Cell and Tissue Research

, Volume 367, Issue 3, pp 607–626 | Cite as

Tissue remodelling in pulmonary fibrosis

  • Lars KnudsenEmail author
  • Clemens Ruppert
  • Matthias Ochs


Many lung diseases result in fibrotic remodelling. Fibrotic lung disorders can be divided into diseases with known and unknown aetiology. Among those with unknown aetiology, idiopathic pulmonary fibrosis (IPF) is a common diagnosis. Because of its progressive character leading to a rapid decline in lung function, it is a fatal disease with poor prognosis and limited therapeutic options. Thus, IPF has motivated many studies in the last few decades in order to increase our mechanistic understanding of the pathogenesis of the disease. The current concept suggests an ongoing injury of the alveolar epithelium, an impaired regeneration capacity, alveolar collapse and, finally, a fibroproliferative response. The origin of lung injury remains elusive but a diversity of factors, which will be discussed in this article, has been shown to be associated with IPF. Alveolar epithelial type II (AE2) cells play a key role in lung fibrosis and their crucial role for epithelial regeneration, stabilisation of alveoli and interaction with fibroblasts, all known to be responsible for collagen deposition, will be illustrated. Whereas mechanisms of collagen deposition and fibroproliferation are the focus of many studies in the field, the awareness of other mechanisms in this disease is currently limited to biochemical and imaging studies including quantitative assessments of lung structure in IPF and animal models assigning alveolar collapse and collapse induration crucial roles for the degradation of the lung resulting in de-aeration and loss of surface area. Dysfunctional AE2 cells, instable alveoli and mechanical stress trigger remodelling that consists of collapsed alveoli absorbed by fibrotic tissue (i.e., collapse induration).


Idiopathic pulmonary fibrosis Mechanical stress Alveolar collapse Alveolar epithelial type 2 cells Collapse induration 



The authors thank Marita Peter for excellent assistance in preparing Fig. 3. This work was supported by the German Research Foundation (DFG, KN 916 1-1) and via the German Center for Lung Research (DZL) by the Federal Ministry of Education and Research (BMBF).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Adamson IY, Bowden DH (1974) The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen. Lab Invest 30:35–42PubMedGoogle Scholar
  2. Adamson IY, Bowden DH, Cote MG, Witschi H (1977) Lung injury induced by butylated hydroxytoluene: cytodynamic and biochemical studies in mice. Lab Invest 36:26–32PubMedGoogle Scholar
  3. Adamson IY, Young L, Bowden DH (1988) Relationship of alveolar epithelial injury and repair to the induction of pulmonary fibrosis. Am J Pathol 130:377–383PubMedPubMedCentralGoogle Scholar
  4. Adamson I, Hedgecock C, Bowden D (1990) Epithelial cell-fibroblast interactions in lung injury and repair. Am J Pathol 137:385–392PubMedPubMedCentralGoogle Scholar
  5. Ahluwalia N, Shea BS, Tager AM (2014) New therapeutic targets in idiopathic pulmonary fibrosis. Aiming to rein in runaway wound-healing responses. Am J Respir Crit Care Med 190:867–878PubMedPubMedCentralCrossRefGoogle Scholar
  6. Ahluwalia N, Grasberger PE, Mugo BM, Feghali-Bostwick C, Pardo A, Selman M, Lagares D, Tager AM (2016) Fibrogenic lung injury induces non-cell-autonomous fibroblast invasion. Am J Respir Cell Mol Biol 54:831–842PubMedCrossRefGoogle Scholar
  7. Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, Vulto I, Xie M, Qi X, Tuder RM, Phillips JA, Lansdorp PM, Loyd JE, Armanios MY (2008) Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A 105:13051–13056PubMedPubMedCentralCrossRefGoogle Scholar
  8. Araki T, Putman RK, Hatabu H, Gao W, Dupuis J, Latourelle JC, Nishino M, Zazueta OE, Kurugol S, Ross JC, San José Estépar R, Schwartz DA, Rosas IO, Washko GR, O’Connor GT, Hunninghake GM (2016) Development and progression of interstitial lung abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med (in press)Google Scholar
  9. Araya J, Kojima J, Takasaka N, Ito S, Fujii S, Hara H, Yanagisawa H, Kobayashi K, Tsurushige C, Kawaishi M, Kamiya N, Hirano J, Odaka M, Morikawa T, Nishimura SL, Kawabata Y, Hano H, Nakayama K, Kuwano K (2013) Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 304:L56–L69PubMedCrossRefGoogle Scholar
  10. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA, Lansdorp PM, Greider CW, Loyd JE (2007) Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 356:1317–1326PubMedCrossRefGoogle Scholar
  11. Ask K, Labiris R, Farkas L, Moeller A, Froese A, Farncombe T, McClelland GB, Inman M, Gauldie J, Kolb MR (2008) Comparison between conventional and “clinical” assessment of experimental lung fibrosis. J Transl Med 6:16PubMedPubMedCentralCrossRefGoogle Scholar
  12. ATS, ERS (2002) American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 165:277–304CrossRefGoogle Scholar
  13. Aumiller V, Balsara N, Wilhelm J, Günther A, Königshoff M (2013) WNT/β-catenin signaling induces IL-1β expression by alveolar epithelial cells in pulmonary fibrosis. Am J Respir Cell Mol Biol 49:96–104PubMedCrossRefGoogle Scholar
  14. Barbas-Filho JV, Ferreira MA, Sesso A, Kairalla RA, Carvalho CR, Capelozzi VL (2001) Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP). J Clin Pathol 54:132–138PubMedPubMedCentralCrossRefGoogle Scholar
  15. Basset F, Ferrans VJ, Soler P, Takemura T, Fukuda Y, Crystal RG (1986) Intraluminal fibrosis in interstitial lung disorders. Am J Pathol 122:443–461PubMedPubMedCentralGoogle Scholar
