Review Article
Current Concept for the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF)
Richard Seonghun Nho*
Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA

Extracellular matrix ; Idiopathic pulmonary fibrosis; Collagen; Integrins

Fibrosis in interstitial lung disease is caused by the accumulation of extracellular matrix proteins within the interstitium and alveolar space of the lung. The majority of severe cases comprise a classification known as idiopathic pulmonary fibrosis (IPF) for which the origin is unknown [1]. IPF is the most severe chronic form of pulmonary fibrosis and results in gradual exchange of normal lung parenchyma with fibrotic tissue and in the irreversible impairment of gas exchange in the lung. IPF is a deadly fibrotic lung disease with a 5 year mortality of 50-70%, comparable to many cancers. The estimated incidence of IPF is 10 per 100,000 individuals with a prevalence of 30 per 100,000 [2]. The current concept for the development of pulmonary fibrosis including IPF is that at least three physiologically balanced processes implicated in the maintenance of lung fibroblasts populations - proliferation, apoptosis of (myo) fibroblasts and production of ECM - are disturbed [3]. Risk factors for IPF include age, male gender and a history of cigarette smoking [4]. A number of genetic mutations such as the surfactant protein C (SFTPC), surfactant protein A2 (SFTPA2) and telomerase (TERT and TERTC) have also been associated with the development of lung fibrosis [5-7]. IPF is characterized by the accumulation of fibroblasts and collagen within the alveolar wall resulting in obliteration of the gas-exchange surface. Morphological studies have demonstrated that subepithelial accumulation of fibroblasts in a lesion termed the “fibroblastic focus” is the sentinel morphological lesion of IPF [8]. Ultrastructural analysis of the fibroblastic focus has revealed that it is composed of alpha-smooth muscle actin-expressing myofibroblasts enmeshed in a matrix rich in polymerized type I collagen [9]. The key role of the myofibroblast in IPF is established by the observation that progressive expansion of the fibroblastic focus by proliferating myofibroblasts depositing type I collagen leads to permanently scarred alveoli [10-13]. Although this study suggests that myofibroblasts are closely linked to the development of lung fibrosis, the origin of myofibroblasts is still unclear. However, it is speculated that circulating fibrocytes derived from bone marrow, epithelial to mesenchymal transition (EMT) and resident fibroblasts are responsible for the appearance of myofibroblasts [14]. Prior to the activation of myofibroblasts, it is generally believed that an initial or repetitive injury occurs to type I alveolar epithelial cells (AEC-I) which constitute the majority of the alveolar surface [15]. When AEC-I is injured, type II alveolar epithelial cells (AECII) are thought to undergo hyperplastic proliferation and release growth factors, cytokines and other substance that subsequently promote the activation of myofibroblasts, which secret collagen and ECMs. The accumulation of ECM and the hyper-proliferation of myofibroblasts ultimately destroy lung parenchyma. In an effort to elucidate the pathogenesis of this deadly disease, several underlying mechanisms have recently been proposed. One of the critical mechanisms in IPF progression is the physical interaction between ECM and cells. Several cell surface receptors including integrins, discoidin domain receptors (DDRs), syndecans and CD44 have been identified as components of a complex systemresponsible for cell immobilization on normal ECM. Among them, integrins have been extensively studied in IPF fibroblasts. ECM is composed of collagens, elastin, proteoglycans (including hyaluronan) and non-collagenous glycoproteins and forms a complex, three-dimensional network among cells of different tissues in an organ-specific manner and reciprocally influences cellular function to modulate diverse fundamental aspects of cell biology [16,17].
Collagens are the most abundant matrix protein in animal tissues and type I collagen is the major component of ECM in skin, bone, ligamnents, etc. Type I collagen is composed of glycin- and proline rich two-α1 (I) and one-α2 (I) chains [18]. It hasbeen well established that the alteration of integrin function is associated with a pathological IPF fibroblast phenotype. An ECM alteration result from abnormal synthesis or degradation of one or more ECM componentsand contributes to the progression of IPF [19]. Interestingly, there is a sharp difference in proliferation profiles of human lung fibroblasts when they are cultured on 2D and 3D type 1 collagen matrices. Studies showed that tissue culture plates coated with 2D monomeric collagen provide a proliferationpermissive environment for normal and IPF lung fibroblasts [20]. Unlike 2D collagen, 3D matrix, which closely imitates the physiological forms of ECM, is composed of polymerized collagen (fibrillar collagen). Immunohistochemical analysis also revealed that α-smooth muscle actin-expressing myofibroblasts are enmeshed in a type I collagen-rich 3D matrix. Unlike 2D matrix, when normal lung fibroblasts attach to 3D polymerized collagen matrix, cell proliferation is suppressed and apoptosis increases. However, IPF fibroblasts elude the proliferation suppressing and apoptosis inducing effects of polymerized collagen matrix [21,22]. Interestingly, mounting evidence points to similarities between IPF and cancer in some aspects of the IPF phenotype and the underlying disease mechanisms. It is well established that PTEN/PI3K/Akt axis is deregulated in IPF and cancer cells [23-27]. This concept is also supported by other research group's findings that oncogenic proteins such as Ras and tumor suppressor proteins p53 become abnormally altered, implicating the development of lung carcinoma in IPF patients [28-30].Thus, these studies strongly suggest that the intrinsic changes of IPF fibroblasts enable them to have a highly proliferative and an apoptosis-resistance phenotype in response to 3D polymerized collagen matrix.
