You're using an outdated browser. Please upgrade to a modern browser for the best experience.
The Pathogenesis of Pulmonary Fibrosis: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Respiratory System
Contributor: Taichiro Goto

Idiopathic pulmonary fibrosis (IPF) is currently considered an epithelium-driven disease wherein dysfunctional aging lung epithelia are exposed to recurrent microinjuries that sabotage regeneration and lead to aberrant epithelial–mesenchymal crosstalk, creating an imbalance between profibrotic and antifibrotic mediators. 

  • idiopathic pulmonary fibrosis
  • lung cancer

1. Dysfunctional Epithelia Trigger Aberrant Wound Healing Processes

It is assumed that fibrosis advances over long periods of time in patients with IPF. Thus, at the time of diagnosis, modifications of lung structure have already been established by the disease and pathological features, such as various stages of epithelial damage, alveolar epithelial cell (AEC) 2s hyperplasia, dense fibrosis, and abnormally proliferating mesenchymal cells, are found. At this time, it is not possible to determine the course of events that have led to lung damage; however, it is accepted that dysfunctional epithelia are key to the pathogenesis of IPF [1].
Under normal conditions of lung injury, AEC1s are replaced with proliferating and differentiating AEC2 cells and stem cells, which restore alveolar integrity by stimulating coagulation, the formation of new vessels, activation and migration of fibroblasts, and synthesis and proper alignment of collagen. Chemokines, such as transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF), are central to these processes. Conversely, continued lung injury or loss of normal restorative capacity invokes an inflammatory phase of the wound healing process. The associated increases in the expression levels of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) create a biochemical environment that favors chronic flaws of regeneration and tissue remodeling [2].

2. Growth Factors Associated with the Initial Stages of Pulmonary Fibrogenesis

2.1. TGF-β

TGF-βs are multifunctional cytokines that are present as three isoforms: TGF-β1, TGF-β2, and TGF-β3. Although the biological activities of these isoforms are indiscrete, TGF-β1 plays a predominant role in pulmonary fibrosis [3]. The three TGF-β receptors, type I (TGFRI), type II (TGFRII), and type III (TGFRIII), have the potential to bind to all three TGF-βs with high affinity. However, TGF-β is the best characterized promoter of extracellular matrix (ECM) production and is considered the strongest chemotactic factor for immune cells, such as monocytes and macrophages. In these cell types, TGF-β activates the release of cytokines, such as PDGF, IL-1β, basic FGF (bFGF), and TNF-α, and autoregulates its own expression. Increases in TGF-β production are consistently observed in epithelial cells and macrophages from lung tissues of patients with IPF [4] and in rodents with bleomycin-induced pulmonary fibrosis [5]. Smad proteins are known as mediators of TGF-β signaling from the membrane to the nucleus [6]. Activated TGF-β receptors induce phosphorylation of Smad2 and Smad3, and complexes of these with other Smad proteins are translocated into the nucleus to regulate transcriptional responses. Studies show that the deficiency of Smad3 attenuates bleomycin-induced pulmonary fibrosis in mice [7] and that the inhibitory Smad7 prevents the phosphorylation of Smad2 and Smad3 via activated TGF-β receptors [8][9].
TGF-β1 is considered the most important mediator of IPF. AEC2s produce TGF-β1 following actin–myosin-mediated cytoskeletal contractions that are induced by the unfolded protein response (UPR) following ανβ6 integrin activation. The αvβ6 integrin/TGF-β1 pathway is a constitutively expressed molecular sensing mechanism that is primed to recognize injurious stimuli. TGF-β1 is a strong profibrotic mediator that promotes the epithelial–mesenchymal transition (EMT); epithelial cell apoptosis; epithelial cell migration; other profibrotic mediator production; circulating fibrocyte recruitment; fibroblast activation and proliferation and transformation into myofibroblasts; and VEGF, connective-tissue growth factor, and other pro-angiogenic mediator production [10].