  16. Bates JH, Davis GS, Majumdar A, Butnor KJ, Suki B (2007) Linking parenchymal disease progression to changes in lung mechanical function by percolation. Am J Respir Crit Care Med 176:617–623PubMedPubMedCentralCrossRefGoogle Scholar
  17. Bilek AM, Dee KC, Gaver DP (2003) Mechanisms of surface-tension-induced epithelial cell damage in a model of pulmonary airway reopening. J Appl Physiol 94:770–783PubMedCrossRefGoogle Scholar
  18. Birkelbach B, Lutz D, Ruppert C, Henneke I, Lopez-Rodriguez E, Guenther A, Ochs M, Mahavadi P, Knudsen L (2015) Linking progression of fibrotic lung remodeling and ultrastructural alterations of alveolar epithelial type II cells in the amiodarone mouse model. Am J Physiol Lung Cell Mol Physiol 309:L63–L75PubMedCrossRefGoogle Scholar
  19. Brantly M, Avila NA, Shotelersuk V, Lucero C, Huizing M, Gahl WA (2000) Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1. Chest 117:129–136PubMedCrossRefGoogle Scholar
  20. Brownell R, Kaminski N, Woodruff PG, Bradford WZ, Richeldi L, Martinez FJ, Collard HR (2016) Precision medicine: the new frontier in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 193:1213–1218PubMedCrossRefGoogle Scholar
  21. Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM (2005) ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med 172:1026–1031PubMedPubMedCentralCrossRefGoogle Scholar
  22. Burkhardt A (1989) Alveolitis and collapse in the pathogenesis of pulmonary fibrosis. Am Rev Respir Dis 140:513–524PubMedCrossRefGoogle Scholar
  23. Cabrera-Benítez NE, Parotto M, Post M, Han B, Spieth PM, Cheng WE, Valladares F, Villar J, Liu M, Sato M, Zhang H, Slutsky AS (2012) Mechanical stress induces lung fibrosis by epithelial-mesenchymal transition. Crit Care Med 40:510–517PubMedPubMedCentralCrossRefGoogle Scholar
  24. Cao Z, Lis R, Ginsberg M, Chavez D, Shido K, Rabbany SY, Fong GH, Sakmar TP, Rafii S, Ding BS (2016) Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis. Nat Med 22:154–162PubMedPubMedCentralCrossRefGoogle Scholar
  25. Carloni A, Poletti V, Fermo L, Bellomo N, Chilosi M (2013) Heterogeneous distribution of mechanical stress in human lung: a mathematical approach to evaluate abnormal remodeling in IPF. J Theor Biol 332:136–140PubMedCrossRefGoogle Scholar
  26. Chilosi M, Carloni A, Rossi A, Poletti V (2013) Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl Res 162:156–173PubMedCrossRefGoogle Scholar
  27. Collard HR, King TE, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK (2003) Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 168:538–542PubMedCrossRefGoogle Scholar
  28. Cool CD, Groshong SD, Rai PR, Henson PM, Stewart JS, Brown KK (2006) Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum. Am J Respir Crit Care Med 174:654–658PubMedPubMedCentralCrossRefGoogle Scholar
  29. Cottin V, Cordier JF (2012) Velcro crackles: the key for early diagnosis of idiopathic pulmonary fibrosis? Eur Respir J 40:519–521PubMedCrossRefGoogle Scholar
  30. Coxson HO, Hogg JC, Mayo JR, Behzad H, Whittall KP, Schwartz DA, Hartley PG, Galvin JR, Wilson JS, Hunninghake GW (1997) Quantification of idiopathic pulmonary fibrosis using computed tomography and histology. Am J Respir Crit Care Med 155:1649–1656PubMedCrossRefGoogle Scholar
  31. Crouch E (1990) Pathobiology of pulmonary fibrosis. Am J Physiol 259:L159–L184PubMedGoogle Scholar
  32. Degryse AL, Tanjore H, Xu XC, Polosukhin VV, Jones BR, McMahon FB, Gleaves LA, Blackwell TS, Lawson WE (2010) Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 299:L442–L452PubMedPubMedCentralCrossRefGoogle Scholar
  33. Ekström M, Gustafson T, Boman K, Nilsson K, Tornling G, Murgia N, Torén K (2014) Effects of smoking, gender and occupational exposure on the risk of severe pulmonary fibrosis: a population-based case–control study. BMJ Open 4:e004018PubMedPubMedCentralCrossRefGoogle Scholar
  34. Endo M, Oyadomari S, Suga M, Mori M, Gotoh T (2005) The ER stress pathway involving CHOP is activated in the lungs of LPS-treated mice. J Biochem 138:501–507PubMedCrossRefGoogle Scholar
  35. Enomoto N, Suda T, Kato M, Kaida Y, Nakamura Y, Imokawa S, Ida M, Chida K (2006) Quantitative analysis of fibroblastic foci in usual interstitial pneumonia. Chest 130:22–29PubMedCrossRefGoogle Scholar
  36. Fehrenbach H (2001) Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res 2:33–46PubMedPubMedCentralCrossRefGoogle Scholar
  37. Fingerlin TE, Murphy E, Zhang W, Peljto AL, Brown KK, Steele MP, Loyd JE, Cosgrove GP, Lynch D, Groshong S, Collard HR, Wolters PJ, Bradford WZ, Kossen K, Seiwert SD, Bois RM du, Garcia CK, Devine MS, Gudmundsson G, Isaksson HJ, Kaminski N, Zhang Y, Gibson KF, Lancaster LH, Cogan JD, Mason WR, Maher TM, Molyneaux PL, Wells AU, Moffatt MF, Selman M, Pardo A, Kim DS, Crapo JD, Make BJ, Regan EA, Walek DS, Daniel JJ, Kamatani Y, Zelenika D, Smith K, McKean D, Pedersen BS, Talbert J, Kidd RN, Markin CR, Beckman KB, Lathrop M, Schwarz MI, Schwartz DA (2013) Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet 45:613–620Google Scholar
  38. Fingerlin TE, Zhang W, Yang IV, Ainsworth HC, Russell PH, Blumhagen RZ, Schwarz MI, Brown KK, Steele MP, Loyd JE, Cosgrove GP, Lynch DA, Groshong S, Collard HR, Wolters PJ, Bradford WZ, Kossen K, Seiwert SD, Bois RM du, Garcia CK, Devine MS, Gudmundsson G, Isaksson HJ, Kaminski N, Zhang Y, Gibson KF, Lancaster LH, Maher TM, Molyneaux PL, Wells AU, Moffatt MF, Selman M, Pardo A, Kim DS, Crapo JD, Make BJ, Regan EA, Walek DS, Daniel JJ, Kamatani Y, Zelenika D, Murphy E, Smith K, McKean D, Pedersen BS, Talbert J, Powers J, Markin CR, Beckman KB, Lathrop M, Freed B, Langefeld CD, Schwartz DA (2016) Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet 17:74Google Scholar
