham MR, Hirschl R, Moya FR, Tibboel D, Van Meurs K: Surfactant does not improve survival rate in preterm infants with congenital diaphragmatic hernia. J Pediatr Surg 2004;39:829-833.
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