• John S. Munger
  • William N. Rom
Part of the Molecular Pathology Library book series (MPLB, volume 1)


Pulmonary fibrosis can be idiopathic or secondary to inflammatory states or injuries (Table 46.1). The tempo ranges from insidious to rapid, and the location of the fibrous tissue can be centered around or in the airways (bronchiolitis obliterans) or in the alveolar compartment (idiopathic pulmonary fibrosis [IPF]). In this chapter, we focus on IPF, the paradigmatic fibrosing lung disorder.
Table 46.1.

Disorders associated with pulmonary fibrosis.


Interstitial Lung Disease Surfactant Protein Lamellar Body Bronchiolitis Obliterans Discoidin Domain Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Noble PW, Homer RJ. Back to the future: historical perspective on the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2005;33(2):113–120.CrossRefPubMedGoogle Scholar
  2. 2.
    Selman M, Pardo A. Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. Respir Res 2002;3(1):3.CrossRefPubMedGoogle Scholar
  3. 3.
    Mora AL, Woods CR, Garcia A, et al. Lung infection with gamma-herpesvirus induces progressive pulmonary fibrosis in Th2-biased mice. Am J Physiol Lung Cell Mol Physiol 2005;289(5):L711–L721.CrossRefPubMedGoogle Scholar
  4. 4.
    Kuhn C 3rd, Boldt J, King TE Jr, Crouch E, Vartio T, McDonald JA. An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis 1989;140(6):1693–1703.PubMedGoogle Scholar
  5. 5.
    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(6 Pt 1):L1192–L1199.PubMedGoogle Scholar
  6. 6.
    Matsuyama W, Watanabe M, Shirahama Y, et al. Discoidin domain receptor 1 contributes to the survival of lung fibroblast in idiopathic pulmonary fibrosis. Am J Pathol 2006;168(3):866–877.CrossRefPubMedGoogle Scholar
  7. 7.
    Acharya PS, Zukas A, Chandan V, Katzenstein AL, Pure E. Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis. Hum Pathol 2006;37(3):352–360.CrossRefPubMedGoogle Scholar
  8. 8.
    Rege TA, Hagood JS. Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis. FASEB J 2006;20(8):1045–1054.CrossRefPubMedGoogle Scholar
  9. 9.
    Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002;110(3):341–350.PubMedGoogle Scholar
  10. 10.
    Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 2001;166(12):7556–7562.PubMedGoogle Scholar
  11. 11.
    Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1994;1(1):71–81.PubMedGoogle Scholar
  12. 12.
    Phillips RJ, Burdick MD, Hong K, et al. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004;114(3):438–446.PubMedGoogle Scholar
  13. 13.
    Moore BB, Murray L, Das A, Wilke CA, Herrygers AB, Toews GB. The Role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am J Respir Cell Mol Biol 2006;35(2):175–181.CrossRefPubMedGoogle Scholar
  14. 14.
    Willis BC, Liebler JM, Luby-Phelps K, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: potential role in idiopathic pulmonary fibrosis. Am J Pathol 2005;166(5):1321–1332.PubMedGoogle Scholar
  15. 15.
    Yao HW, Xie QM, Chen JQ, Deng YM, Tang HF. TGF-β1 induces alveolar epithelial to mesenchymal transition in vitro. Life Sci 2004;76(1):29–37.CrossRefPubMedGoogle Scholar
  16. 16.
    Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000;16(3):534–554.CrossRefPubMedGoogle Scholar
  17. 17.
    Cantin AM, Hubbard RC, Crystal RG. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1989;139(2):370–372.PubMedGoogle Scholar
  18. 18.
    Waghray M, Cui Z, Horowitz JC, et al. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J 2005;19(7):854–856.PubMedGoogle Scholar
  19. 19.
    Barcellos-Hoff MH, Dix TA. Redox-mediated activation of latent transforming growth factor-β1. Mol Endocrinol 1996;10(9):1077–1083.CrossRefPubMedGoogle Scholar
  20. 20.
    Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal 2006;8(1–2):76–87.CrossRefPubMedGoogle Scholar
  21. 21.
    Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353(21):2229–2242.CrossRefPubMedGoogle Scholar
  22. 22.
    Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc 2006;3(4):350–356.CrossRefPubMedGoogle Scholar
  23. 23.
    Lee CG, Kang HR, Homer RJ, Chupp G, Elias JA. Transgenic Modeling of Transforming Growth Factor-β1: Role of Apoptosis in Fibrosis and Alveolar Remodeling. Proc Am Thorac Soc 2006;3(5):418–423.CrossRefPubMedGoogle Scholar
  24. 24.
    Lee CG, Cho SJ, Kang MJ, et al. Early growth response gene 1-mediated apoptosis is essential for transforming growth factor β1-induced pulmonary fibrosis. J Exp Med 2004;200(3):377–389.CrossRefPubMedGoogle Scholar
  25. 25.
    Li X, Shu R, Filippatos G, Uhal BD. Apoptosis in lung injury and remodeling. J Appl Physiol 2004;97(4):1535–1542.CrossRefPubMedGoogle Scholar
  26. 26.
    Vandivier RW, Henson PM, Douglas IS. Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 2006;129(6):1673–1682.CrossRefPubMedGoogle Scholar
  27. 27.
    Branton MH, Kopp JB. TGF-β and fibrosis. Microbes Infect 1999;1(15):1349–1365.CrossRefPubMedGoogle Scholar
  28. 28.
    Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-β1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997;100(4):768–776.CrossRefPubMedGoogle Scholar