  39. Fletcher C, Peto R (1977) The natural history of chronic airflow obstruction. Br Med J 1:1645–1648PubMedPubMedCentralCrossRefGoogle Scholar
  40. Froese AR, Shimbori C, Bellaye PS, Ask K, Inman M, Obex S, Fatima S, Jenkins G, Gauldie J, Kolb M (2016) Stretch induced activation of TGF-β1 in pulmonary fibrosis. Am J Respir Crit Care Med 194:84–96PubMedCrossRefGoogle Scholar
  41. Fukuda Y, Ferrans VJ, Schoenberger CI, Rennard SI, Crystal RG (1985) Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis. Am J Pathol 118:452–475PubMedPubMedCentralGoogle Scholar
  42. Fukuhara A, Tanino Y, Ishii T, Inokoshi Y, Saito K, Fukuhara N, Sato S, Saito J, Ishida T, Yamaguchi H, Munakata M (2013) Pulmonary fibrosis in dyskeratosis congenita with TINF2 gene mutation. Eur Respir J 42:1757–1759PubMedCrossRefGoogle Scholar
  43. Fulmer JD, Bienkowski RS, Cowan MJ, Breul SD, Bradley KM, Ferrans VJ, Roberts WC, Crystal RG (1980) Collagen concentration and rates of synthesis in idiopathic pulmonary fibrosis. Am Rev Respir Dis 122:289–301PubMedGoogle Scholar
  44. Funke M, Zhao Z, Xu Y, Chun J, Tager AM (2012) The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol 46:355–364PubMedPubMedCentralCrossRefGoogle Scholar
  45. Funke M, Knudsen L, Lagares D, Ebener S, Probst CK, Fontaine BA, Franklin A, Kellner M, Kühnel M, Matthieu S, Grothausmann R, Chun J, Roberts JD, Ochs M, Tager AM (2016) LPA signaling through the LPA1 receptor is required for alveolarization. Am J Respir Cell Mol Biol 55:105–116PubMedCrossRefGoogle Scholar
  46. Galvin JR, Frazier AA, Franks TJ (2010) Collaborative radiologic and histopathologic assessment of fibrotic lung disease. Radiology 255:692–706PubMedCrossRefGoogle Scholar
  47. Gazdhar A, Fachinger P, Leer C van, Pierog J, Gugger M, Friis R, Schmid R, Geiser T (2007) Gene transfer of hepatocyte growth factor by electroporation reduces bleomycin-induced lung fibrosis. Am J Physiol Lung Cell Mol Physiol 292:L529–L536Google Scholar
  48. Gazdhar A, Temuri A, Knudsen L, Gugger M, Schmid RA, Ochs M, Geiser T (2013a) Targeted gene transfer of hepatocyte growth factor to alveolar type II epithelial cells reduces lung fibrosis in rats. Hum Gene Ther 24:105–116PubMedCrossRefGoogle Scholar
  49. Gazdhar A, Susuri N, Hostettler K, Gugger M, Knudsen L, Roth M, Ochs M, Geiser T (2013b) HGF expressing stem cells in usual interstitial pneumonia originate from the bone marrow and are antifibrotic. Plos One 8:e65453Google Scholar
  50. Gehr P, Bachofen M, Weibel ER (1978) The normal human lung: ultrastructure and morphometric estimation of diffusion capacity. Respir Physiol 32:121–140PubMedCrossRefGoogle Scholar
  51. Geiser T (2003) Idiopathic pulmonary fibrosis—a disorder of alveolar wound repair? Swiss Med Wkly 133:405–411PubMedGoogle Scholar
  52. Ghebre YT, Raghu G (2016) Idiopathic pulmonary fibrosis: novel concepts of proton pump inhibitors as antifibrotic drug. Am J Respir Crit Care Med 193:1345–1352PubMedCrossRefGoogle Scholar
  53. Gibson GJ, Pride NB (1977) Pulmonary mechanics in fibrosing alveolitis: the effects of lung shrinkage. Am Rev Respir Dis 116:637–647PubMedCrossRefGoogle Scholar
  54. Günther A, Schmidt R, Nix F, Yabut-Perez M, Guth C, Rosseau S, Siebert C, Grimminger F, Morr H, Velcovsky H, Seeger W (1999) Surfactant abnormalities in idiopathic pulmonary fibrosis, hypersensitivity pneumonitis and sarcoidosis. Eur Respir J 14:565–573PubMedCrossRefGoogle Scholar
  55. Harada T, Watanabe K, Nabeshima K, Hamasaki M, Iwasaki H (2013) Prognostic significance of fibroblastic foci in usual interstitial pneumonia and non-specific interstitial pneumonia. Respirology 18:278–283PubMedCrossRefGoogle Scholar
  56. Haschek WM, Witschi H (1979) Pulmonary fibrosis—a possible mechanism. Toxicol Appl Pharmacol 51:475–487PubMedCrossRefGoogle Scholar
  57. Haschek WM, Brody AR, Klein-Szanto AJ, Witschi H (1981) Animal model of human disease. Diffuse interstitial pulmonary fibrosis. Pulmonary fibrosis in mice induced by treatment with butylated hydroxytoluene and oxygen. Am J Pathol 105:333–335PubMedPubMedCentralGoogle Scholar
  58. Heise RL, Stober V, Cheluvaraju C, Hollingsworth JW, Garantziotis S (2011) Mechanical stretch induces epithelial-mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunity. J Biol Chem 286:17435–17444PubMedPubMedCentralCrossRefGoogle Scholar
  59. Hinz B (2012) Mechanical aspects of lung fibrosis: a spotlight on the myofibroblast. Proc Am Thorac Soc 9:137–147PubMedCrossRefGoogle Scholar
  60. Hinz B, Suki B (2016) Does breathing amplify fibrosis? Am J Respir Crit Care Med 194:9–11PubMedCrossRefGoogle Scholar
  61. Hobi N, Ravasio A, Haller T (2012) Interfacial stress affects rat alveolar type II cell signaling and gene expression. Am J Physiol Lung Cell Mol Physiol 303:L117–L129PubMedPubMedCentralCrossRefGoogle Scholar
  62. Horowitz JC, Thannickal VJ (2006) Epithelial-mesenchymal interactions in pulmonary fibrosis. Semin Respir Crit Care Med 27:600–612PubMedPubMedCentralCrossRefGoogle Scholar
  63. Howell DC, Goldsack NR, Marshall RP, McAnulty RJ, Starke R, Purdy G, Laurent GJ, Chambers RC (2001) Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis. Am J Pathol 159:1383–1395PubMedPubMedCentralCrossRefGoogle Scholar