2.2. PDGF

PDGF is a potent chemoattractant for mesenchymal cells and induces the proliferation of fibroblasts and the synthesis of ECM. Activated homologous A and B subunits of PDGF can form three dimeric PDGF isoforms. Alveolar macrophages with IPF produce higher volumes of PDGF-B mRNA and protein [11][12]. AEC2s and mesenchymal cells also express abnormal levels of PDGF in animal models [13]. Moreover, PDGF-B transgenic mice develop lung disease with diffusely emphysematous lung lesions and inflammation/fibrosis in focal areas [14]. In agreement, intratracheal instillation of recombinant human PDGF-B into rats produces fibrotic lesions that are concentrated around large airways and blood vessels [15]. In another study, gene transfer of an extracellular domain of the PDGF receptor ameliorated bleomycin-induced pulmonary fibrosis in a mouse model [16]. Insulin-like growth factor (IGF)-1 also promoted fibroblast proliferation synergistically with PGDF [17]. Accordingly, alveolar macrophages from patients with IPF expressed IGF-1 mRNA and protein at greater levels than those in normal alveolar macrophages [17][18].

2.3. FGF

bFGF is a stimulator of fibroblast and endothelial cell proliferation that has been correlated with the proliferative aspects of fibrosis. In particular, bFGF expression is up-regulated at various periods of wound healing, and recombinant bFGF has been shown to accelerate wound healing. Accordingly, anti-bFGF antibody inhibited the formation of granulated tissue and normal wound repair. Alveolar macrophages are a predominant source of bFGF in intra-alveolar fibrotic areas following acute lung injury [19]. In a study of IPF, mast cells were found to be the predominant bFGF-producing cells, and bFGF levels were associated with bronchoalveolar lavage cellularity and with the severity of gas exchange abnormalities [20].

2.4. TGF-α

TGF-α induces proliferation in endothelial cells, epithelial cells, and fibroblasts, and is present in fibrotic areas [21]. In proliferative fibrotic lesions in rats with asbestos- or bleomycin-induced pulmonary fibrosis, AECs and macrophages had elevated expression levels of TGF-α [22]. Similarly, in transgenic mice expressing human TGF-α, proliferative fibrotic responses in interstitial and pleural surfaces were epithelial cell specific [23]. These results indicate that TGF-α is involved in cell proliferation under fibrotic conditions following lung injury.

2.5. Keratinocyte Growth Factor (KGF)

KGF is produced by mesenchymal cells, and the KGF receptor is expressed in the epithelial tissues of developing lungs. In rats, KGF accelerated the functional differentiation of AEC2s, and the intratracheal instillation of KGF significantly improved bleomycin-induced pulmonary fibrosis [24]. These data suggest that KGF participates in the maintenance and repair of alveolar epithelium and has potential in the treatment of lung injury and pulmonary fibrosis.

2.6. Hepatocyte Growth Factor (HGF)

HGF is produced by mesenchymal cells and has been identified as a potent mitogen for mature hepatocytes. The HGF receptor is a c-Met proto-oncogene product that is predominantly expressed in various types of epithelial cells. HGF levels are higher in bronchoalveolar lavage fluid and serum from patients with IPF than in serum from healthy people [25][26]. HGF is also highly expressed by hyperplastic AECs and macrophages in lung tissues of patients with IPF. In in vitro studies of epithelial cells, HGF promoted DNA synthesis in AEC2s [27]. The administration of HGF also inhibited fibrotic changes in mice with bleomycin-induced lung injury [28]. Promisingly, the combination of HGF and interferon-γ (IFN-γ) enhanced the migratory activity of A549 cells by up-regulating the c-Met/HGF receptor [29]. Based on these observations, HGF treatments may offer a novel strategy for promoting the repair of inflammatory lung damage for patients with pulmonary fibrosis.

3. Changes in AEC2s that Lead to Aberrant Tissue Repair

Repetitive exposures of alveolar epithelium to microinjuries, such as infection, smoking, toxic environmental inhalants, and gastroesophageal reflux, contribute to AEC1 damage. AEC2s normally regenerate damaged cells, but when dysfunctional, their ability to reestablish homeostasis is impaired. This condition is considered indicative of the pathogenesis of IPF [30][31].

3.1. UPR

High cellular activity leads to protein over-expression, and if unchecked, it can cause endoplasmic reticulum (ER) stress. The correcting protective pathway is stimulated by the imbalance between cellular demand for protein synthesis and the capacity of the ER to dispose of unfolded or damaged proteins. This protective pathway is known as UPR, and it re-establishes ER homeostasis. To this end, this pathway inhibits protein translation, targets proteins for degradation, and induces apoptosis when overwhelmed. The activation of UPR stimulates the expression of profibrotic mediators, such as TGF-β1, PDGF, C-X-C motif chemokine 12 (CXCL12), and chemokine C-C motif ligand 2 (CCL2), and thus, can lead to apoptosis [32].