  29. 29.
    Kolb M, Margetts PJ, Galt T, et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med 2001;163(3 Pt 1):770–777.PubMedGoogle Scholar
  30. 30.
    Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β. J Exp Med 2001;194(6):809–821.CrossRefPubMedGoogle Scholar
  31. 31.
    Shi Y, Massague J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 2003;113(6):685–700.CrossRefPubMedGoogle Scholar
  32. 32.
    Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFβ activation. J Cell Sci 2003;116 (Pt 2):217–224.CrossRefPubMedGoogle Scholar
  33. 33.
    Annes JP, Chen Y, Munger JS, Rifkin DB. Integrin αvβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J Cell Biol 2004;165(5):723–734.CrossRefPubMedGoogle Scholar
  34. 34.
    Jenkins RG, Su X, Su G, et al. Ligation of protease-activated receptor 1 enhances αvβ6 integrin-dependent TGF-β activation and promotes acute lung injury. J Clin Invest 2006;116(6):1606–1614.CrossRefPubMedGoogle Scholar
  35. 35.
    Munger JS, Huang X, Kawakatsu H, et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999;96(3):319–328.CrossRefPubMedGoogle Scholar
  36. 36.
    Morris DG, Huang X, Kaminski N, et al. Loss of integrin αvβ6-mediated TGF-β activation causes MMP12-dependent emphysema. Nature 2003;422(6928):169–173.CrossRefPubMedGoogle Scholar
  37. 37.
    Yehualaeshet T, O’Connor R, Green-Johnson J, et al. Activation of rat alveolar macrophage-derived latent transforming growth factor β1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am J Pathol 1999;155(3):841–851.PubMedGoogle Scholar
  38. 38.
    Abreu JG, Ketpura NI, Reversade B, De Robertis EM. Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β. Nat Cell Biol 2002;4(8):599–604.PubMedGoogle Scholar
  39. 39.
    Dong C, Zhu S, Wang T, et al. Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc Natl Acad Sci USA 2002;99(6):3908–3913.CrossRefPubMedGoogle Scholar
  40. 40.
    Doran P, Egan JJ. Herpesviruses: a cofactor in the pathogenesis of idiopathic pulmonary fibrosis? Am J Physiol Lung Cell Mol Physiol 2005;289(5):L709–L710.CrossRefPubMedGoogle Scholar
  41. 41.
    Tang YW, Johnson JE, Browning PJ, et al. Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. J Clin Microbiol 2003;41(6):2633–2640.CrossRefPubMedGoogle Scholar
  42. 42.
    Kelly BG, Lok SS, Hasleton PS, et al. A rearranged form of Epstein-Barr virus DNA is associated with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2002;166(4):510–513.CrossRefPubMedGoogle Scholar
  43. 43.
    Strieter RM, Belperio JA, Keane MP. CXC chemokines in angiogenesis related to pulmonary fibrosis. Chest 2002;122(6 Suppl):298S–301S.CrossRefPubMedGoogle Scholar
  44. 44.
    Burdick MD, Murray LA, Keane MP, et al. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med 2005;171(3):261–268.CrossRefPubMedGoogle Scholar
  45. 45.
    Beers MF, Mulugeta S. Surfactant protein C biosynthesis and its emerging role in conformational lung disease. Annu Rev Physiol 2005;67:663–696.CrossRefPubMedGoogle Scholar
  46. 46.
    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(6):521–530.CrossRefPubMedGoogle Scholar
  47. 47.
    Amin RS, Wert SE, Baughman RP, et al. Surfactant protein deficiency in familial interstitial lung disease. J Pediatr 2001;139(1):85–92.CrossRefPubMedGoogle Scholar
  48. 48.
    Lawson WE, Polosukhin VV, Stathopoulos GT, et al. Increased and prolonged pulmonary fibrosis in surfactant protein C-deficient mice following intratracheal bleomycin. Am J Pathol 2005;167(5):1267–1277.PubMedGoogle Scholar
  49. 49.
    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(52):52739–5246.CrossRefPubMedGoogle Scholar
  50. 50.
    Morgan NV, Pasha S, Johnson CA, et al. A germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8). Am J Hum Genet 2006;78(1):160–166.CrossRefPubMedGoogle Scholar
  51. 51.
    Bonifacino JS. Insights into the biogenesis of lysosome-related organelles from the study of the Hermansky-Pudlak syndrome. Ann NY Acad Sci 2004;1038:103–114.CrossRefPubMedGoogle Scholar
  52. 52.
    Li W, Rusiniak ME, Chintala S, Gautam R, Novak EK, Swank RT. Murine Hermansky-Pudlak syndrome genes: regulators of lysosome-related organelles. Bioessays 2004;26(6):616–628.CrossRefPubMedGoogle Scholar
  53. 53.
    Lyerla TA, Rusiniak ME, Borchers M, et al. Aberrant lung structure, composition, and function in a murine model of Hermansky-Pudlak syndrome. Am J Physiol Lung Cell Mol Physiol 2003;285(3):L643–L653.PubMedGoogle Scholar
  54. 54.
    Grutters JC, du Bois RM. Genetics of fibrosing lung diseases. Eur Respir J 2005;25(5):915–927.CrossRefPubMedGoogle Scholar
  55. 55.
    Selman M, Lin HM, Montano M, et al. Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Hum Genet 2003;113(6):542–550.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • John S. Munger
    • 1
  • William N. Rom
    • 2
  1. 1.Department of Medicine and Cell BiologyNew York University School of MedicineNew YorkUSA
  2. 2.Department of Medicine and Environmental MedicineNew York University School of MedicineNew YorkUSA

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