  64. Huaux F, Louahed J, Hudspith B, Meredith C, Delos M, Renauld JC, Lison D (1998) Role of interleukin-10 in the lung response to silica in mice. Am J Respir Cell Mol Biol 18:51–59PubMedCrossRefGoogle Scholar
  65. Hunninghake GM, Hatabu H, Okajima Y, Gao W, Dupuis J, Latourelle JC, Nishino M, Araki T, Zazueta OE, Kurugol S, Ross JC, San José Estépar R, Murphy E, Steele MP, Loyd JE, Schwarz MI, Fingerlin TE, Rosas IO, Washko GR, O’Connor GT, Schwartz DA (2013) MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med 368:2192–2200PubMedPubMedCentralCrossRefGoogle Scholar
  66. Ikegami M, Whitsett JA, Martis PC, Weaver TE (2005) Reversibility of lung inflammation caused by SP-B deficiency. Am J Physiol Lung Cell Mol Physiol 289:L962–L970PubMedCrossRefGoogle Scholar
  67. Jones DP (2006) Extracellular redox state: refining the definition of oxidative stress in aging. Rejuvenation Res 9:169–181PubMedCrossRefGoogle Scholar
  68. Katzenstein A (1985) Pathogenesis of “fibrosis” in interstitial pneumonia: an electron microscopic study. Hum Pathol 16:1015–1024PubMedCrossRefGoogle Scholar
  69. Katzenstein A, Mukhopadhyay S, Myers J (2008) Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Hum Pathol 39:1275–1294PubMedCrossRefGoogle Scholar
  70. Kawanami O, Ferrans VJ, Crystal RG (1982) Structure of alveolar epithelial cells in patients with fibrotic lung disorders. Lab Invest 46:39–53PubMedGoogle Scholar
  71. King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW, Group AS (2014) A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 370:2083–2092PubMedCrossRefGoogle Scholar
  72. Kinnula VL, Myllärniemi M (2008) Oxidant-antioxidant imbalance as a potential contributor to the progression of human pulmonary fibrosis. Antioxid Redox Signal 10:727–738PubMedCrossRefGoogle Scholar
  73. Knippenberg S, Ueberberg B, Maus R, Bohling J, Ding N, Tort Tarres M, Hoymann HG, Jonigk D, Izykowski N, Paton JC, Ogunniyi AD, Lindig S, Bauer M, Welte T, Seeger W, Guenther A, Sisson TH, Gauldie J, Kolb M, Maus UA (2015) Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin. Thorax 70:636–646PubMedCrossRefGoogle Scholar
  74. Knudsen L, Atochina-Vasserman EN, Massa CB, Birkelbach B, Guo CJ, Scott P, Haenni B, Beers MF, Ochs M, Gow AJ (2015) The role of inducible nitric oxide synthase for interstitial remodeling of alveolar septa in surfactant protein D-deficient mice. Am J Physiol Lung Cell Mol Physiol 309:L959–L969PubMedPubMedCentralCrossRefGoogle Scholar
  75. Knudsen L, Lopez-Rodriguez E, Berndt L, Boden C, Bates J, Smith B (2016) Pressure dependent alveolar derecruitment is linked with surfactant dysfunction in bleomycin-induced acute lung injury. Am J Respir Crit Care Med 193:A4813Google Scholar
  76. Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J (2001) Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest 107:1529–1536PubMedPubMedCentralCrossRefGoogle Scholar
  77. Kolb M, White ES, Gauldie J (2016) Mucking around in the genome: MUC5B in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 193:355–357PubMedCrossRefGoogle Scholar
  78. Königshoff M, Eickelberg O (2010) WNT signaling in lung disease: a failure or a regeneration signal? Am J Respir Cell Mol Biol 42:21–31PubMedCrossRefGoogle Scholar
  79. Königshoff M, Balsara N, Pfaff EM, Kramer M, Chrobak I, Seeger W, Eickelberg O (2008) Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One 3:e2142PubMedPubMedCentralCrossRefGoogle Scholar
  80. Königshoff M, Kramer M, Balsara N, Wilhelm J, Amarie O, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Günther A, Eickelberg O (2009) WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest 119:772–787PubMedPubMedCentralGoogle Scholar
  81. Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, Lang G, Fink L, Bohle R, Seeger W, Weaver T, Guenther A (2008) Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 178:838–846PubMedPubMedCentralCrossRefGoogle Scholar
  82. Korfei M, Schmitt S, Ruppert C, Henneke I, Markart P, Loeh B, Mahavadi P, Wygrecka M, Klepetko W, Fink L, Bonniaud P, Preissner KT, Lochnit G, Schaefer L, Seeger W, Guenther A (2011) Comparative proteomic analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and lung transplant donor lungs. J Proteome Res 10:2185–2205PubMedCrossRefGoogle Scholar
  83. Korfei M, Beck D von der, Henneke I, Markart P, Ruppert C, Mahavadi P, Ghanim B, Klepetko W, Fink L, Meiners S, Krämer OH, Seeger W, Vancheri C, Guenther A (2013) Comparative proteome analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP) and organ donors. J Proteomics 85:109–128Google Scholar
  84. Korfei M, Ruppert C, Loeh B, Mahavadi P, Guenther A (2016) The role of endoplasmic reticulum (ER) stress in pulmonary fibrosis. Endoplasmic Reticulum Stress Dis 3:16–49Google Scholar
  85. Kropski JA, Mitchell DB, Markin C, Polosukhin VV, Choi L, Johnson JE, Lawson WE, Phillips JA, Cogan JD, Blackwell TS, Loyd JE (2014) A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia. Chest 146:e1–e7PubMedPubMedCentralCrossRefGoogle Scholar
  86. Kuhn C, McDonald JA (1991) The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. Am J Pathol 138:1257–1265PubMedPubMedCentralGoogle Scholar
  87. Kuhn C, Boldt J, King TE, Crouch E, Vartio T, McDonald JA (1989) An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis 140:1693–1703PubMedCrossRefGoogle Scholar
  88. Kulkarni T, O’Reilly P, Antony VB, Gaggar A, Thannickal VJ (2016) Matrix remodeling in pulmonary fibrosis and emphysema. Am J Respir Cell Mol Biol 54:751–760PubMedCrossRefGoogle Scholar
