Advances in physiology and biochemistry have provided fundamental insights into the role of pulmonary surfactant in the pathogenesis and treatment of preterm infants with respiratory distress syndrome. Identification of the surfactant proteins, lipid transporters, and transcriptional networks regulating their expression has provided the tools and insights needed to discern the molecular and cellular processes regulating the production and function of pulmonary surfactant prior to and after birth. Mutations in genes regulating surfactant homeostasis have been associated with severe lung disease in neonates and older infants. Biophysical and transgenic mouse models have provided insight into the mechanisms underlying surfactant protein and alveolar homeostasis. These studies have provided the framework for understanding the structure and function of pulmonary surfactant, which has informed understanding of the pathogenesis of diverse pulmonary disorders previously considered idiopathic. This review considers the pulmonary surfactant system and the genetic causes of acute and chronic lung disease caused by disruption of alveolar homeostasis.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Metzger RJ, Klein OD, Martin GR, Krasnow MA. 1.  2008. The branching programme of mouse lung development. Nature 453:745–50 [Google Scholar]
  2. Perl AK, Wert SE, Nagy A, Lobe CG, Whitsett JA. 2.  2002. Early restriction of peripheral and proximal cell lineages during formation of the lung. PNAS 99:10482–87 [Google Scholar]
  3. Morrisey EE, Hogan BL. 3.  2010. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev. Cell 18:8–23 [Google Scholar]
  4. Warburton D, El-Hashash A, Carraro G, Tiozzo C, Sala F. 4.  et al. 2010. Lung organogenesis. Curr. Top. Dev. Biol. 90:73–158 [Google Scholar]
  5. Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH. 5.  et al. 1996. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 10:60–69 [Google Scholar]
  6. Que J, Luo X, Schwartz RJ, Hogan BL. 6.  2009. Multiple roles for Sox2 in the developing and adult mouse trachea. Development 136:1899–907 [Google Scholar]
  7. Tompkins DH, Besnard V, Lange AW, Keiser AR, Wert SE. 7.  et al. 2011. Sox2 activates cell proliferation and differentiation in the respiratory epithelium. Am. J. Respir. Cell Mol. Biol. 45:101–10 [Google Scholar]
  8. Rockich BE, Hrycaj SM, Shih HP, Nagy MS, Ferguson MA. 8.  et al. 2013. Sox9 plays multiple roles in the lung epithelium during branching morphogenesis. PNAS 110:E4456–64 [Google Scholar]
  9. Hajihosseini MK, Wilson S, De Moerlooze L, Dickson C. 9.  2001. A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes. PNAS 98:3855–60 [Google Scholar]
  10. Zackai EH, McDonald-McGinn DM, Stolle C, Huff DS. 10.  2003. Craniosynostosis with tracheal sleeve: a patient with Pfeiffer syndrome, tracheal sleeve and additional malformations in whom an FGFR2 mutation was found. Clin. Dysmorphol. 12:209 [Google Scholar]
  11. Kang S, Graham JM Jr, Olney AH, Biesecker LG. 11.  1997. GLI3 frameshift mutations cause autosomal dominant Pallister–Hall syndrome. Nat. Genet. 15:266–68 [Google Scholar]
  12. Williamson KA, Hever AM, Rainger J, Rogers RC, Magee A. 12.  et al. 2006. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum. Mol. Genet. 15:1413–22 [Google Scholar]
  13. Guillot L, Carre A, Szinnai G, Castanet M, Tron E. 13.  et al. 2010. NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome.”. Hum. Mutat. 31:E1146–62 [Google Scholar]
  14. Hamvas A, Deterding RR, Wert SE, White FV, Dishop MK. 14.  et al. 2013. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 144:794–804 [Google Scholar]
