Advertisement

Mutations in Surfactant Protein C and Interstitial Lung Disease

  • Ralph J. Panos
  • James P. Bridges
Chapter
Part of the Respiratory Medicine book series (RM)

Abstract

Less than 5% of all cases of idiopathic interstitial lung disease (ILD) are due to familial pulmonary fibrosis. The clinical manifestations of familial pulmonary fibrosis are indistinguishable from the presenting symptoms in sporadic idiopathic pulmonary fibrosis. Mutations in SFTPC, the gene encoding surfactant protein C (SP-C), have been identified in kindreds with familial ILD as well as individuals with sporadic IPF. SP-C is a surfactant-associated protein that is essential for the reduction in surface tension at the air–liquid interface within the alveolus and the prevention of end-expiratory alveolar collapse. Because of its hydrophobic properties, SP-C is synthesized as a proprotein that is processed within the secretory pathway of alveolar type II cells as it is conducted to the lamellar body, the intracellular storage site of surfactant. The carboxy terminus of the proprotein appears to function as an intramolecular chaperone that guides posttranslational processing of the SP-C protein and the majority of mutations associated with ILD occur within this domain. Over 50 distinct SFTPC mutations have been identified and individuals with SP-C mutations range in age from infants to adults. The clinical manifestations extend from fatal respiratory failure to no clinically apparent respiratory symptoms. The pattern of inheritance appears to be autosomal dominant with variable penetrance. In infants and children, the most common histopathological pattern is nonspecific interstitial pneumonitis with features of pulmonary alveolar proteinosis. In contrast, usual interstitial pneumonitis is the most frequent pattern in adults. These mutations may cause lung fibrosis through protein misprocessing within the endoplasmic reticulum activating the unfolded protein response, proteasome dysfunction, and alveolar epithelial cell death. Alveolar type II cells expressing SP-C mutant proteins may be more susceptible to environmental factors that may trigger epithelial cell injury, death, and the development of parenchymal fibrosis. Understanding the pathogenetic mechanisms by which mutations in SP-C cause pulmonary fibrosis provides unique insights into the cellular and molecular pathogenesis of the idiopathic interstitial lung diseases.

Keywords

familial interstitial lung disease idiopathic interstitial lung disease surfactant protein surfactant protein C 

References

  1. 1.
    Green FH. Overview of pulmonary fibrosis. Chest 2002;122:334S–39S.PubMedGoogle Scholar
  2. 2.
    Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med 1994;150:967–72.PubMedGoogle Scholar
  3. 3.
    American Thoracic Society. Idiopathic pulmonary fibrosis: Diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161:646–64.Google Scholar
  4. 4.
    Olson AL, Swigris JJ, Lezotte DC, Norris JM, Wilson CG, Brown KK. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med 2007;176(3):277–84.PubMedGoogle Scholar
  5. 5.
    Crystal RG, Bitterman PB, Mossman B, et al. Future research directions in idiopathic pulmonary fibrosis: Summary of a National Heart, Lung, and Blood Institute working group. Am J Respir Crit Care Med 2002;166:236–46.PubMedGoogle Scholar
  6. 6.
    Crystal RG, Fulmer JD, Roberts WC, Moss ML, Line BR, Reynolds HY. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med 1976;85:769–88.PubMedGoogle Scholar
  7. 7.
    Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest 2001;107:1529–36.Google Scholar
  8. 8.
    Hardie WD, Le Cras TD, Jiang K, Tichelaar JW, Azhar M, Korfhagen TR. Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2004;286:L741–L49.PubMedGoogle Scholar
  9. 9.
    Fujita M, Shannon JM, Irvin CG, et al. Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2001;280:L39–L49.PubMedGoogle Scholar
  10. 10.
    Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med 2001;194: 809–21.PubMedGoogle Scholar
  11. 11.
    Zhu Z, Homer RJ, Wang Z, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999;103:779–88.PubMedGoogle Scholar
  12. 12.
    Chen ES, Greenlee BM, Wills-Karp M, Moller DR. Attenuation of lung inflammation and fibrosis in interferon-gamma-deficient mice after intratracheal bleomycin. Am J Respir Cell Mol Biol 2001;24:545–55.PubMedGoogle Scholar
  13. 13.
    Zhao J, Shi W, Wang YL, et al. Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol 2002;282:L585–L93.PubMedGoogle Scholar
  14. 14.
    Nagase T, Uozumi N, Ishii S, et al. A pivotal role of cytosolic phospholipase A(2) in bleomycin-induced pulmonary fibrosis. Nat Med 2002;8:480–84.PubMedGoogle Scholar
  15. 15.
    Peters-Golden M, Bailie M, Marshall T, et al. Protection from pulmonary fibrosis in leukotriene-deficient mice. Am J Respir Crit Care Med 2002;165:229–35.PubMedGoogle Scholar
  16. 16.
    Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: Prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136–51.PubMedGoogle Scholar
  17. 17.
    Munger JS, Huang X, Kawakatsu H, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: A mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999;96:319–28.PubMedGoogle Scholar
  18. 18.
    Kaminski N, Allard JD, Pittet JF, et al. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc Natl Acad Sci USA 2000;97:1778–83.Google Scholar
  19. 19.
    Strieter RM. Pathogenesis and natural history of usual interstitial pneumonia: The whole story or the last chapter of a long novel. Chest 2005;128:526S–32S.PubMedGoogle Scholar
  20. 20.