  89. Kuwano K, Kunitake R, Kawasaki M, Nomoto Y, Hagimoto N, Nakanishi Y, Hara N (1996) P21Waf1/Cip1/Sdi1 and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 154:477–483PubMedCrossRefGoogle Scholar
  90. Lawson W, Crossno P, Polosukhin V, Roldan J, Cheng D, Lane K, Blackwell T, Xu C, Markin C, Ware L, Miller G, Loyd J, Blackwell T (2008) Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am J Physiol Lung Cell Mol Physiol 294:L1119–L1126PubMedCrossRefGoogle Scholar
  91. Lazenby A, Crouch E, McDonald J, Kuhn C (1990) Remodeling of the lung in bleomycin-induced pulmonary fibrosis in the rat. An immunohistochemical study of laminin, type IV collagen, and fibronectin. Am Rev Respir Dis 142:206–214PubMedCrossRefGoogle Scholar
  92. Leslie KO (2012) Idiopathic pulmonary fibrosis may be a disease of recurrent, tractional injury to the periphery of the aging lung: a unifying hypothesis regarding etiology and pathogenesis. Arch Pathol Lab Med 136:591–600PubMedCrossRefGoogle Scholar
  93. Leuenberger A, Gazdhar A, Herrmann G, Ochs M, Geiser T, Knudsen L (2012) Cell-specific expression of human HGF by alveolar type II cells induces remodeling of septal wall tissue in the lung: a morphometric study. J Appl Physiol 113:799–807PubMedCrossRefGoogle Scholar
  94. Ley B, Collard HR, King TE (2011) Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 183:431–440PubMedCrossRefGoogle Scholar
  95. Li Y, Jiang D, Liang J, Meltzer EB, Gray A, Miura R, Wogensen L, Yamaguchi Y, Noble PW (2011) Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. J Exp Med 208:1459–1471PubMedPubMedCentralCrossRefGoogle Scholar
  96. Liu F, Mih JD, Shea BS, Kho AT, Sharif AS, Tager AM, Tschumperlin DJ (2010) Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J Cell Biol 190:693–706PubMedPubMedCentralCrossRefGoogle Scholar
  97. Liu F, Lagares D, Choi KM, Stopfer L, Marinković A, Vrbanac V, Probst CK, Hiemer SE, Sisson TH, Horowitz JC, Rosas IO, Fredenburgh LE, Feghali-Bostwick C, Varelas X, Tager AM, Tschumperlin DJ (2015) Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol 308:L344–L357PubMedCrossRefGoogle Scholar
  98. Lok SS, Stewart JP, Kelly BG, Hasleton PS, Egan JJ (2001) Epstein-Barr virus and wild p53 in idiopathic pulmonary fibrosis. Respir Med 95:787–791PubMedCrossRefGoogle Scholar
  99. Lopez-Rodriguez E, Boden C, Echaide M, Perez-Gil J, Kolb MR, Gauldie J, Maus UA, Ochs M, Knudsen L (2016a) Surfactant dysfunction during over-expression of TGF-β1 precedes profibrotic lung remodeling in vivo. Am J Physiol Lung Cell Mol Physiol 310:L1260–L1271PubMedCrossRefGoogle Scholar
  100. Lopez-Rodriguez E, Laucamp C, Hidalgo A, Cruz A, Perez-Gil J, Ochs M, Knudsen L (2016b) Using pulmonary surfactant as pirfenidone vehicle to target lung epithelium in bleoycin-induced lung fibrosis. Am J Respir Crit Care Med 193:A2378Google Scholar
  101. Lutz D, Gazdhar A, Lopez-Rodriguez E, Ruppert C, Mahavadi P, Guenther A, Klepetko W, Bates JH, Smith B, Geiser T, Ochs M, Knudsen L (2015) Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis. Am J Respir Cell Mol Biol 52:232–243PubMedCrossRefGoogle Scholar
  102. Mahavadi P, Korfei M, Henneke I, Liebisch G, Schmitz G, Gochuico BR, Markart P, Bellusci S, Seeger W, Ruppert C, Guenther A (2010) Epithelial stress and apoptosis underlie Hermansky-Pudlak syndrome-associated interstitial pneumonia. Am J Respir Crit Care Med 182:207–219PubMedPubMedCentralCrossRefGoogle Scholar
  103. Mahavadi P, Henneke I, Ruppert C, Knudsen L, Venkatesan S, Liebisch G, Chambers RC, Ochs M, Schmitz G, Vancheri C, Seeger W, Korfei M, Guenther A (2014) Altered surfactant homeostasis and alveolar epithelial cell stress in amiodarone-induced lung fibrosis. Toxicol Sci 142:285–297PubMedCrossRefGoogle Scholar
  104. Mahavadi P, Knudsen L, Venkatesan S, Henneke I, Hegermann J, Wrede C, Ochs M, Ahuja S, Chillappagari S, Ruppert C, Seeger W, Korfei M, Günther A (2015) Regulation of macroautophagy in amiodarone induced pulmonary fibrosis. J Pathol Clin Res 1:252–263PubMedPubMedCentralCrossRefGoogle Scholar
  105. Mai C, Verleden SE, McDonough JE, Willems S, De Wever W, Coolen J, Dubbeldam A, Van Raemdonck DE, Verbeken EK, Verleden GM, Hogg JC, Vanaudenaerde BM, Wuyts WA, Verschakelen JA (2016) Thin-section CT features of idiopathic pulmonary fibrosis correlated with Micro-CT and histologic analysis. Radiology (in press)Google Scholar
  106. Maitra M, Wang Y, Gerard RD, Mendelson CR, Garcia CK (2010) Surfactant protein A2 mutations associated with pulmonary fibrosis lead to protein instability and endoplasmic reticulum stress. J Biol Chem 285:22103–22113PubMedPubMedCentralCrossRefGoogle Scholar
  107. Marchand-Adam S, Fabre A, Mailleux AA, Marchal J, Quesnel C, Kataoka H, Aubier M, Dehoux M, Soler P, Crestani B (2006) Defect of pro-hepatocyte growth factor activation by fibroblasts in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 174:58–66PubMedCrossRefGoogle Scholar
  108. Mascheroni D, Kolobow T, Fumagalli R, Moretti MP, Chen V, Buckhold D (1988) Acute respiratory failure following pharmacologically induced hyperventilation: an experimental animal study. Intensive Care Med 15:8–14PubMedCrossRefGoogle Scholar
  109. Mason RJ, Leslie CC, McCormick-Shannon K, Deterding RR, Nakamura T, Rubin JS, Shannon JM (1994) Hepatocyte growth factor is a growth factor for rat alveolar type II cells. Am J Respir Cell Mol Biol 11:561–567PubMedCrossRefGoogle Scholar
  110. Mead J, Takishima T, Leith D (1970) Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol 28:596–608PubMedGoogle Scholar