  15. Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z. 15.  et al. 2009. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am. J. Hum. Genet. 84:780–91 [Google Scholar]
  16. Xu Y, Wang Y, Besnard V, Ikegami M, Wert SE. 16.  et al. 2012. Transcriptional programs controlling perinatal lung maturation. PLOS ONE 7:e37046 [Google Scholar]
  17. Avery ME, Mead J. 17.  1959. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J. Dis. Child. 97:517–23 [Google Scholar]
  18. Whitsett JA, Wert SE, Weaver TE. 18.  2010. Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease. Annu. Rev. Med. 61:105–19 [Google Scholar]
  19. Bohinski RJ, Di Lauro R, Whitsett JA. 19.  1994. The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis. Mol. Cell. Biol. 14:5671–81 [Google Scholar]
  20. DeFelice M, Silberschmidt D, DiLauro R, Xu Y, Wert SE. 20.  et al. 2003. TTF-1 phosphorylation is required for peripheral lung morphogenesis, perinatal survival, and tissue-specific gene expression. J. Biol. Chem. 278:35574–83 [Google Scholar]
  21. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E. 21.  et al. 2013. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants—2013 update. Neonatology 103:353–68 [Google Scholar]
  22. Polin RA, Carlo WA. 22.  Comm. Fetus Newborn 2014. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics 133:156–63 [Google Scholar]
  23. Bridges JP, Ludwig MG, Mueller M, Kinzel B, Sato A. 23.  et al. 2013. Orphan G protein-coupled receptor GPR116 regulates pulmonary surfactant pool size. Am. J. Respir. Cell Mol. Biol. 49:348–57 [Google Scholar]
  24. Yang MY, Hilton MB, Seaman S, Haines DC, Nagashima K. 24.  et al. 2013. Essential regulation of lung surfactant homeostasis by the orphan G protein-coupled receptor GPR116. Cell Rep. 3:1457–64 [Google Scholar]
  25. Clark JC, Wert SE, Bachurski CJ, Stahlman MT, Stripp BR. 25.  et al. 1995. Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. PNAS 92:7794–98 [Google Scholar]
  26. Korfhagen TR, Bruno MD, Ross GF, Huelsman KM, Ikegami M. 26.  et al. 1996. Altered surfactant function and structure in SP-A gene targeted mice. PNAS 93:9594–99 [Google Scholar]
  27. Ikegami M, Whitsett JA, Jobe A, Ross G, Fisher J, Korfhagen T. 27.  2000. Surfactant metabolism in SP-D gene-targeted mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 279:L468–76 [Google Scholar]
  28. Ikegami M, Na CL, Korfhagen TR, Whitsett JA. 28.  2005. Surfactant protein D influences surfactant ultrastructure and uptake by alveolar type II cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 288:L552–61 [Google Scholar]
  29. McCormack FX, Whitsett JA. 29.  2002. The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung. J. Clin. Investig. 109:707–12 [Google Scholar]
  30. Kingma PS, Whitsett JA. 30.  2006. In defense of the lung: surfactant protein A and surfactant protein D. Curr. Opin. Pharmacol. 6:277–83 [Google Scholar]
  31. Ariki S, Nishitani C, Kuroki Y. 31.  2012. Diverse functions of pulmonary collectins in host defense of the lung. J. Biomed. Biotechnol. 2012:532071 [Google Scholar]
  32. Trapnell BC, Whitsett JA, Nakata K. 32.  2003. Pulmonary alveolar proteinosis. N. Engl. J. Med. 349:2527–39 [Google Scholar]
  33. Perez-Gil J, Weaver TE. 33.  2010. Pulmonary surfactant pathophysiology: current models and open questions. Physiology 25:132–41 [Google Scholar]
  34. Ikegami M, Grant S, Korfhagen T, Scheule RK, Whitsett JA. 34.  2009. Surfactant protein-D regulates the postnatal maturation of pulmonary surfactant lipid pool sizes. J. Appl. Physiol. 106:1545–52 [Google Scholar]