3.2. Epithelial–Mesenchymal Transition (EMT)

EMT is a molecular reprograming process, and in AEC2s, it is induced by UPR and enhanced by profibrotic mediators and signaling pathways. Under these conditions, epithelial cells express mesenchymal cell-associated genes, detach from basement membranes, and migrate and down-regulate their typical markers. The most used marker of these transitioning cells is alpha smooth-muscle actin (αSMA). However, EMT occurs during development and in cancerous and fibrotic tissues, but it is not involved in the restoration of tissues through wound healing processes [32].

3.3. Wnt-β-Catenin Signaling

Other key pathways of IPF are related to the deregulation of embryological programs, such as Wnt-β-catenin signaling, which has been associated with EMT and fibrogenesis following activation by TGF-β1, sonic hedgehog, gremlin-1, and phosphatase and tensin homolog. Deregulation of these pathways confers resistance to apoptosis and offers proliferative advantages to cells [33].

4. Endothelium and Coagulation

Damage to alveolar structures and the loss of AECs with basement membranes involves alveolar vessels and leads to increased vascular permeability. Wound clots form during this early phase of wound healing responses, and sequentially, new vessels are formed through the proliferation of endothelial cells and endothelial progenitor cells (EPCs). Patients with IPF with failure of re-endothelization have significantly decreased numbers of EPCs, likely resulting in dysfunctional alveolar–capillary barriers, profibrotic responses, and compensatively augmented VEGF expression. This series of endothelial changes could stimulate fibrotic processes and abnormalities of vessel functions, contributing to cardio–respiratory declines and advanced disease. Furthermore, endothelial cells may undergo a mesenchymal transition with similar consequences as those of EMT [34].
Endothelial and epithelial damage also activates coagulation cascades during the early phases of wound healing. Coagulation proteinases have several cellular effects on wound healing. In particular, the tissue factor-dependent pathway is central to the pathogenesis of IPF and promotes a pro-coagulation state with increased levels of inhibitors of plasminogen activation, active fibrinolysis, and protein C. Under these pro-coagulation conditions, degradation of ECM is decreased, resulting in profibrotic effects and the induction of fibroblast differentiation into myofibroblasts via proteinase-activated receptors [2].

5. Immunogenic Changes that Lead to Pulmonary Fibrosis

The pathobiology of IPF is led by aberrant epithelial–mesenchymal signaling, but inflammation may also play an important role because inflammatory cells are involved in normal wound healing from early phases. Initially, macrophages produce cytokines that induce inflammatory responses and participate in the transition to healing environments by recruiting fibroblasts, epithelial cells, and endothelial cells. If injury persists, neutrophils and monocytes are recruited, and the production of reactive oxygen species exacerbates epithelial damage. The resulting imbalances between antioxidants and pro-oxidants may also promote apoptosis of epithelial cells and activation of pathways that impair function. Finally, monocytes and macrophages produce PDGF, CCL2, macrophage colony stimulating factor, and colony stimulating factor 1. These proteins may also have direct profibrotic effects [30][35].
The roles of lymphocytes in IPF are still unclear. However, some lymphocytic cytokines are considered profibrotic due to their direct effects on the activities of fibroblast and myofibroblast. Th-1, Th-2, and Th-17 T-cells have been clearly associated with the pathogenesis of IPF. The Th1 T-cell subset produces IL-1α, TNF-α, PDGF, and TGF-β1 and has net profibrotic effects. Th2 and Th17 responses appear more important in the pathogenesis of IPF. In particular, the typical Th2 interleukin IL-4 induces IL-5, IL-13, and TGF-β1 expression, leading to the recruitment of macrophages, mast cells, eosinophils, and mesenchymal cells and the direct activation of fibroblasts. Additionally, fibroblasts from patients with IPF are hyperresponsive to IL-13, which has a positive effect on fibroblast activity and enhances the production of ECM. The Th17 T-cell subset indirectly promotes fibrosis by increasing TGF-β1 levels. Th17 cells are also positively regulated by TGF-β1, suggesting the presence of a positive feedback loop [2]. Numbers of regulatory T-cells are reportedly lower in bronchoalveolar lavage fluid and peripheral blood samples from patients with IPF than in those of healthy subjects. Regulatory T-cells (Tregs) play a crucial role in immune tolerance and the prevention of autoimmunity; deficiencies in numbers and functions of these T-cells play an important role in the initial phases of pathogenesis of IPF. The function of Treg in IPF is severely impaired due to reduced number of infiltrating Tregs in addition to dysfunction of Tregs. Interestingly, the compromised Treg function in bronchoalveolar lavage is associated with parameters of the disease severity of IPF, indicating a causal relationship between the development of IPF and impaired immune regulation mediated by Tregs [36]. Previous studies have demonstrated low IFN-γ levels in the lungs of patients with IPF. IFN-γ inhibits fibroblastic activity and abolishes Th2 responses. However, further studies are required to characterize the roles of inflammation in the pathobiology of IPF. Currently, the early stages of IPF are poorly understood, as are the mechanisms of disease progression [35][37]. Nonetheless, pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) was designed to have anti-inflammatory and antifibrotic effects and was efficacious in the clinical setting [38].