    Willis BC, du Bois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc 2006;3:377–82.PubMedGoogle Scholar
  21. 21.
    Wang D, Haviland DL, Burns AR, Zsigmond E, Wetsel RA. A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells. Proc Natl Acad Sci USA 2007;104:4449–54.Google Scholar
  22. 22.
    Cool CD, Groshong SD, Rai PR, Henson PM, Stewart JS, Brown KK. Fibroblast foci are not discrete sites of lung injury or repair: The fibroblast reticulum. Am J Respir Crit Care Med 2006;174:654–58.PubMedGoogle Scholar
  23. 23.
    Grutters JC, du Bois RM. Genetics of fibrosing lung diseases. Eur Respir J 2005;25: 915–27.PubMedGoogle Scholar
  24. 24.
    Hodgson U, Laitinen T, Tukiainen P. Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: Evidence of founder effect among multiplex families in Finland. Thorax 2002;57:338–42.PubMedGoogle Scholar
  25. 25.
    Loyd JE. Pulmonary fibrosis in families. Am J Respir Cell Mol Biol 2003;29:S47–S50.PubMedGoogle Scholar
  26. 26.
    Auwerx J, Boogaerts M, Ceuppens JL, Demedts M. Defective host defence mechanisms in a family with hypocalciuric hypercalcaemia and coexisting interstitial lung disease. Clin Exp Immunol 1985;62:57–64.PubMedGoogle Scholar
  27. 27.
    Schneider EL, Epstein CJ, Kaback MJ, Brandes D. Severe pulmonary involvement in adult Gaucher’s disease. Report of three cases and review of the literature. Am J Med 1977;63:475–80.PubMedGoogle Scholar
  28. 28.
    Terry RD, Sperry WM, Brodoff B. Adult lipidosis resembling Niemann-Pick’s disease. Am J Pathol 1954;30:263–85.PubMedGoogle Scholar
  29. 29.
    Malik SK, Pardee N, Martin CJ. Involvement of the lungs in tuberous sclerosis. Chest 1970;58:538–40.PubMedGoogle Scholar
  30. 30.
    Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med 1981;305:1617–27.Google Scholar
  31. 31.
    Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007;356:1317–26.Google Scholar
  32. 32.
    Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci USA 2007;104:7552–57.Google Scholar
  33. 33.
    Brasch F, Griese M, Tredano M, et al. Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene. Eur Respir J 2004;24:30–39.PubMedGoogle Scholar
  34. 34.
    Cameron HS, Somaschini M, Carrera P, et al. A common mutation in the surfactant protein C gene associated with lung disease. J Pediatr 2005;146:370–75.PubMedGoogle Scholar
  35. 35.
    Hamvas A. Inherited surfactant protein-B deficiency and surfactant protein-C associated disease: Clinical features and evaluation. Semin Perinatol 2006;30:316–26.PubMedGoogle Scholar
  36. 36.
    Hamvas A, Nogee LM, White FV, et al. Progressive lung disease and surfactant dysfunction with a deletion of surfactant protein C gene. Am J Respir Cell Mol Biol 2004;30:771–76.PubMedGoogle Scholar
  37. 37.
    Lawson WE, Grant SW, Ambrosini V, et al. Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax 2004;59:977–80.PubMedGoogle Scholar
  38. 38.
    Nogee LM, Dunbar AE, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001;344:573–79.PubMedGoogle Scholar
  39. 39.
    Nogee LM, Dunbar AE III, Wert S, Askin F, Hamvas A, Whitsett JA. Mutations in the surfactant protein C gene associated with interstitial lung disease. Chest 2002;121: 20S–21S.PubMedGoogle Scholar
  40. 40.
    Percopo S, Cameron HS, Nogee LM, Pettinato G, Montella S, Santamaria F. Variable phenotype associated with SP-C gene mutations: Fatal case with the I73T mutation. Eur Respir J 2004;24:1072–73.Google Scholar
  41. 41.
    Rosen DM, Waltz DA. Hydroxychloroquine and surfactant protein C deficiency. N Engl J Med 2005;352:207–8.Google Scholar
  42. 42.
    Soraisham AS, Tierney AJ, Amin HJ. Neonatal respiratory failure associated with mutation in the surfactant protein C gene. J Perinatol 2006;26:67–70.PubMedGoogle Scholar
  43. 43.
    Stevens PA, Pettenazzo A, Brasch F, et al. Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene. Pediatr Res 2005;57:89–98.PubMedGoogle Scholar
  44. 44.
    Thomas AQ, Lane K, Phillips J III, et al. 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 2002;165:1322–28.Google Scholar
  45. 45.
    Tredano M, Griese M, Brasch F, et al. Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am J Med Genet A 2004;126:18–26.Google Scholar
  46. 46.
    Beers MF, Mulugeta S. Surfactant protein C biosynthesis and its emerging role in conformational lung disease. Annu Rev Physiol 2005;67:663–96.PubMedGoogle Scholar
  47. 47.
    Crystal RG, Bitterman PB, Rennard SI, Hance AJ, Keogh BA. Interstitial lung diseases of unknown cause. Disorders characterized by chronic inflammation of the lower respiratory tract (first of two parts). N Engl J Med 1984;310:154–66.PubMedGoogle Scholar
  48. 48.
    Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:810–16.PubMedGoogle Scholar
  49. 49.
    Gribbin J, Hubbard RB, Le Jeune I, Smith CJ, West J, Tata LJ. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax 2006;61:980–85.PubMedGoogle Scholar
  50. 50.
    Mannino DM, Etzel RA, Parrish RG. Pulmonary fibrosis deaths in the United States, 1979–1991. An analysis of multiple-cause mortality data. Am J Respir Crit Care Med 1996;153:1548–52.Google Scholar
  51. 51.
    Livingstone JL, Lewis JG, Reid L, Jefferson KE. Diffuse interstitial pulmonary fibrosis. A clinical, radiological, and pathological study based on 45 patients. Q J Med 1964;33: 71–103.PubMedGoogle Scholar
  52. 52.
    Scadding JG. Chronic diffuse interstitial fibrosis of the lungs. Br Med J 1960;1:443–50.PubMedGoogle Scholar
  53. 53.
    Wright PH, Heard BE, Steel SJ, Turner-Warwick M. Cryptogenic fibrosing alveolitis: Assessment by graded trephine lung biopsy histology compared with clinical, radiographic, and physiological features. Br J Dis Chest 1981;75:61–70.PubMedGoogle Scholar
  54. 54.
    Gaensler EA, Goff AM, Prowse CM. Desquamative interstitial pneumonia. N Engl J Med 1966;274:113–28.PubMedGoogle Scholar
  55. 55.
    Liebow AA, Steer A, Billingsley JG. Desquamative interstitial pneumonia. Am J Med 1965;39:369–404.PubMedGoogle Scholar
  56. 56.
    Epler GR, McLoud TC, Gaensler EA, Mikus JP, Carrington CB. Normal chest roentgenograms in chronic diffuse infiltrative lung disease. N Engl J Med 1978;298: 934–39.PubMedGoogle Scholar
  57. 57.
    Sahn SA, Schwarz MI. Desquamative interstitial pneumonia with a normal chest radiograph. Br J Dis Chest 1974;68:228–34.PubMedGoogle Scholar
  58. 58.
    Orens JB, Kazerooni EA, Martinez FJ, et al. The sensitivity of high-resolution CT in detecting idiopathic pulmonary fibrosis proved by open lung biopsy: A prospective study. Chest 1995;108:109–15.PubMedGoogle Scholar
  59. 59.
    Johnson THJ. Radiology and honeycomb lung disease. Am J Roentgenol Radium Ther Nucl Med 1968;104:810–21.PubMedGoogle Scholar
  60. 60.
    Genereux GP. The end-stage lung: Pathogenesis, pathology, and radiology. Radiology 1975;116:279–89.PubMedGoogle Scholar
  61. 61.
    Lynch DA, Travis WD, Muller NL, et al. Idiopathic interstitial pneumonias: CT features. Radiology 2005;236:10–21.PubMedGoogle Scholar
  62. 62.
    Fischer T, Reynolds JH, Trotter SE. The idiopathic interstitial pneumonias: A beginners guide. Imaging 2004;16:37–49.Google Scholar
  63. 63.
    British Medical Association. The diagnosis, assessment and treatment of diffuse parenchymal lung disease in adults: Introduction. Thorax 1999;54(Suppl 1):S1–S14.Google Scholar
  64. 64.
    Aziz ZA, Wells AU, Hansell DM, et al. HRCT diagnosis of diffuse parenchymal lung disease: Inter-observer variation. Thorax 2004;59:506–11.PubMedGoogle Scholar
  65. 65.
    Lynch DA, David Godwin J, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: Diagnosis and prognosis. Am J Respir Crit Care Med 2005;172:488–93.PubMedGoogle Scholar
  66. 66.
    Renzi G, Milic-Emili J, Grassino AE. The pattern of breathing in diffuse lung fibrosis. Bull Eur Physiopathol Respir 1982;18:461–72.PubMedGoogle Scholar
  67. 67.
    Renzi G, Milic-Emili J, Grassino AE. Breathing pattern in sarcoidosis and idiopathic pulmonary fibrosis. Ann NY Acad Sci 1986;465:482–90.PubMedGoogle Scholar
  68. 68.
    Keogh BA, Crystal RG. Clinical significance of pulmonary function tests. Pulmonary function testing in interstitial pulmonary disease. What does it tell us? Chest 1980;78:856–65.Google Scholar
  69. 69.
    Watters LC, King TE, Schwarz MI, Waldron JA, Stanford RE, Cherniack RM. A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. Am Rev Respir Dis 1986;133:97–103.PubMedGoogle Scholar
  70. 70.
    Wagner PD, Dantzker DR, Dueck R, de Polo JL, Wasserman K, West JB. Distribution of ventilation-perfusion ratios in patients with interstitial lung disease. Chest 1976;69:256–57.PubMedGoogle Scholar
  71. 71.
    Jernudd-Wilhelmsson Y, Hornblad Y, Hedenstierna G. Ventilation-perfusion relationships in interstitial lung disease. Eur J Respir Dis 1986;68:39–49.PubMedGoogle Scholar
  72. 72.
    Eary JF, Fisher MC, Cerqueira MD. Idiopathic pulmonary fibrosis: Another cause of ventilation/perfusion mismatch. Clin Nucl Med 1986;11:396–99.PubMedGoogle Scholar
  73. 73.