  35. Wert SE, Whitsett JA, Nogee LM. 35.  2009. Genetic disorders of surfactant dysfunction. Pediatr. Dev. Pathol. 12:253–74 [Google Scholar]
  36. Dishop MK. 36.  2011. Paediatric interstitial lung disease: classification and definitions. Paediatr. Respir. Rev. 12:230–37 [Google Scholar]
  37. Kurland G, Deterding RR, Hagood JS, Young LR, Brody AS. 37.  et al. 2013. An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy. Am. J. Respir. Crit. Care Med. 188:376–94 [Google Scholar]
  38. Vorbroker DK, Profitt SA, Nogee LM, Whitsett JA. 38.  1995. Aberrant processing of surfactant protein C in hereditary SP-B deficiency. Am. J. Physiol. Lung Cell. Mol. Physiol. 268:L647–56 [Google Scholar]
  39. Nogee LM, Wert SE, Proffit SA, Hull WM, Whitsett JA. 39.  2000. Allelic heterogeneity in hereditary surfactant protein B (SP-B) deficiency. Am. J. Respir. Crit. Care Med. 161:973–81 [Google Scholar]
  40. Whitsett JA, Weaver TE. 40.  2002. Hydrophobic surfactant proteins in lung function and disease. N. Engl. J. Med. 347:2141–48 [Google Scholar]
  41. Nogee LM. 41.  2004. Alterations in SP-B and SP-C expression in neonatal lung disease. Annu. Rev. Physiol. 66:601–23 [Google Scholar]
  42. Dunbar AE 3rd, Wert SE, Ikegami M, Whitsett JA, Hamvas A. 42.  et al. 2000. Prolonged survival in hereditary surfactant protein B (SP-B) deficiency associated with a novel splicing mutation. Pediatr. Res. 48:275–82 [Google Scholar]
  43. Hamvas A. 43.  2010. Evaluation and management of inherited disorders of surfactant metabolism. Chin. Med. J. 123:2943–47 [Google Scholar]
  44. Palomar LM, Nogee LM, Sweet SC, Huddleston CB, Cole FS, Hamvas A. 44.  2006. Long-term outcomes after infant lung transplantation for surfactant protein B deficiency related to other causes of respiratory failure. J. Pediatr. 149:548–53 [Google Scholar]
  45. Mulugeta S, Nguyen V, Russo SJ, Muniswamy M, Beers MF. 45.  2005. A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation. Am. J. Respir. Cell Mol. Biol. 32:521–30 [Google Scholar]
  46. Johansson H, Nordling K, Weaver TE, Johansson J. 46.  2006. The Brichos domain-containing C-terminal part of pro-surfactant protein C binds to an unfolded poly-val transmembrane segment. J. Biol. Chem. 281:21032–39 [Google Scholar]
  47. Glasser SW, Detmer EA, Ikegami M, Na CL, Stahlman MT, Whitsett JA. 47.  2003. Pneumonitis and emphysema in sp-C gene targeted mice. J. Biol. Chem. 278:14291–98 [Google Scholar]
  48. Glasser SW, Witt TL, Senft AP, Baatz JE, Folger D. 48.  et al. 2009. Surfactant protein C-deficient mice are susceptible to respiratory syncytial virus infection. Am. J. Physiol. Lung Cell. Mol. Physiol. 297:L64–72 [Google Scholar]
  49. Glasser SW, Senft AP, Maxfield MD, Ruetschilling TL, Baatz JE. 49.  et al. 2013. Genetic replacement of surfactant protein-C reduces respiratory syncytial virus induced lung injury. Respir. Res. 14:19 [Google Scholar]
  50. Tanjore H, Blackwell TS, Lawson WE. 50.  2012. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 302:L721–29 [Google Scholar]
  51. Kropski JA, Lawson WE, Young LR, Blackwell TS. 51.  2013. Genetic studies provide clues on the pathogenesis of idiopathic pulmonary fibrosis. Dis. Model. Mech. 6:9–17 [Google Scholar]
  52. Thurm T, Kaltenborn E, Kern S, Griese M, Zarbock R. 52.  2013. SFTPC mutations cause SP-C degradation and aggregate formation without increasing ER stress. Eur. J. Clin. Investig. 43:791–800 [Google Scholar]
  53. Nogee LM, Dunbar AE 3rd, Wert SE, Askin F, Hamvas A, Whitsett JA. 53.  2001. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N. Engl. J. Med. 344:573–79 [Google Scholar]