  111. Mercer R, Crapo J (1990) Spatial distribution of collagen and elastin fibers in the lungs. J Appl Physiol 69:756–765PubMedGoogle Scholar
  112. Milioli G, Bosi M, Poletti V, Tomassetti S, Grassi A, Riccardi S, Terzano MG, Parrino L (2016) Sleep and respiratory sleep disorders in idiopathic pulmonary fibrosis. Sleep Med Rev 26:57–63PubMedCrossRefGoogle Scholar
  113. Molyneaux PL, Maher TM (2013) The role of infection in the pathogenesis of idiopathic pulmonary fibrosis. Eur Respir Rev 22:376–381PubMedCrossRefGoogle Scholar
  114. Moorsel CH van, Hoffman TW, Batenburg AA van, Klay D, Vis JJ van der, Grutters JC (2015) Understanding idiopathic interstitial pneumonia: a gene-based review of stressed lungs. Biomed Res Int 2015:304186Google Scholar
  115. Mulugeta S, Nguyen V, Russo S, Muniswamy M, Beers M (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 32:521–530PubMedPubMedCentralCrossRefGoogle Scholar
  116. Mulugeta S, Maguire JA, Newitt JL, Russo SJ, Kotorashvili A, Beers MF (2007) Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms. Am J Physiol Lung Cell Mol Physiol 293:L720–L729PubMedCrossRefGoogle Scholar
  117. Mulugeta S, Nureki S, Beers MF (2015) Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 309:L507–L525PubMedPubMedCentralCrossRefGoogle Scholar
  118. Myers J, Katzenstein A (1988) Epithelial necrosis and alveolar collapse in the pathogenesis of usual interstitial pneumonia. Chest 94:1309–1311PubMedCrossRefGoogle Scholar
  119. Myllärniemi M, Kaarteenaho R (2015) Pharmacological treatment of idiopathic pulmonary fibrosis—preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine. Eur Clin Respir J 10:2Google Scholar
  120. Nakano Y, Yang IV, Walts AD, Watson AM, Helling BA, Fletcher AA, Lara AR, Schwarz MI, Evans CM, Schwartz DA (2016) MUC5B promoter variant rs35705950 affects MUC5B expression in the distal airways in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 193:464–466PubMedPubMedCentralCrossRefGoogle Scholar
  121. Nakatani Y, Nakamura N, Sano J, Inayama Y, Kawano N, Yamanaka S, Miyagi Y, Nagashima Y, Ohbayashi C, Mizushima M, Manabe T, Kuroda M, Yokoi T, Matsubara O (2000) Interstitial pneumonia in Hermansky-Pudlak syndrome: significance of florid foamy swelling/degeneration (giant lamellar body degeneration) of type-2 pneumocytes. Virchows Arch 437:304–313PubMedCrossRefGoogle Scholar
  122. Nicholson AG, Fulford LG, Colby TV, du Bois RM, Hansell DM, Wells AU (2002) The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 166:173–177PubMedCrossRefGoogle Scholar
  123. Nieman GF, Gatto LA, Habashi NM (2015) Impact of mechanical ventilation on the pathophysiology of progressive acute lung injury. J Appl Physiol 119:1245–1261PubMedGoogle Scholar
  124. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, Bois RM du, Group CS (2011) Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 377:1760–1769Google Scholar
  125. Nogee L, Dunbar A, Wert S, Askin F, Hamvas A, Whitsett J (2001) A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 344:573–579PubMedCrossRefGoogle Scholar
  126. Noth I, Anstrom KJ, Calvert SB, Andrade J de, Flaherty KR, Glazer C, Kaner RJ, Olman MA, (IPFnet) IPFCRN (2012) A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 186:88–95Google Scholar
  127. Noth I, Zhang Y, Ma SF, Flores C, Barber M, Huang Y, Broderick SM, Wade MS, Hysi P, Scuirba J, Richards TJ, Juan-Guardela BM, Vij R, Han MK, Martinez FJ, Kossen K, Seiwert SD, Christie JD, Nicolae D, Kaminski N, Garcia JG (2013) Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med 1:309–317PubMedPubMedCentralCrossRefGoogle Scholar
  128. Ochs M (2010) The closer we look the more we see? Quantitative microscopic analysis of the pulmonary surfactant system. Cell Physiol Biochem 25:27–40PubMedCrossRefGoogle Scholar
  129. Oldham JM, Ma SF, Martinez FJ, Anstrom KJ, Raghu G, Schwartz DA, Valenzi E, Witt L, Lee C, Vij R, Huang Y, Strek ME, Noth I, Investigators I (2015) TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 192:1475–1482PubMedPubMedCentralCrossRefGoogle Scholar
  130. Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG (2003) Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A 100:8407–8411PubMedPubMedCentralCrossRefGoogle Scholar
  131. Pardo A, Cabrera S, Maldonado M, Selman M (2016) Role of matrix metalloproteinases in the pathogenesis of idiopathic pulmonary fibrosis. Respir Res 17:23PubMedPubMedCentralCrossRefGoogle Scholar
  132. Phin S, Marchand-Adam S, Fabre A, Marchal-Somme J, Bantsimba-Malanda C, Kataoka H, Soler P, Crestani B (2010) Imbalance in the pro-hepatocyte growth factor activation system in bleomycin-induced lung fibrosis in mice. Am J Respir Cell Mol Biol 42:286–293PubMedCrossRefGoogle Scholar
  133. Postle AD, Henderson NG, Koster G, Clark HW, Hunt AN (2011) Analysis of lung surfactant phosphatidylcholine metabolism in transgenic mice using stable isotopes. Chem Phys Lipids 164:549–555PubMedCrossRefGoogle Scholar
  134. Putman RK, Rosas IO, Hunninghake GM (2014) Genetics and early detection in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 189:770–778PubMedPubMedCentralCrossRefGoogle Scholar
  135. Putman RK, Hatabu H, Araki T, Gudmundsson G, Gao W, Nishino M, Okajima Y, Dupuis J, Latourelle JC, Cho MH, El-Chemaly S, Coxson HO, Celli BR, Fernandez IE, Zazueta OE, Ross JC, Harmouche R, Estépar RS, Diaz AA, Sigurdsson S, Gudmundsson EF, Eiríksdottír G, Aspelund T, Budoff MJ, Kinney GL, Hokanson JE, Williams MC, Murchison JT, MacNee W, Hoffmann U, O’Donnell CJ, Launer LJ, Harrris TB, Gudnason V, Silverman EK, O’Connor GT, Washko GR, Rosas IO, Hunninghake GM, Investigators EoCLtIPSEE, Investigators C (2016) Association between interstitial lung abnormalities and all-cause mortality. JAMA 315:672–681PubMedPubMedCentralCrossRefGoogle Scholar