    Eaton T, Young P, Milne D, Wells AU. Six-minute walk, maximal exercise tests: Reproducibility in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005;171:1150–57.Google Scholar
  74. 74.
    Lederer DJ, Arcasoy SM, Wilt JS, D’Ovidio F, Sonett JR, Kawut SM. Six-minute-walk distance predicts waiting list survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:659–64.PubMedGoogle Scholar
  75. 75.
    Flaherty KR, Andrei AC, Murray S, et al. Idiopathic pulmonary fibrosis: Prognostic value of changes in physiology and six-minute-walk test. Am J Respir Crit Care Med 2006;174:803–9.Google Scholar
  76. 76.
    Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005;142:963–67.PubMedGoogle Scholar
  77. 77.
    Kim DS, Park JH, Park BK, Lee JS, Nicholson AG, Colby T. Acute exacerbation of idiopathic pulmonary fibrosis: Frequency and clinical features. Eur Respir J 2006;27:143–50.PubMedGoogle Scholar
  78. 78.
    Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171: 1040–47.Google Scholar
  79. 79.
    Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005;128:1475–82.Google Scholar
  80. 80.
    Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:636–43.PubMedGoogle Scholar
  81. 81.
    Kondoh Y, Taniguchi H, Kitaichi M, et al. Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med 2006;100:1753–59.Google Scholar
  82. 82.
    Hiwatari N, Shimura S, Takishima T, Shirato K. Bronchoalveolar lavage as a possible cause of acute exacerbation in idiopathic pulmonary fibrosis patients. Tohoku J Exp Med 1994;174:379–86.PubMedGoogle Scholar
  83. 83.
    Al-Hameed FM, Sharma S. Outcome of patients admitted to the intensive care unit for acute exacerbation of idiopathic pulmonary fibrosis. Can Respir J 2004;11:117–22.PubMedGoogle Scholar
  84. 84.
    Parambil JG, Myers JL, Ryu JH. Histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing surgical lung biopsy. Chest 2005;128:3310–15.Google Scholar
  85. 85.
    Inase N, Sawada M, Ohtani Y, et al. Cyclosporin A followed by the treatment of acute exacerbation of idiopathic pulmonary fibrosis with corticosteroid. Intern Med 2003;42:565–70.PubMedGoogle Scholar
  86. 86.
    Homma S, Sakamoto S, Kawabata M, et al. Cyclosporin treatment in steroid-resistant and acutely exacerbated interstitial pneumonia. Intern Med 2005;44:1144–50.Google Scholar
  87. 87.
    Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003;3:CD002880.PubMedGoogle Scholar
  88. 88.
    Davies HR, Richeldi L, Walters EH. Immunomodulatory agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003;3:CD003134.PubMedGoogle Scholar
  89. 89.
    Raghu G, Depaso WJ, Cain K, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: A prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis 1991;144:291–96.PubMedGoogle Scholar
  90. 90.
    Collard HR, Ryu JH, Douglas WW, et al. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest 2004;125:2169–74.Google Scholar
  91. 91.
    Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125–33.PubMedGoogle Scholar
  92. 92.
    Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229–42.Google Scholar
  93. 93.
    Hunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2285–87.Google Scholar
  94. 94.
    Steele MP, Speer MC, Loyd JE, et al. Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med 2005;172:1146–52.Google Scholar
  95. 95.
    Rosas IO, Kaminski N. When it comes to genes – IPF or NSIP, familial or sporadic – they’re all the same. Am J Respir Crit Care Med 2007;175:5–6.PubMedGoogle Scholar
  96. 96.
    Marshall RP, Puddicombe A, Cookson WO, Laurent GJ. Adult familial cryptogenic fibrosing alveolitis in the UK. Thorax 2000;55:143–46.PubMedGoogle Scholar
  97. 97.
    Rosas IO, Ren P, Avila NA, et al. Early interstitial lung disease in familial pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:698–705.PubMedGoogle Scholar
  98. 98.
    Bitterman PB, Rennard SI, Keogh BA, Wewers MD, Adelberg S, Crystal RG. Familial idiopathic pulmonary fibrosis: Evidence of lung inflammation in unaffected family members. N Engl J Med 1986;314:1343–47.Google Scholar
  99. 99.
    Yang IV, Burch LH, Steele MP, et al. Gene expression profiling of familial and sporadic interstitial pneumonia. Am J Respir Crit Care Med 2007;175:45–54.PubMedGoogle Scholar
  100. 100.
    Chibbar R, Shih F, Baga M, et al. Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis. Mod Pathol 2004;17:973–80.PubMedGoogle Scholar
  101. 101.
    Setoguchi Y, Ikeda T, Fukuchi Y. Clinical features and genetic analysis of surfactant protein C in adult-onset familial interstitial pneumonia. Respirology 2006;11(Suppl):S41–S45.PubMedGoogle Scholar
  102. 102.
    Markart P, Ruppert C, Wygrecka M, et al. Surfactant protein C mutations in sporadic forms of idiopathic interstitial pneumonias. Eur Respir J 2007;29:134–37.PubMedGoogle Scholar
  103. 103.
    Lahti M, Marttila R, Hallman M. Surfactant protein C gene variation in the Finnish population – association with perinatal respiratory disease. Eur J Hum Genet 2004;12:312–20.PubMedGoogle Scholar
  104. 104.