  54. Nogee LM, Dunbar AE 3rd, Wert S, Askin F, Hamvas A, Whitsett JA. 54.  2002. Mutations in the surfactant protein C gene associated with interstitial lung disease. Chest 121:Suppl.20S–21S [Google Scholar]
  55. Thomas AQ, Lane K, Phillips J 3rd, Prince M, Markin C. 55.  et al. 2002. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am. J. Respir. Crit. Care Med. 165:1322–28 [Google Scholar]
  56. Katzenstein AL, Gordon LP, Oliphant M, Swender PT. 56.  1995. Chronic pneumonitis of infancy. A unique form of interstitial lung disease occurring in early childhood. Am. J. Surg. Pathol. 19:439–47 [Google Scholar]
  57. Bridges JP, Xu Y, Na CL, Wong HR, Weaver TE. 57.  2006. Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. J. Cell Biol. 172:395–407 [Google Scholar]
  58. Avital A, Hevroni A, Godfrey S, Cohen S, Maayan C. 58.  et al. 2014. Natural history of five children with surfactant protein C mutations and interstitial lung disease. Pediatr. Pulmonol. 491097–105
  59. Lawson WE, Grant SW, Ambrosini V, Womble KE, Dawson EP. 59.  et al. 2004. Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax 59:977–80 [Google Scholar]
  60. van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ. 60.  et al. 2010. Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort. Am. J. Respir. Crit. Care Med. 182:1419–25 [Google Scholar]
  61. Hepping N, Griese M, Lohse P, Garbe W, Lange L. 61.  2013. Successful treatment of neonatal respiratory failure caused by a novel surfactant protein C p.Cys121Gly mutation with hydroxychloroquine. J. Perinatol. 33:492–94 [Google Scholar]
  62. Cheong N, Madesh M, Gonzales LW, Zhao M, Yu K. 62.  et al. 2006. Functional and trafficking defects in ATP binding cassette A3 mutants associated with respiratory distress syndrome. J. Biol. Chem. 281:9791–800 [Google Scholar]
  63. Matsumura Y, Ban N, Ueda K, Inagaki N. 63.  2006. Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency. J. Biol. Chem. 281:34503–14 [Google Scholar]
  64. Matsumura Y, Ban N, Inagaki N. 64.  2008. Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 295:L698–707 [Google Scholar]
  65. Weichert N, Kaltenborn E, Hector A, Woischnik M, Schams A. 65.  et al. 2011. Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells. Respir. Res. 12:4 [Google Scholar]
  66. Brasch F, Schimanski S, Muhlfeld C, Barlage S, Langmann T. 66.  et al. 2006. Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. Am. J. Respir. Crit. Care Med. 174:571–80 [Google Scholar]
  67. Bullard JE, Wert SE, Nogee LM. 67.  2006. ABCA3 deficiency: neonatal respiratory failure and interstitial lung disease. Semin. Perinatol. 30:327–34 [Google Scholar]
  68. Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. 68.  2004. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N. Engl. J. Med. 350:1296–303 [Google Scholar]
  69. Somaschini M, Nogee LM, Sassi I, Danhaive O, Presi S. 69.  et al. 2007. Unexplained neonatal respiratory distress due to congenital surfactant deficiency. J. Pediatr. 150:649–53.e1 [Google Scholar]
  70. Edwards V, Cutz E, Viero S, Moore AM, Nogee L. 70.  2005. Ultrastructure of lamellar bodies in congenital surfactant deficiency. Ultrastruct. Pathol. 29:503–9 [Google Scholar]
  71. Doan ML, Guillerman RP, Dishop MK, Nogee LM, Langston C. 71.  et al. 2008. Clinical, radiological and pathological features of ABCA3 mutations in children. Thorax 63:366–73 [Google Scholar]
  72. Young LR, Nogee LM, Barnett B, Panos RJ, Colby TV, Deutsch GH. 72.  2008. Usual interstitial pneumonia in an adolescent with ABCA3 mutations. Chest 134:192–95 [Google Scholar]