Priorresearch strongly suggest that the understanding the role of cell-ECM interaction is crucial in IPF pathogenesis. This physiological process that accompanies normal wound repair is aberrant in IPF fibroblasts and is mediated by pathological integrin signaling [20]. The α and β chains of integrinscooperate in a specific mode in which the extracellular portion of the α chainis responsible for the ligand-binding specificity of the complex whereasthe intracellular domain of the β chain is associated with the induction of intracellular signaling cascades. Recent studies further revealed that β1 integrin regulates the crucial PTEN/PI3K/Akt axis, thereby altering IPF fibroblast cell phenotype in response to type I collagen matrix [20,21] and this signaling pathway is closely linked to cell proliferation, migration and apoptosis. Thus the precise understanding of the altered PTEN/PI3K/Akt dependent pathway is thought to be vital for the elucidation of IPF pathogenesis.Various profibrotic factors such as TGF-β1, PDGF, ET-1, TNF-α, heat shock protein 47 (HSP47), connective tissue growth factor (CTGF), IL-4, insulinlike growth factor (IGF) and its binding proteins are also known to be associated with the regulation of fibrosis [31]. Furthermore, recent studies suggest epigenetic alterationssuch as DNA methylation, histone modification and microRNAs also contribute the development of IPF. From this concept, the pathological role of DNA methyl transferases (Dnmts), histone acetyltransferases (HATS) and deacetylases (HDACs) havebeen highlighted in the development of lung fibrosis [32-34]. Several miRNAsare known to play a major role of conductors in the pathogenesis of fibrosis [35]. It has been found that about 40 miRNAs have also been linked to fibrosis in various organs and disease settings [36]. Among them, miR155, miR-15b, miR-16, mir21, mir23a, miR26a/b, miR-30c and miR338 are though to be associated with lung fibrosis [36]. However current knowledge about the role of these factors are limited and there should be more future research work needed to establish the pathological function of these regulators in lung fibrosis. Although there has been some progress in understanding the pathogenesis of IPF, the etiology and genesis of IPF remains unknown, and there is still no proven effective therapy available due to the lack of understanding for crucial pathological mechanisms in IPF. Therefore, the precise elucidation of IPF pathogenesis is vital to develop IPF therapy and to further prevent the progression of this deadly disease. In summary, the complexity and heterogeneity exist in IPF studies and the understanding of genetic and epigenetic alterations in the development of lung fibrosis is required for future investigation, and these efforts will ultimately lead to find effective therapeutic targets for the treatment of IPF.

  1. Loomis-King H, Flaherty KR, Moore BB. Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis. 2013; Curr Opin Pharmacol.13: 377-385.
  2. Gay SE, Kazerooni EA, Toews GB, Lynch JP 3rd, Gross BH, Cascade PN, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. 1998; Am J Respir Crit Care Med.157: 1063-1072.
  3. Todd NW, Luzina IG, Atamas SP. Molecular and cellular mechanisms of pulmonary fibrosis. 2012; Fibrogenesis Tissue Repair.5: 11.
  4. Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. 1997; Am J Respir Crit Care Med.155: 242-248.
  5. Thomas AQ, Lane K, Phillips J 3rd, Prince M, Markin C, Speer M, 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: 1322-8.
  6. Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. 2009; Am J Hum Genet.84: 52-59.
  7. Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. 2008; Proc Natl Acad Sci U S A.105: 13051-13056.
  8. Kuhn C, McDonald JA. The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. 1991; Am J Pathol.138: 1257-1265.
  9. 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. 1989; Am Rev Respir Dis.140: 1693-1703.
  10. Basset F, Ferrans VJ, Soler P, Takemura T, Fukuda Y, Crystal RG.Intraluminal fibrosis in interstitial lung disorders. 1986; Am J Pathol.122: 443-461.
  11. Fukuda Y, Ishizaki M, Masuda Y, Kimura G, Kawanami O, Masugi Y. The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. 1987; Am J Pathol.126: 171-182.
  12. Gay SE, Kazerooni EA, Toews GB, Lynch JP 3rd, Gross BH, Cascade PN, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. 1998; Am J Respir Crit Care Med.157: 1063-1072.
  13. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. 1998; Am J Respir Crit Care Med.157: 1301-1315.
  14. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. 2007; Am J Pathol.170: 1807-1816.