    Farrell PM, Avery ME. Hyaline membrane disease. Am Rev Respir Dis 1975;111:657–88.PubMedGoogle Scholar
  105. 105.
    Robertson B, Halliday HL. Principles of surfactant replacement. Biochim Biophys Acta 1998;1408:346–61.PubMedGoogle Scholar
  106. 106.
    Hafner D, Beume R, Kilian U, Krasznai G, Lachmann B. Dose-response comparisons of five lung surfactant factor (LSF) preparations in an animal model of adult respiratory distress syndrome (ARDS). Br J Pharmacol 1995;115:451–58.PubMedGoogle Scholar
  107. 107.
    Hawgood S, Ogawa A, Yukitake K, et al. Lung function in premature rabbits treated with recombinant human surfactant protein C. Am J Respir Crit Care Med 1996;154:484–90.PubMedGoogle Scholar
  108. 108.
    Davis AJ, Jobe AH, Häfner D, Ikegami M. Lung function in premature lambs and rabbits treated with a recombinant SP-C surfactant. Am J Respir Crit Care Med 1998;157:553–59.PubMedGoogle Scholar
  109. 109.
    McCormack FX, Whitsett JA. The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung. J Clin Invest 2002;109:707–12.PubMedGoogle Scholar
  110. 110.
    Weaver TE, Conkright JJ. Function of surfactant proteins B and C. Annu Rev Physiol 2001;63:555–78.PubMedGoogle Scholar
  111. 111.
    Hyatt BA, Resnik ER, Johnson NS, Lohr JL, Cornfield DN. Lung specific developmental expression of the Xenopus laevis surfactant protein C and B genes. Gene Expr Patterns 2007;7:8–14.PubMedGoogle Scholar
  112. 112.
    Glasser SW, Korfhagen TR, Perme CM, Pilot-Matias TJ, Kister SE, Whitsett JA. Two SP-C genes encoding human pulmonary surfactant proteolipid. J Biol Chem 1988;263: 10326–31.Google Scholar
  113. 113.
    Russo SJ, Wang W, Lomax CA, Beers MF. Structural requirements for intracellular targeting of SP-C proprotein. Am J Physiol 1999;277:L1034–L44.Google Scholar
  114. 114.
    Conkright JJ, Bridges JP, Na CL, et al. Secretion of surfactant protein C, an integral membrane protein, requires the N-terminal propeptide. J Biol Chem 2001;276:14658–64.Google Scholar
  115. 115.
    Keller A, Eistetter HR, Voss T, Schafer KP. The pulmonary surfactant protein C (SP-C) precursor is a type II transmembrane protein. Biochem J 1991;277:493–99.PubMedGoogle Scholar
  116. 116.
    Wang WJ, Russo SJ, Mulugeta S, Beers MF. Biosynthesis of surfactant protein C (SP-C): Sorting of SP-C proprotein involves homomeric association via a signal anchor domain. J Biol Chem 2002;277:19929–37.Google Scholar
  117. 117.
    Vorbroker DK, Voorhout WF, Weaver TE, Whitsett JA. Posttranslational processing of surfactant protein C in rat Type II cells. Am J Physiol Lung Cell Mol Physiol 1995;269: L727–L33.Google Scholar
  118. 118.
    Beers MF, Lomax C. Synthesis and processing of hydrophobic surfactant protein C by isolated rat Type II cells. Am J Physiol-Lung Cell Mol Physiol 1995;13:L744–L53.Google Scholar
  119. 119.
    Curstedt T, Johansson J, Persson P, et al. Hydrophobic surfactant-associated polypeptides: SP-C is a lipopeptide with two palmitoylated cysteine residues, whereas SP-B lacks covalently linked fatty acyl groups. Proc Natl Acad Sci USA 1990;87:2985–89.Google Scholar
  120. 120.
    Vorbroker DK, Dey C, Weaver TE, Whitsett JA. Surfactant protein-C precursor is palmitoylated and associates with subcellular membranes. Biochim Biophys Acta 1992;1105: 161–69.PubMedGoogle Scholar
  121. 121.
    Gustafsson M, Curstedt T, Jornvall H, Johansson J. Reverse-phase HPLC of the hydrophobic pulmonary surfactant proteins: Detection of a surfactant protein C isoform containing Nepsilon-palmitoyl-lysine. Biochem J 1997;326:799–806.PubMedGoogle Scholar
  122. 122.
    Johansson J, Nilsson G, Stromberg R, Robertson B, Jornvall H, Curstedt T. Secondary structure and biophysical activity of synthetic analogues of the pulmonary surfactant polypeptide SP-C. Biochem J 1995;307:535–41.PubMedGoogle Scholar
  123. 123.
    Johansson J, Curstedt T. Molecular structures and interactions of pulmonary surfactant components. Eur J Biochem 1997;244:675–93.PubMedGoogle Scholar
  124. 124.
    Johansson J. Structure and properties of surfactant protein C. Biochim Biophys Acta Biochimica et Biophysica Acta – Mol Bas Dis 1998;1408:161–72.Google Scholar
  125. 125.
    Veldhuizen R, Nag K, Orgeig S, Possmayer F. The role of lipids in pulmonary surfactant. Biochim Biophys Acta 1998;1408:90–108.PubMedGoogle Scholar
  126. 126.