  73. Flamein F, Riffault L, Muselet-Charlier C, Pernelle J, Feldmann D. 73.  et al. 2012. Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children. Hum. Mol. Genet. 21:765–75 [Google Scholar]
  74. Cooke KR, Nishinakamura R, Martin TR, Kobzik L, Brewer J. 74.  et al. 1997. Persistence of pulmonary pathology and abnormal lung function in IL-3/GM-CSF/IL-5 βc receptor-deficient mice despite correction of alveolar proteinosis after BMT. Bone Marrow Transplant. 20:657–62 [Google Scholar]
  75. Reed JA, Ikegami M, Robb L, Begley CG, Ross G, Whitsett JA. 75.  2000. Distinct changes in pulmonary surfactant homeostasis in common β-chain and GM-CSF-deficient mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 278:L1164–71 [Google Scholar]
  76. Trapnell BC, Whitsett JA. 76.  2002. GM-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu. Rev. Physiol. 64:775–802 [Google Scholar]
  77. Kitamura T, Tanaka N, Watanabe J, Uchida Kanegasaki S. 77.  et al. 1999. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 190:875–80 [Google Scholar]
  78. Martinez-Moczygemba M, Doan ML, Elidemir O, Fan LL, Cheung SW. 78.  et al. 2008. Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRα gene in the X chromosome pseudoautosomal region 1. J. Exp. Med. 205:2711–16 [Google Scholar]
  79. Suzuki T, Sakagami T, Rubin BK, Nogee LM, Wood RE. 79.  et al. 2008. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J. Exp. Med. 205:2703–10 [Google Scholar]
  80. Suzuki T, Sakagami T, Young LR, Carey BC, Wood RE. 80.  et al. 2010. Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am. J. Respir. Crit. Care Med. 182:1292–304 [Google Scholar]
  81. Dirksen U, Nishinakamura R, Groneck P, Hattenhorst U, Nogee L. 81.  et al. 1997. Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common β chain expression. J. Clin. Investig. 100:2211–17 [Google Scholar]
  82. Tanaka T, Motoi N, Tsuchihashi Y, Tazawa R, Kaneko C. 82.  et al. 2011. Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB. J. Med. Genet. 48:205–9 [Google Scholar]
  83. Suzuki T, Maranda B, Sakagami T, Catellier P, Couture CY. 83.  et al. 2011. Hereditary pulmonary alveolar proteinosis caused by recessive CSF2RB mutations. Eur. Respir. J. 37:201–4 [Google Scholar]
  84. Luisetti M, Kadija Z, Mariani F, Rodi G, Campo I, Trapnell BC. 84.  2010. Therapy options in pulmonary alveolar proteinosis. Ther. Adv. Respir. Dis. 4:239–48 [Google Scholar]
  85. Tazawa R, Trapnell BC, Inoue Y, Arai T, Takada T. 85.  et al. 2010. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 181:1345–54 [Google Scholar]
  86. Luisetti M, Kroneberg P, Suzuki T, Kadija Z, Muellinger B. 86.  et al. 2011. Physical properties, lung deposition modeling, and bioactivity of recombinant GM-CSF aerosolised with a highly efficient nebulizer. Pulm. Pharmacol. Ther. 24:123–27 [Google Scholar]
  87. Malur A, Kavuru MS, Marshall I, Barna BP, Huizar I. 87.  et al. 2012. Rituximab therapy in pulmonary alveolar proteinosis improves alveolar macrophage lipid homeostasis. Respir. Res. 13:46 [Google Scholar]
  88. Leth S, Bendstrup E, Vestergaard H, Hilberg O. 88.  2013. Autoimmune pulmonary alveolar proteinosis: treatment options in year 2013. Respirology 18:82–91 [Google Scholar]
  89. Lachmann N, Happle C, Ackermann M, Luttge D, Wetzke M. 89.  et al. 2014. Gene correction of human induced pluripotent stem cells repairs the cellular phenotype in pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 189:167–82 [Google Scholar]
  90. Suzuki T, Mayhew C, Sallese A, Chalk C, Carey BC. 90.  et al. 2014. Use of induced pluripotent stem cells to recapitulate pulmonary alveolar proteinosis pathogenesis. Am. J. Respir. Crit. Care Med. 189:183–93 [Google Scholar]