6. Interactions Between ECM and Mesenchymal Cells, Fibrocytes, Fibroblasts, and Myofibroblasts

Contributions of mesenchymal cells, and particularly fibroblasts and myofibroblasts, are crucial for the pathogenesis of IPF. These cells are recruited, activated, and induced to differentiate and proliferate in the abnormal biochemical environments that are created by activated epithelial and endothelial cells. Although the initial trigger and source of mesenchymal cell recruitment remain unclear, the current published consensus defines fibroblasts and myofibroblasts as the key cell types for IPF. Circulating fibrocytes, pulmonary fibroblasts, and myofibroblasts have also been identified among mesenchymal cells that are involved in IPF [39]. The most recent studies of these processes are summarized in a well-integrated review [40].

This entry is adapted from the peer-reviewed paper 10.3390/ijms20061461

References

  1. Liu, Y.M.; Nepali, K.; Liou, J.P. Idiopathic Pulmonary Fibrosis: Current Status, Recent Progress, and Emerging Targets. J. Med. Chem. 2017, 60, 527–553.
  2. Betensley, A.; Sharif, R.; Karamichos, D. A Systematic Review of the Role of Dysfunctional Wound Healing in the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis. J. Clin. Med. 2016, 6, 2.
  3. Coker, R.K.; Laurent, G.J.; Shahzeidi, S.; Lympany, P.A.; du Bois, R.M.; Jeffery, P.K.; McAnulty, R.J. Transforming growth factors-beta(1), -beta(2), and -beta(3) stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis. Am. J. Pathol. 1997, 150, 981–991.
  4. Khalil, N.; O’Connor, R.N.; Unruh, H.W.; Warren, P.W.; Flanders, K.C.; Kemp, A.; Bereznay, O.H.; Greenberg, A.H. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 1991, 5, 155–162.
  5. Raghow, B.; Irish, P.; Kang, A.H. Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis. J. Clin. Investig. 1989, 84, 1836–1842.
  6. Heldin, C.H.; Miyazono, K.; ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997, 390, 465–471.
  7. Zhao, J.; Shi, W.; Wang, Y.L.; Chen, H.; Bringas, P., Jr.; Datto, M.B.; Frederick, J.P.; Wang, X.F.; Warburton, D. Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am. J. Physiol. Lung Cell Mol. Physiol. 2002, 282, L585–L593.
  8. Nakao, A.; Afrakhte, M.; Moren, A.; Nakayama, T.; Christian, J.L.; Heuchel, R.; Itoh, S.; Kawabata, M.; Heldin, N.E.; Heldin, C.H.; et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997, 389, 631–635.
  9. Hayashi, H.; Abdollah, S.; Qiu, Y.; Cai, J.; Xu, Y.Y.; Grinnell, B.W.; Richardson, M.A.; Topper, J.N.; Gimbrone, M.A., Jr.; Wrana, J.L.; et al. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 1997, 89, 1165–1173.
  10. Grimminger, F.; Gunther, A.; Vancheri, C. The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis. Eur. Respir. J. 2015, 45, 1426–1433.
  11. Antoniades, H.N.; Bravo, M.A.; Avila, R.E.; Galanopoulos, T.; Neville-Golden, J.; Maxwell, M.; Selman, M. Platelet-derived growth factor in idiopathic pulmonary fibrosis. J. Clin. Investig. 1990, 86, 1055–1064.
  12. Martinet, Y.; Rom, W.N.; Grotendorst, G.R.; Martin, G.R.; Crystal, R.G. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 1987, 317, 202–209.