    Gustafsson M, Griffiths WJ, Furusjo E, Johansson J. The palmitoyl groups of lung surfactant protein C reduce unfolding into a fibrillogenic intermediate. J Mol Biol 2001;310: 937–50.PubMedGoogle Scholar
  127. 127.
    Johansson H, Nordling K, Weaver TE, Johansson J. The Brichos domain-containing C-terminal part of pro-surfactant protein C binds to an unfolded poly-val transmembrane segment. J Biol Chem 2006;281:21032–39.Google Scholar
  128. 128.
    Glasser SW, Detmer EA, Ikegami M, Na C-L, Stahlman MT, Whitsett JA. Pneumonitis and emphysema in sp-C gene targeted mice. J Biol Chem 2003;278:14291–98.Google Scholar
  129. 129.
    Amin RS, Wert SE, Baughman RP, et al. Surfactant protein deficiency in familial interstitial lung disease. J Pediatr 2001;139:85–92.PubMedGoogle Scholar
  130. 130.
    Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: Application of a novel classification scheme. Am J Respir Crit Care Med 2007;176: 1120–28.Google Scholar
  131. 131.
    Stevens FJ, Argon Y. Protein folding in the ER. Semin Cell Dev Biol 1999;10:443–54.PubMedGoogle Scholar
  132. 132.
    Meusser B, Hirsch C, Jarosch E, Sommer T. ERAD: The long road to destruction. Nat Cell Biol 2005;7:766–72.PubMedGoogle Scholar
  133. 133.
    Ye YH, Shibata Y, Yun C, Ron D, Rapoport TA. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 2004;429:841–47.PubMedGoogle Scholar
  134. 134.
    Lilley BN, Ploegh HL. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 2004;429:834–40.PubMedGoogle Scholar
  135. 135.
    Wahlman J, Demartino GN, Skach WR, Bulleid NJ, Brodsky JL, Johnson AE. Real-time fluorescence detection of ERAD substrate retrotranslocation in a mammalian in vitro system. Cell 2007;129:943–55.PubMedGoogle Scholar
  136. 136.
    Oda Y, Hosokawa N, Wada I, Nagata K. EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin [Comment]. Science 2003;299:1394–97.Google Scholar
  137. 137.
    Molinari M, Calanca V, Galli C, Lucca P, Paganetti P. Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle [Comment]. Science 2003;299: 1397–1400.PubMedGoogle Scholar
  138. 138.
    Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem 2005;74:739–89.PubMedGoogle Scholar
  139. 139.
    Bernales S, Papa FR, Walter P. Intracellular signaling by the unfolded protein response. Annu Rev Cell Dev Biol 2006;22:487–508.PubMedGoogle Scholar
  140. 140.
    Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519–29.PubMedGoogle Scholar
  141. 141.
    Lee AH, Chu GC, Iwakoshi NN, Glimcher LH. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J 2005;24:4368–80.Google Scholar
  142. 142.
    Reimold AM, Iwakoshi NN, Manis J, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 2001;412:300–307.PubMedGoogle Scholar
  143. 143.
    Mimura N, Hamada H, Kashio M, et al. Aberrant quality control in the endoplasmic reticulum impairs the biosynthesis of pulmonary surfactant in mice expressing mutant BiP. Cell Death Differ 2007;14(8):1475–85.Google Scholar
  144. 144.
    Johnson AL, Braidotti P, Pietra GG, et al. Post-translational processing of surfactant protein-C proprotein: Targeting motifs in the NH(2)-terminal flanking domain are cleaved in late compartments. Am J Respir Cell Mol Biol 2001;24:253–63.PubMedGoogle Scholar
  145. 145.
    Kabore AF, Wang WJ, Russo SJ, Beers MF. Biosynthesis of surfactant protein C: Characterization of aggresome formation by EGFP chimeras containing propeptide mutants lacking conserved cysteine residues. J Cell Sci 2001;114:293–302.PubMedGoogle Scholar
  146. 146.
    Bridges JP, Wert SE, Nogee LM, Weaver TE. Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. J Biol Chem 2003;278:52739–46.Google Scholar
  147. 147.
    Bridges JP, Xu Y, Na CL, Wong HR, Weaver TE. Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. J Cell Biol 2006;172:395–407.PubMedGoogle Scholar
  148. 148.
    Wang WJ, Mulugeta S, Russo SJ, Beers MF. Deletion of exon 4 from human surfactant protein C results in aggresome formation and generation of a dominant negative. J Cell Sci 2003;116:683–92.PubMedGoogle Scholar
  149. 149.
    Mulugeta S, Nguyen V, Russo SJ, Muniswamy M, Beers MF. 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 2005;32:521–30.PubMedGoogle Scholar
  150. 150.
    Arvan P, Zhao X, Ramos-Castaneda J, Chang A. Secretory pathway quality control operating in Golgi, plasmalemmal, and endosomal systems [Review]. Traffic 2002;3:771–80.Google Scholar
  151. 151.
    Uhal BD, Joshi I, Hughes WF, Ramos C, Pardo A, Selman M. Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. Am J Physiol 1998;275:L1192–L99.Google Scholar
  152. 152.
    Barbas-Filho JV, Ferreira MA, Sesso A, Kairalla RA, Carvalho CR, Capelozzi VL. Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP). J Clin Pathol 2001;54:132–38.PubMedGoogle Scholar
  153. 153.