  91. Price M, Lazzaro D, Pohl T, Mattei MG, Ruther U. 91.  et al. 1992. Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain. Neuron 8:241–55 [Google Scholar]
  92. Galambos C, Levy H, Cannon CL, Vargas SO, Reid LM. 92.  et al. 2010. Pulmonary pathology in thyroid transcription factor-1 deficiency syndrome. Am. J. Respir. Crit. Care Med. 182:549–54 [Google Scholar]
  93. Kleinlein B, Griese M, Liebisch G, Krude H, Lohse P. 93.  et al. 2011. Fatal neonatal respiratory failure in an infant with congenital hypothyroidism due to haploinsufficiency of the NKX2-1 gene: alteration of pulmonary surfactant homeostasis. Arch. Dis. Child. Fetal Neonatal Ed. 96:F453–56 [Google Scholar]
  94. Iwatani N, Mabe H, Devriendt K, Kodama M, Miike T. 94.  2000. Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure. J. Pediatr. 137:272–76 [Google Scholar]
  95. Maquet E, Costagliola S, Parma J, Christophe-Hobertus C, Oligny LL. 95.  et al. 2009. Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. J. Clin. Endocrinol. Metab. 94:197–203 [Google Scholar]
  96. Salerno T, Peca D, Menchini L, Schiavino A, Petreschi F. 96.  et al. 2014. Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF-1/NKX2.1 gene. Pediatr. Pulmonol. 49:E42–44 [Google Scholar]
  97. Barnett CP, Mencel JJ, Gecz J, Waters W, Kirwin SM. 97.  et al. 2012. Choreoathetosis, congenital hypothyroidism and neonatal respiratory distress syndrome with intact NKX2-1. Am. J. Med. Genet. A 158A:3168–73 [Google Scholar]
  98. Kalinichenko VV, Lim L, Stolz DB, Shin B, Rausa FM. 98.  et al. 2001. Defects in pulmonary vasculature and perinatal lung hemorrhage in mice heterozygous null for the Forkhead Box f1 transcription factor. Dev. Biol. 235:489–506 [Google Scholar]
  99. Rabah R, Poulik JM. 99.  2001. Congenital alveolar capillary dysplasia with misalignment of pulmonary veins associated with hypoplastic left heart syndrome. Pediatr. Dev. Pathol. 4:167–74 [Google Scholar]
  100. Alameh J, Bachiri A, Devisme L, Truffert P, Rakza T. 100.  et al. 2002. Alveolar capillary dysplasia: a cause of persistent pulmonary hypertension of the newborn. Eur. J. Pediatr. 161:262–66 [Google Scholar]
  101. Antao B, Samuel M, Kiely E, Spitz L, Malone M. 101.  2006. Congenital alveolar capillary dysplasia and associated gastrointestinal anomalies. Fetal Pediatr. Pathol. 25:137–45 [Google Scholar]
  102. Miranda J, Rocha G, Soares P, Morgado H, Baptista MJ. 102.  et al. 2013. A novel mutation in FOXF1 gene associated with alveolar capillary dysplasia with misalignment of pulmonary veins, intestinal malrotation and annular pancreas. Neonatology 103:241–45 [Google Scholar]
  103. Nguyen L, Riley MM, Sen P, Galambos C. 103.  2013. Alveolar capillary dysplasia with misalignment of pulmonary veins with a wide spectrum of extrapulmonary manifestations. Pathol. Int. 63:519–21 [Google Scholar]
  104. Sen P, Yang Y, Navarro C, Silva I, Szafranski P. 104.  et al. 2013. Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. Hum. Mutat. 34:801–11 [Google Scholar]
  105. Kolble K, Lu J, Mole SE, Kaluz S, Reid KB. 105.  1993. Assignment of the human pulmonary surfactant protein D gene (SFTP4) to 10q22-q23 close to the surfactant protein A gene cluster. Genomics 17:294–98 [Google Scholar]
  106. Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F. 106.  et al. 2009. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am. J. Hum. Genet. 84:52–59 [Google Scholar]