  15. Günther A, Korfei M, Mahavadi P, von der Beck D, Ruppert C, Markart P. Unravelling the progressive pathophysiology of idiopathic pulmonary fibrosis. 2012; Eur Respir Rev.21: 152-160.
  16. Hubmacher D, Apte SS. The biology of the extracellular matrix: novel insights. 2013; Curr Opin Rheumatol.25: 65-70.
  17. ynes RO. The extracellular matrix: not just pretty fibrils. 2009; Science.326: 1216-1219.
  18. hosh AK. Factors involved in the regulation of type I collagen gene expression: implication in fibrosis. 2002; Exp Biol Med (Maywood).227: 301-314.
  19. Lu P, Takai K, Weaver VM, Werb Z. Extracellular matrix degradation and remodeling in development and disease. 2011; Cold Spring Harb Perspect Biol.3.
  20. Xia H, Diebold D, Nho R, Perlman D, Kleidon J, Kahm J, et al. Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. 2008; J Exp Med.205: 1659-1672.
  21. Nho RS, Hergert P, Kahm J, Jessurun J, Henke C. Pathological alteration of FoxO3a activity promotes idiopathic pulmonary fibrosis fibroblast proliferation on type i collagen matrix. 2011; Am J Pathol.179: 2420-2430.
  22. Koyama H, Raines EW, Bornfeldt KE, Roberts JM, Ross R. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. 1996; Cell.87: 1069-1078.
  23. Takahashi T, Munakata M, Ohtsuka Y, Nisihara H, Nasuhara Y, Kamachi-Satoh A, et al. Expression and alteration of ras and p53 proteins in patients with lung carcinoma accompanied by idiopathic pulmonary fibrosis. 2002; Cancer.95: 624-633.
  24. Kawasaki H, Ogura T, Yokose T, Nagai K, Nishiwaki Y, Esumi H. p53 gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis. 2001; Hum Pathol.32: 1043-1049.
  25. Vancheri C, Failla M, Crimi N, Raghu G. Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology. 2010; Eur Respir J.35: 496-504.
  26. Kushibe K, Kawaguchi T, Takahama M, Kimura M, Tojo T, Taniguchi S. Operative indications for lung cancer with idiopathic pulmonary fibrosis. 2007; Thorac Cardiovasc Surg.55: 505-508.
  27. Minegishi Y, Sudoh J, Kuribayasi H, Mizutani H, Seike M, Azuma A, et al. The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small cell lung cancer with idiopathic interstitial pneumonias. 2011; Lung Cancer.71: 70-74.
  28. Parsa AT, Holland EC. Cooperative translational control of gene expression by Ras and Akt in cancer. 2004; Trends Mol Med.10: 607-613.
  29. Ozawa Y, Suda T, Naito T, Enomoto N, Hashimoto D, Fujisawa T, et al.Cumulative incidence of and predictive factors for lung cancer in IPF. 2009; Respirology.14: 723-728.
  30. Takahashi T, Munakata M, Ohtsuka Y, Nisihara H, Nasuhara Y, Kamachi-Satoh A, et al. Expression and alteration of ras and p53 proteins in patients with lung carcinoma accompanied by idiopathic pulmonary fibrosis. 2002; Cancer.95: 624-633.
  31. Razzaque MS, Taguchi T. Pulmonary fibrosis: cellular and molecular events. 2003; Pathol Int.53: 133-145.
  32. Bechtel W, McGoohan S, Zeisberg EM, Müller GA, Kalbacher H, Salant DJ, et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. 2010; Nat Med.16: 544-550.
  33. Sanders YY, Ambalavanan N, Halloran B, Zhang X, Liu H, Crossman DK, et al. Altered DNA methylation profile in idiopathic pulmonary fibrosis. 2012; Am J Respir Crit Care Med.186: 525-535.
  34. Hu B, Gharaee-Kermani M, Wu Z, Phan SH. Epigenetic regulation of myofibroblast differentiation by DNA methylation. 2010; Am J Pathol.177: 21-28.
  35. Chau BN, Brenner DA. What goes up must come down: the emerging role of microRNA in fibrosis. 2011; Hepatology.53: 4-6.
  36. Vettori S, Gay S, Distler O. Role of MicroRNAs in Fibrosis. 2012; Open Rheumatol J. 6: 130-139.

Cite this article: Nho RS (2013) Current Concept for the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). Clin Res Pulmonol 1: 1008.
Right Table
Content:   Home  |  Aims & Scope  |  Early Online  |  Current Issue  | 
Journal Info:   Editorial Board  |  Article Processing Charges  |  FAQs
Contact Us
2952 Market Street, Suite 140
San Diego, California 92102, USA
Tel: 1-619-373-8030
Fax: 1-619-793-4845
Toll free number: 1-800-762-9856
Copyright © 2013 JSciMed Central. All rights reserved.