  13. Liu, J.Y.; Morris, G.F.; Lei, W.H.; Hart, C.E.; Lasky, J.A.; Brody, A.R. Rapid activation of PDGF-A and -B expression at sites of lung injury in asbestos-exposed rats. Am. J. Respir. Cell Mol. Biol. 1997, 17, 129–140.
  14. Hoyle, G.W.; Li, J.; Finkelstein, J.B.; Eisenberg, T.; Liu, J.Y.; Lasky, J.A.; Athas, G.; Morris, G.F.; Brody, A.R. Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice overexpressing platelet-derived growth factor. Am. J. Pathol. 1999, 154, 1763–1775.
  15. Yi, E.S.; Lee, H.; Yin, S.; Piguet, P.; Sarosi, I.; Kaufmann, S.; Tarpley, J.; Wang, N.S.; Ulich, T.R. Platelet-derived growth factor causes pulmonary cell proliferation and collagen deposition in vivo. Am. J. Pathol. 1996, 149, 539–548.
  16. Yoshida, M.; Sakuma-Mochizuki, J.; Abe, K.; Arai, T.; Mori, M.; Goya, S.; Matsuoka, H.; Hayashi, S.; Kaneda, Y.; Kishimoto, T. In vivo gene transfer of an extracellular domain of platelet-derived growth factor beta receptor by the HVJ-liposome method ameliorates bleomycin-induced pulmonary fibrosis. Biochem. Biophys. Res. Commun. 1999, 265, 503–508.
  17. Rom, W.N.; Basset, P.; Fells, G.A.; Nukiwa, T.; Trapnell, B.C.; Crysal, R.G. Alveolar macrophages release an insulin-like growth factor I-type molecule. J. Clin. Investig. 1988, 82, 1685–1693.
  18. Bitterman, P.B.; Adelberg, S.; Crystal, R.G. Mechanisms of pulmonary fibrosis. Spontaneous release of the alveolar macrophage-derived growth factor in the interstitial lung disorders. J. Clin. Investig. 1983, 72, 1801–1813.
  19. Henke, C.; Marineili, W.; Jessurun, J.; Fox, J.; Harms, D.; Peterson, M.; Chiang, L.; Doran, P. Macrophage production of basic fibroblast growth factor in the fibroproliferative disorder of alveolar fibrosis after lung injury. Am. J. Pathol. 1993, 143, 1189–1199.
  20. Inoue, Y.; King, T.E., Jr.; Tinkle, S.S.; Dockstader, K.; Newman, L.S. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am. J. Pathol. 1996, 149, 2037–2054.
  21. Liu, J.Y.; Morris, G.F.; Lei, W.H.; Corti, M.; Brody, A.R. Up-regulated expression of transforming growth factor-alpha in the bronchiolar-alveolar duct regions of asbestos-exposed rats. Am. J. Pathol. 1996, 149, 205–217.
  22. Madtes, D.K.; Busby, H.K.; Strandjord, T.P.; Clark, J.G. Expression of transforming growth factor-alpha and epidermal growth factor receptor is increased following bleomycin-induced lung injury in rats. Am. J. Respir. Cell Mol. Biol. 1994, 11, 540–551.
  23. Korfhagen, T.R.; Swantz, R.J.; Wert, S.E.; McCarty, J.M.; Kerlakian, C.B.; Glasser, S.W.; Whitsett, J.A. Respiratory epithelial cell expression of human transforming growth factor-alpha induces lung fibrosis in transgenic mice. J. Clin. Investig. 1994, 93, 1691–1699.
  24. Sugahara, K.; Iyama, K.; Kuroda, M.J.; Sano, K. Double intratracheal instillation of keratinocyte growth factor prevents bleomycin-induced lung fibrosis in rats. J. Pathol. 1998, 186, 90–98.
  25. Sakai, T.; Satoh, K.; Matsushima, K.; Shindo, S.; Abe, S.; Abe, T.; Motomiya, M.; Kawamoto, T.; Kawabata, Y.; Nakamura, T.; et al. Hepatocyte growth factor in bronchoalveolar lavage fluids and cells in patients with inflammatory chest diseases of the lower respiratory tract: Detection by RIA and in situ hybridization. Am. J. Respir. Cell Mol. Biol. 1997, 16, 388–397.