  136. Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, Sillery JK, Pope CE, Pellegrini CA (2006) High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 27:136–142PubMedCrossRefGoogle Scholar
  137. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ, Fibrosis AEJACoIP (2011) An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 183:788–824PubMedCrossRefGoogle Scholar
  138. Raghu G, Anstrom KJ, King TE, Lasky JA, Martinez FJ, Network IPFCR (2012) Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 366:1968–1977PubMedCrossRefGoogle Scholar
  139. Raghu G, Wells AU, Nicholson AG, Richeldi L, Flaherty KR, Le Maulf F, Stowasser S, Schlenker-Herceg R, Hansell DM (2016) Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am J Respir Crit Care Med (in press)Google Scholar
  140. Ravasio A, Hobi N, Bertocchi C, Jesacher A, Dietl P, Haller T (2011) Interfacial sensing by alveolar type II cells: a new concept in lung physiology? Am J Physiol Cell Physiol 300:C1456–C1465PubMedPubMedCentralCrossRefGoogle Scholar
  141. Richeldi L, Bois RM, du Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR, Investigators IT (2014) Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 370:2071–2082Google Scholar
  142. Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, Noble PW, Hogan BL (2011) Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A 108:E1475–E1483PubMedPubMedCentralCrossRefGoogle Scholar
  143. Ruppert C, Markart P, Wygrecka M, Preissner KT, Günther A (2008) Role of coagulation and fibrinolysis in lung and renal fibrosis. Hamostaseologie 28:34–36Google Scholar
  144. Saito A, Nagase T (2015) Hippo and TGF-β interplay in the lung field. Am J Physiol Lung Cell Mol Physiol 309:L756–L767PubMedGoogle Scholar
  145. Sánchez-Pulido L, Devos D, Valencia A (2002) BRICHOS: a conserved domain in proteins associated with dementia, respiratory distress and cancer. Trends Biochem Sci 27:329–332PubMedCrossRefGoogle Scholar
  146. Schiller HJ, McCann UG, Carney DE, Gatto LA, Steinberg JM, Nieman GF (2001) Altered alveolar mechanics in the acutely injured lung. Crit Care Med 29:1049–1055PubMedCrossRefGoogle Scholar
  147. Schürch S, Bachofen H, Possmayer F (2001) Surface activity in situ, in vivo, and in the captive bubble surfactometer. Comp Biochem Physiol A Mol Integr Physiol 129:195–207PubMedCrossRefGoogle Scholar
  148. Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, Fingerlin TE, Zhang W, Gudmundsson G, Groshong SD, Evans CM, Garantziotis S, Adler KB, Dickey BF, Bois RM du, Yang IV, Herron A, Kervitsky D, Talbert JL, Markin C, Park J, Crews AL, Slifer SH, Auerbach S, Roy MG, Lin J, Hennessy CE, Schwarz MI, Schwartz DA (2011) A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 364:1503–1512Google Scholar
  149. Seibold MA, Smith RW, Urbanek C, Groshong SD, Cosgrove GP, Brown KK, Schwarz MI, Schwartz DA, Reynolds SD (2013) The idiopathic pulmonary fibrosis honeycomb cyst contains a mucocilary pseudostratified epithelium. PLoS One 8:e58658PubMedPubMedCentralCrossRefGoogle Scholar
  150. Selman M, Pardo A (2006) Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc 3:364–372PubMedCrossRefGoogle Scholar
  151. Selman M, Pardo A (2014) Revealing the pathogenic and aging-related mechanisms of the enigmatic idiopathic pulmonary fibrosis. An integral model. Am J Respir Crit Care Med 189:1161–1172PubMedCrossRefGoogle Scholar
  152. Selman M, Montaño M, Ramos C, Chapela R (1986) Concentration, biosynthesis and degradation of collagen in idiopathic pulmonary fibrosis. Thorax 41:355–359PubMedPubMedCentralCrossRefGoogle Scholar
  153. Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J (1997) Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest 100:768–776PubMedPubMedCentralCrossRefGoogle Scholar
  154. Sisson T, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A, Dave A, Engelhardt J, Liu X, White E, Thannickal V, Moore B, Christensen P, Simon R (2010) Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med 181:254–263PubMedCrossRefGoogle Scholar
  155. Slutsky AS, Ranieri VM (2013) Ventilator-induced lung injury. N Engl J Med 369:2126–2136PubMedCrossRefGoogle Scholar
  156. Smith BJ, Grant KA, Bates JH (2013) Linking the development of ventilator-induced injury to mechanical function in the lung. Ann Biomed Eng 41:527–536PubMedCrossRefGoogle Scholar
  157. Tager AM, LaCamera P, Shea BS, Campanella GS, Selman M, Zhao Z, Polosukhin V, Wain J, Karimi-Shah BA, Kim ND, Hart WK, Pardo A, Blackwell TS, Xu Y, Chun J, Luster AD (2008) The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med 14:45–54PubMedCrossRefGoogle Scholar
  158. Taskar VS, Coultas DB (2006) Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc 3:293–298PubMedCrossRefGoogle Scholar
  159. Thomas AQ, Lane K, Phillips J, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, Roberts R, Haines J, Stahlman M, Loyd JE (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 165:1322–1328PubMedCrossRefGoogle Scholar
  160. Thrall RS, Phan SH, McCormick JR, Ward PA (1981) The development of bleomycin-induced pulmonary fibrosis in neutrophil-depleted and complement-depleted rats. Am J Pathol 105:76–81PubMedPubMedCentralGoogle Scholar
  161. Todd NW, Atamas SP, Luzina IG, Galvin JR (2015) Permanent alveolar collapse is the predominant mechanism in idiopathic pulmonary fibrosis. Expert Rev Respir Med 9:411–418PubMedCrossRefGoogle Scholar