  107. Maitra M, Wang Y, Gerard RD, Mendelson CR, Garcia CK. 107.  2010. Surfactant protein A2 mutations associated with pulmonary fibrosis lead to protein instability and endoplasmic reticulum stress. J. Biol. Chem. 285:22103–13 [Google Scholar]
  108. Maitra M, Cano CA, Garcia CK. 108.  2012. Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-β1 secretion. PNAS 109:21064–69 [Google Scholar]
  109. Maitra M, Dey M, Yuan WC, Nathanielsz PW, Garcia CK. 109.  2013. Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor β1 secretion in lung epithelial cells. J. Biol. Chem. 288:27159–71 [Google Scholar]
  110. Ferreira Francisco FA, Pereira e Silva JL, Hochhegger B, Zanetti G, Marchiori E. 110.  2013. Pulmonary alveolar microlithiasis. State-of-the-art review. Respir. Med. 107:1–9 [Google Scholar]
  111. Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U. 111.  et al. 2006. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am. J. Hum. Genet. 79:650–56 [Google Scholar]
  112. Huqun Izumi S, Miyazawa H, Ishii K, Uchiyama B. 112.  et al. 2007. Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis. Am. J. Respir. Crit. Care Med. 175:263–68 [Google Scholar]
  113. Yin X, Wang H, Wu D, Zhao G, Shao J, Dai Y. 113.  2013. SLC34A2 gene mutation of pulmonary alveolar microlithiasis: report of four cases and review of literatures. Respir. Med. 107:217–22 [Google Scholar]
  114. Ozcelik U, Yalcin E, Ariyurek M, Ersoz DD, Cinel G. 114.  et al. 2010. Long-term results of disodium etidronate treatment in pulmonary alveolar microlithiasis. Pediatr. Pulmonol. 45:514–17 [Google Scholar]
  115. Garcia CK, Wright WE, Shay JW. 115.  2007. Human diseases of telomerase dysfunction: insights into tissue aging. Nucleic Acids Res. 35:7406–16 [Google Scholar]
  116. Armanios M. 116.  2012. Telomerase and idiopathic pulmonary fibrosis. Mutat. Res. 730:52–58 [Google Scholar]
  117. Gansner JM, Rosas IO. 117.  2013. Telomeres in lung disease. Transl. Res. 162:343–52 [Google Scholar]
  118. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG. 118.  et al. 2007. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356:1317–26 [Google Scholar]
  119. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G. 119.  et al. 2007. Adult-onset pulmonary fibrosis caused by mutations in telomerase. PNAS 104:7552–57 [Google Scholar]
  120. Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC. 120.  et al. 2008. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. PNAS 105:13051–56 [Google Scholar]
  121. Alder JK, Cogan JD, Brown AF, Anderson CJ, Lawson WE. 121.  et al. 2011. Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLOS Genet. 7:e1001352 [Google Scholar]
  122. Mushiroda T, Wattanapokayakit S, Takahashi A, Nukiwa T, Kudoh S. 122.  et al. 2008. A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis. J. Med. Genet. 45:654–56 [Google Scholar]
  123. Parry EM, Alder JK, Qi X, Chen JJ, Armanios M. 123.  2011. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117:5607–11 [Google Scholar]
  124. Fernandez BA, Fox G, Bhatia R, Sala E, Noble B. 124.  et al. 2012. A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients: clinical and genetic features. Respir. Res. 13:64 [Google Scholar]
  125. Diaz de Leon A, Cronkhite JT, Katzenstein AL, Godwin JD, Raghu G. 125.  et al. 2010. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLOS ONE 5:e10680 [Google Scholar]
  126. Garcia CK. 126.  2011. Idiopathic pulmonary fibrosis: update on genetic discoveries. Proc. Am. Thorac. Soc. 8:158–62 [Google Scholar]
  127. Devine MS, Garcia CK. 127.  2012. Genetic interstitial lung disease. Clin. Chest Med. 33:95–110 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error