  26. Maeda, J.; Ueki, N.; Hada, T.; Higashino, K. Elevated serum hepatocyte growth factor/scatter factor levels in inflammatory lung disease. Am. J. Respir. Crit. Care Med. 1995, 152, 1587–1591.
  27. Shiratori, M.; Michalopoulos, G.; Shinozuka, H.; Singh, G.; Ogasawara, H.; Katyal, S.L. Hepatocyte growth factor stimulates DNA synthesis in alveolar epithelial type II cells in vitro. Am. J. Respir. Cell Mol. Biol. 1995, 12, 171–180.
  28. Yaekashiwa, M.; Nakayama, S.; Ohnuma, K.; Sakai, T.; Abe, T.; Satoh, K.; Matsumoto, K.; Nakamura, T.; Takahashi, T.; Nukiwa, T. Simultaneous or delayed administration of hepatocyte growth factor equally represses the fibrotic changes in murine lung injury induced by bleomycin. A morphologic study. Am. J. Respir. Crit. Care Med. 1997, 156, 1937–1944.
  29. Nagahori, T.; Dohi, M.; Matsumoto, K.; Saitoh, K.; Honda, Z.I.; Nakamura, T.; Yamamoto, K. Interferon-gamma upregulates the c-Met/hepatocyte growth factor receptor expression in alveolar epithelial cells. Am. J. Respir. Cell Mol. Biol. 1999, 21, 490–497.
  30. Coward, W.R.; Saini, G.; Jenkins, G. The pathogenesis of idiopathic pulmonary fibrosis. Ther. Adv. Respir. Dis. 2010, 4, 367–388.
  31. Evans, C.M.; Fingerlin, T.E.; Schwarz, M.I.; Lynch, D.; Kurche, J.; Warg, L.; Yang, I.V.; Schwartz, D.A. Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways. Physiol. Rev. 2016, 96, 1567–1591.
  32. Wolters, P.J.; Collard, H.R.; Jones, K.D. Pathogenesis of idiopathic pulmonary fibrosis. Annu. Rev. Pathol. 2014, 9, 157–179.
  33. King, T.E., Jr.; Pardo, A.; Selman, M. Idiopathic pulmonary fibrosis. Lancet 2011, 378, 1949–1961.
  34. Malli, F.; Koutsokera, A.; Paraskeva, E.; Zakynthinos, E.; Papagianni, M.; Makris, D.; Tsilioni, I.; Molyvdas, P.A.; Gourgoulianis, K.I.; Daniil, Z. Endothelial progenitor cells in the pathogenesis of idiopathic pulmonary fibrosis: An evolving concept. PLoS ONE 2013, 8, e53658.
  35. Zolak, J.S.; de Andrade, J.A. Idiopathic pulmonary fibrosis. Immunol. Allergy Clin. N. Am. 2012, 32, 473–485.
  36. Kotsianidis, I.; Nakou, E.; Bouchliou, I.; Tzouvelekis, A.; Spanoudakis, E.; Steiropoulos, P.; Sotiriou, I.; Aidinis, V.; Margaritis, D.; Tsatalas, C.; et al. Global impairment of CD4+CD25+FOXP3+ regulatory T cells in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2009, 179, 1121–1130.
  37. King, T.E., Jr.; Bradford, W.Z.; Castro-Bernardini, S.; Fagan, E.A.; Glaspole, I.; Glassberg, M.K.; Gorina, E.; Hopkins, P.M.; Kardatzke, D.; Lancaster, L.; et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014, 370, 2083–2092.
  38. Costabel, U.; Albera, C.; Lancaster, L.H.; Lin, C.Y.; Hormel, P.; Hulter, H.N.; Noble, P.W. An Open-Label Study of the Long-Term Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (RECAP). Respiration 2017, 94, 408–415.
  39. Hinz, B. Mechanical aspects of lung fibrosis: A spotlight on the myofibroblast. Proc. Am. Thorac. Soc. 2012, 9, 137–147.
  40. Sgalla, G.; Iovene, B.; Calvello, M.; Ori, M.; Varone, F.; Richeldi, L. Idiopathic pulmonary fibrosis: Pathogenesis and management. Respir. Res. 2018, 19, 32.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Academic Video Service
Feedback