  162. Toumpanakis D, Kastis GA, Zacharatos P, Sigala I, Michailidou T, Kouvela M, Glynos C, Divangahi M, Roussos C, Theocharis SE, Vassilakopoulos T (2010) Inspiratory resistive breathing induces acute lung injury. Am J Respir Crit Care Med 182:1129–1136PubMedCrossRefGoogle Scholar
  163. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK (2007) Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A 104:7552–7557PubMedPubMedCentralCrossRefGoogle Scholar
  164. Uhal BD, Nguyen H (2013) The Witschi hypothesis revisited after 35 years: genetic proof from SP-C BRICHOS domain mutations. Am J Physiol Lung Cell Mol Physiol 305:L906–L911PubMedPubMedCentralCrossRefGoogle Scholar
  165. Uhal BD, Joshi I, Hughes WF, Ramos C, Pardo A, Selman M (1998) Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. Am J Physiol 275:L1192–L1199PubMedGoogle Scholar
  166. Vyshedskiy A, Alhashem RM, Paciej R, Ebril M, Rudman I, Fredberg JJ, Murphy R (2009) Mechanism of inspiratory and expiratory crackles. Chest 135:156–164PubMedCrossRefGoogle Scholar
  167. Waisberg D, Barbas-Filho J, Parra E, Fernezlian S, Ribeiro de Carvalho C, Kairalla R, Capelozzi V (2010) Abnormal expression of telomerase/apoptosis limits type II alveolar epithelial cell replication in the early remodeling of usual interstitial pneumonia/idiopathic pulmonary fibrosis. Hum Pathol 41:385–391PubMedCrossRefGoogle Scholar
  168. Wambach JA, Casey AM, Fishman MP, Wegner DJ, Wert SE, Cole FS, Hamvas A, Nogee LM (2014) Genotype-phenotype correlations for infants and children with ABCA3 deficiency. Am J Respir Crit Care Med 189:1538–1543PubMedPubMedCentralCrossRefGoogle Scholar
  169. Wang WJ, Mulugeta S, Russo SJ, Beers MF (2003) Deletion of exon 4 from human surfactant protein C results in aggresome formation and generation of a dominant negative. J Cell Sci 116:683–692PubMedCrossRefGoogle Scholar
  170. Weibel E (2009) What makes a good lung? Swiss Med Wkly 139:375–386PubMedGoogle Scholar
  171. Weibel E, Federspiel W, Fryder-Doffey F, Hsia C, König M, Stalder-Navarro V, Vock R (1993) Morphometric model for pulmonary diffusing capacity. I. Membrane diffusing capacity. Respir Physiol 93:125–149PubMedCrossRefGoogle Scholar
  172. Weichert N, Kaltenborn E, Hector A, Woischnik M, Schams A, Holzinger A, Kern S, Griese M (2011) Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells. Respir Res 12:4PubMedPubMedCentralCrossRefGoogle Scholar
  173. Wilson TA, Bachofen H (1982) A model for mechanical structure of the alveolar duct. J Appl Physiol 52:1064–1070PubMedGoogle Scholar
  174. Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B (2014) Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther 349:209–220PubMedCrossRefGoogle Scholar
  175. Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664PubMedPubMedCentralCrossRefGoogle Scholar
  176. Yamada M, Kubo H, Kobayashi S, Ishizawa K, Numasaki M, Ueda S, Suzuki T, Sasaki H (2004) Bone marrow-derived progenitor cells are important for lung repair after lipopolysaccharide-induced lung injury. J Immunol 172:1266–1272PubMedCrossRefGoogle Scholar
  177. Yang J, Wheeler SE, Velikoff M, Kleaveland KR, LaFemina MJ, Frank JA, Chapman HA, Christensen PJ, Kim KK (2013) Activated alveolar epithelial cells initiate fibrosis through secretion of mesenchymal proteins. Am J Pathol 183:1559–1570PubMedPubMedCentralCrossRefGoogle Scholar
  178. Yang J, Velikoff M, Canalis E, Horowitz JC, Kim KK (2014) Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor. Am J Physiol Lung Cell Mol Physiol 306:L786–L796PubMedPubMedCentralCrossRefGoogle Scholar
  179. Young LR, Nogee LM, Barnett B, Panos RJ, Colby TV, Deutsch GH (2008) Usual interstitial pneumonia in an adolescent with ABCA3 mutations. Chest 134:192–195PubMedCrossRefGoogle Scholar
  180. Zhang R, Pan Y, Fanelli V, Wu S, Luo AA, Islam D, Han B, Mao P, Ghazarian M, Zeng W, Spieth PM, Wang D, Khang J, Mo H, Liu X, Uhlig S, Liu M, Laffey J, Slutsky AS, Li Y, Zhang H (2015) Mechanical stress and the induction of lung fibrosis via the midkine signaling pathway. Am J Respir Crit Care Med 192:315–323PubMedCrossRefGoogle Scholar
  181. Zhang X, Zhang Y, Tao B, Teng L, Li Y, Cao R, Gui Q, Ye M, Mou X, Cheng H, Hu H, Zhou R, Wu X, Xie Q, Ning W, Lai M, Shen H, Feng GS, Ke Y (2012) Loss of Shp2 in alveoli epithelia induces deregulated surfactant homeostasis, resulting in spontaneous pulmonary fibrosis. FASEB J 26:2338–2350PubMedCrossRefGoogle Scholar
  182. Zhou Y, Huang X, Hecker L, Kurundkar D, Kurundkar A, Liu H, Jin TH, Desai L, Bernard K, Thannickal VJ (2013) Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest 123:1096–1108PubMedPubMedCentralCrossRefGoogle Scholar
  183. Ziegler E (1881) Lehrbuch der allgemeinen und speziellen pathologischen Anatomie für Ärzte und Studirende. Fischer, JenaGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Lars Knudsen
    • 1
    • 2
    • 3
    Email author
  • Clemens Ruppert
    • 4
    • 5
  • Matthias Ochs
    • 1
    • 2
    • 3
  1. 1.Institute of Functional and Applied AnatomyHannover Medical SchoolHannoverGermany
  2. 2.Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL)Hannover Medical SchoolHannoverGermany
  3. 3.REBIRTH, Cluster of ExcellenceHannover Medical SchoolHannoverGermany
  4. 4.Department of Internal MedicineJustus-Liebig-University GiessenGiessenGermany
  5. 5.Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL)Universities of Giessen and MarburgGiessenGermany

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