    Plataki M, Koutsopoulos AV, Darivianaki K, Delides G, Siafakas NM, Bouros D. Expression of apoptotic and antiapoptotic markers in epithelial cells in idiopathic pulmonary fibrosis. Chest 2005;127:266–74.PubMedGoogle Scholar
  154. 154.
    Kuwano K, Hagimoto N, Tanaka T, et al. Expression of apoptosis-regulatory genes in epithelial cells in pulmonary fibrosis in mice. J Pathol 2000;190:221–29.PubMedGoogle Scholar
  155. 155.
    Hagimoto N, Kuwano K, Miyazaki H, et al. Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen. Am J Respir Cell Mol Biol 1997;17: 272–78.PubMedGoogle Scholar
  156. 156.
    Wang R, Ibarra-Sunga O, Verlinski L, Pick R, Uhal BD. Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 2000;279:L143–L51.PubMedGoogle Scholar
  157. 157.
    Kuwano K, Kunitake R, Maeyama T, et al. Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 2001;280: L316–L25.PubMedGoogle Scholar
  158. 158.
    Wei ML. Hermansky-Pudlak syndrome: A disease of protein trafficking and organelle function. Pigment Cell Res 2006;19:19–42.PubMedGoogle Scholar
  159. 159.
    Young LR, Pasula R, Gulleman PM, Deutsch GH, McCormack FX. Susceptibility of Hermansky-Pudlak mice to bleomycin-induced type ii cell apoptosis and fibrosis. Am J Respir Cell Mol Biol 2007;37(1):67–74.PubMedGoogle Scholar
  160. 160.
    Stahlman MT, Besnard V, Wert SE, et al. Expression of ABCA3 in developing lung and other tissues. J Histochem Cytochem 2006;55(1):71–83.PubMedGoogle Scholar
  161. 161.
    Matsumura Y, Sakai H, Sasaki M, Ban N, Inagaki N. ABCA3-mediated choline-phospholipids uptake into intracellular vesicles in A549 cells. FEBS Lett 2007;581(17): 3139–44.Google Scholar
  162. 162.
    Cheong N, Madesh M, Gonzales LW, et al. Functional and trafficking defects in ATP binding cassette A3 mutants associated with respiratory distress syndrome. J Biol Chem 2006;281:9791–800.PubMedGoogle Scholar
  163. 163.
    Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 2004;350:1296–303.PubMedGoogle Scholar
  164. 164.
    Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM. ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med 2005;172:1026–31.Google Scholar
  165. 165.
    Hammel M, Michel G, Hoefer C, et al. Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies. Biochem Biophys Res Commun 2007;359(4):947–51.PubMedGoogle Scholar
  166. 166.
    Fitzgerald ML, Xavier R, Haley KJ, et al. ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol. J Lipid Res 2007;48:621–32.PubMedGoogle Scholar
  167. 167.
    Ban N, Matsumura Y, Sakai H, et al. ABCA3 as a lipid transporter in pulmonary surfactant biogenesis. J Biol Chem 2007;282:9628–34.Google Scholar
  168. 168.
    Cheong N, Zhang H, Muniswamy M, et al. ABCA3 is critical for lamellar body biogenesis in vivo. J Biol Chem 2007;282(33):23811–17.Google Scholar
  169. 169.
    Matsumura Y, Ban N, Ueda K, Inagaki N. Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency. J Biol Chem 2006;281:34503–14.Google Scholar
  170. 170.
    Pittet JF, Griffiths MJD, Geiser T, et al. TGF-beta is a critical mediator of acute lung injury. J Clin Invest 2001;107:1537–44.Google Scholar
  171. 171.
    Chua F, Gauldie J, Laurent GJ. Pulmonary fibrosis: Searching for model answers. Am J Respir Cell Mol Biol 2005;33:9–13.PubMedGoogle Scholar
  172. 172.
    Borzone G, Moreno R, Urrea R, Meneses M, Oyarzun M, Lisboa C. Bleomycin-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;163:1648–53.Google Scholar
  173. 173.
    Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 2004;4: 583–94.PubMedGoogle Scholar
  174. 174.
    Elias JA, Zheng T, Lee CG, et al. Transgenic modeling of interleukin-13 in the lung. Chest 2003;123:339S–45S.PubMedGoogle Scholar
  175. 175.
    Keane MP, Belperio JA, Burdick MD, Strieter RM. IL-12 attenuates bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2001;281:L92–L97.PubMedGoogle Scholar
  176. 176.
    Gunther A, Lubke N, Ermert M, et al. Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits. Am J Respir Crit Care Med 2003;168:1358–65.Google Scholar
  177. 177.
    Eitzman DT, McCoy RD, Zheng X, et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 1996;97:232–37.PubMedGoogle Scholar
  178. 178.
    Swaisgood CM, French EL, Noga C, Simon RH, Ploplis VA. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. Am J Pathol 2000;157:177–87.PubMedGoogle Scholar
  179. 179.
    Hattori N, Degen JL, Sisson TH, et al. Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice. J Clin Invest 2000;106:1341–50.Google Scholar
  180. 180.
    Zuo F, Kaminski N, Eugui E, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci USA 2002;99: 6292–97.Google Scholar
  181. 181.
    Cosgrove GP, Schwarz MI, Geraci MW, Brown KK, Worthen GS. Overexpression of matrix metalloproteinase-7 in pulmonary fibrosis. Chest 2002;121:25S–26S.PubMedGoogle Scholar
  182. 182.
    Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling. Am J Respir Cell Mol Biol 2003;28:12–24.PubMedGoogle Scholar
  183. 183.
    Kim KH, Burkhart K, Chen P, et al. Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice. Am J Respir Cell Mol Biol 2005;33:271–79.PubMedGoogle Scholar
  184. 184.
    Khalil N, O’Connor RN, Flanders KC, Unruh H. TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: An immunohistochemical study. Am J Respir Cell Mol Biol 1996;14:131–38.PubMedGoogle Scholar
  185. 185.
    Khalil N, O’Connor RN, Unruh HW, et al. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 1991;5:155–62.PubMedGoogle Scholar
  186. 186.
    Raghow B, Irish P, Kang AH. Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis. J Clin Invest 1989;84:1836–42.Google Scholar
  187. 187.
    Giri SN, Hyde DM, Hollinger MA. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. Thorax 1993;48: 959–66.PubMedGoogle Scholar
  188. 188.
    Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997;100:768–76.PubMedGoogle Scholar
  189. 189.
    Lee CG, Kang HR, Homer RJ, Chupp G, Elias JA. Transgenic modeling of transforming growth factor-beta(1): Role of apoptosis in fibrosis and alveolar remodeling. Proc Am Thorac Soc 2006;3:418–23.PubMedGoogle Scholar
  190. 190.
    Lee CG, Cho SJ, Kang MJ, et al. Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis. J Exp Med 2004;200:377–89.PubMedGoogle Scholar
  191. 191.
    Huang XZ, Wu JF, Cass D, et al. Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J Cell Biol 1996;133:921–28.PubMedGoogle Scholar
  192. 192.
    Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: New insights in signaling, development, and disease. J Cell Biol 2006;172:973–81.PubMedGoogle Scholar
  193. 193.
    Kim KK, Kugler MC, Wolters PJ, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 2006;103:13180–85.Google Scholar
  194. 194.
    Yao HW, Xie QM, Chen JQ, Deng YM, Tang HF. TGF-beta1 induces alveolar epithelial to mesenchymal transition in vitro. Life Sci 2004;76:29–37.PubMedGoogle Scholar
  195. 195.
    Wu Z, Yang L, Cai L, et al. Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an alpha-smooth muscle actin-Cre transgenic mouse. Respir Res 2007;8:1.PubMedGoogle Scholar
  196. 196.
    Willis BC, Liebler JM, Luby-Phelps K, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: Potential role in idiopathic pulmonary fibrosis. Am J Pathol 2005;166:1321–32.Google Scholar
  197. 197.
    Rubenstein RC, Egan ME, Zeitlin PL. In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR. J Clin Invest 1997;100:2457–65.Google Scholar
  198. 198.
    Rubenstein RC, Lyons BM. Sodium 4-phenylbutyrate downregulates HSC70 expression by facilitating mRNA degradation. Am J Physiol Lung Cell Mol Physiol 2001;281: L43–L51.PubMedGoogle Scholar
  199. 199.
    Newmark HL, Young CW. Butyrate and phenylacetate as differentiating agents: Practical problems and opportunities. J Cell Biochem Suppl 1995;22:247–53.PubMedGoogle Scholar
  200. 200.
    Zeitlin PL, Diener-West M, Rubenstein RC, Boyle MP, Lee CK, Brass-Ernst L. Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. Mol Ther 2002;6:119–26.PubMedGoogle Scholar
  201. 201.
    Constantoulakis P, Knitter G, Stamatoyannopoulos G. Butyrate stimulates HbF in adult baboons. Prog Clin Biol Res 1989;316B:351–61.PubMedGoogle Scholar
  202. 202.
    Faller DV, Perrine SP. Butyrate in the treatment of sickle cell disease and beta-thalassemia. Curr Opin Hematol 1995;2:109–17.PubMedGoogle Scholar
  203. 203.
    Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci USA 2000;97:1796–801.PubMedGoogle Scholar
  204. 204.
    Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006;313:1137–40.Google Scholar
  205. 205.
    D’Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet 2007;369:587–96.PubMedGoogle Scholar
  206. 206.
    Furst DE. Optimizing combination chemotherapy for rheumatoid arthritis. Ann NY Acad Sci 1993;696:285–91.PubMedGoogle Scholar
  207. 207.
    Orci L, Ravazzola M, Amherdt M, et al. Conversion of proinsulin to insulin occurs coordinately with acidification of maturing secretory vesicles. J Cell Biol 1986;103:2273–81.Google Scholar
  208. 208.
    Beers MF. Inhibition of cellular processing of surfactant protein C by drugs affecting intracellular pH gradients. J Biol Chem 1996;271:14361–70.Google Scholar
  209. 209.
    Lee HL, Ryu JH, Wittmer MH, et al. Familial idiopathic pulmonary fibrosis: Clinical features and outcome. Chest 2005;127:2034–41.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Ralph J. Panos
    • 1
  • James P. Bridges
    • 2
  1. 1.Department of Internal MedicineUniversity of Cincinnati School of Medicine, Cincinnati VA Medical CenterCincinnatiUSA
  2. 2.Department of Neonatology in Pulmonary BiologyChildren’s Hospital Medical CenterCincinnatiUSA

Personalised recommendations