| Home | E-Submission | Sitemap | Contact Us
Korean J Intern Med > Volume 29(3); 2014 > Article
Lee, Park, Cho, Zhou, Han, Yoon, Chae, Elias, and Lee: Modifiers of TGF-β1 effector function as novel therapeutic targets of pulmonary fibrosis

Abstract

Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-β1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-β1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-β1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-β1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-β1 could be an alternative approach that selectively inhibits TGF-β1-stimulated fibrotic tissue response while preserving major physiological function of TGF-β1. Recent studies from our laboratory revealed that TGF-β1 crosstalk with epidermal growth factor receptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays a critical role in the development or progression of pulmonary fibrosis. In addition, chitotriosidase, a true chitinase in humans, has been identified to have modulating capacity of TGF-β1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-β1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-β1 plays a significant role.

INTRODUCTION

Fibrosis is a serious pathologic condition with excessive deposition of collagenous matrix that frequently results into a tissue stiffness and ultimately causes organ failure leading to death. As a result, it has been reported that about 45% of all deaths in developed countries are associated with some type of fibroproliferative diseases [1]. However, currently no effective therapies are available for the intervention of this devastating lung disease. In addition, the exact pathogenetic mechanism of tissue fibrosis is still largely elusive.
Idiopathic pulmonary fibrosis (IPF), a prototypic fibrotic disorder in the lung, is a progressive lung disease characterized by epithelial damage, fibroproliferative matrix deposition and parenchymal remodeling [2,3,4]. During the last decades, significant efforts have been directed to identify cells, mediators, and pathways responsible for pulmonary fibrosis. The myofibroblasts are known as the majors cells for increased accumulation of collagen and other extracelluar matrix in the lung, but the origin of these cells are not completely understood [5,6,7]. The role of transforming growth factor(TGF)-β1 as a central mediator of tissue fibrosis was first recognized decades ago, numerous publications strongly still support its major role in a variety of fibrotic diseases [8,9,10,11]. Accordingly, TGF-β1 and its signaling pathways have been regarded as attractive therapeutic targets to control fibroproliferative diseases including pulmonary fibrosis [12,13].
Recently, transgenic (Tg) mice overexpressing TGF-β1 in the lung using lung-specific Clara cell 10 kDa (CC10) or surfactant protein C (SP-C) promoters were generated to define the direct in vivo effector function of TGF-β1 [14,15]. In earlier studies, fetal-lethality was a serious problem to get live transgene expressing animals because TGF-β1 plays a critical role in the development of airways [14]. Later, live lung-specific TGF-β1 Tg mice were successfully generated using a tight regulated inducible system (CC10-tTS-rtTA-TGF-β1), and these mice provided an exciting opportunity to look into the effector function of TGF-β1 in the adult lung [15].
Intriguingly, the studies using CC10-tTS-rtTA-TGF-β1 Tg mice first identified that TGF-β1 induced epithelial cell death or injury response in the lung, followed by fibrotic tissue response [15]. These studies further demonstrated that apoptotic cellular response is a critical event for subsequent TGF-β1-stimulated fibroproliferative repair response, suggesting controlling cellular apoptosis could be an effective therapeutic option for pulmonary fibrosis. The Tg approach was also successfully employed to identify a number of downstream mediators of TGF-β1 in the lung, and some of these mediators, such as connective tissue growth factor and platelet-derived growth factor, were also shown to be effective therapeutic targets of pulmonary fibrosis [16].
Among downstream mediators of TGF-β1 in the lung, it is interesting to note that amphiregulin (AR), an epidermal growth factor receptor (EGFR) ligand prominently induced by TGF-β1, plays a critical role in pulmonary fibrosis [17]. Intervention of either AR expression or EGFR signaling significantly reduced TGF-β1-induced pulmonary fibrosis, suggesting a critical role of EGFR signaling in this process [17]. The development and progression of pulmonary fibrosis are also significantly affected by other factors modulating the expression or activation of TGF-β1 or its signaling pathways. Recent studies from our laboratory identified chitotriosidase (Chit1), a true chitinase (Cs) commonly detected in humans, was significantly associated with incidence of scleroderma-associated interstitial lung disease (SSc-ILD) and circulation levels of Chit1 were inversely correlated with lung function of SSc-ILD patients [18]. Interestingly, in vitro studies using a fibroblast cell line further identified that Chit1 sensitized TGF-β1 signaling by enhancing TGF-β1 receptor expression and activation of mitogen-activated protein kinase (MAPK)-Erk signaling.
These studies suggest that there are multiple factors (collectively designated as "modifiers" in this review) that significantly modulate the final outcome of TGF-β1-induced tissue responses. These modifiers would be more effective and tolerable targets for the intervention of pulmonary fibrosis than simple TGF-β1 blockers, because vital physiologic function of TGF-β1 can be substantially preserved in this way. In this review, these exciting new approaches targeted to "modifiers" of TGF-β1 for the intervention of pulmonary fibrosis are being highlighted with general introduction of the role and effector function of TGF-β1 in the pathogenesis of pulmonary fibrosis.

TGF-β1: CENTRAL MEDIATOR OF IPF

TGF-β1 is believed to play an important role in the pathogenesis of IPF because it is expressed in an exaggerated fashion in IPF where, in contrast to controls, a sizable percentage is biologically active [19,20,21]. The important role that TGF-β1 may play in this disorder can be seen in studies that demonstrate that TGF-β1 is a critical mediator of pulmonary fibrosis after bleomycin injury [22,23] and that high dose adenoviral TGF-β1 transfer causes progressive pulmonary fibrosis in vivo [24,25] and IPF-like fibroblastic foci in in vitro explants [21]. Interestingly, the apposition of apoptosis, fibrosis and exaggerated TGF-β1 expression is well documented in IPF [26,27,28,29], and recent studies with TGF-β1 Tg mice highlighted the importance of epithelial cell apoptosis in the pathogenesis of pulmonary fibrosis [15]. All these studies suggest that TGF-β1 plays a critical role in pulmonary fibrosis through regulation of injury and repair responses. However, the factors that control these TGF-β1 responses and the genetic and other processes that allow TGF-β1 to contribute to the pathogenesis of fibrosis are still largely elusive and need to be further defined in future studies.

TGF-β1 AND ITS EFFECTOR FUNCTION AND GENETIC MODIFIERS

TGF-β1 family proteins are multifunctional cytokines that play pivotal roles in diverse biologic processes including cell growth and survival, cell and tissue differentiation, development, inflammation, immunity and tissue remodeling and repair.
On superficial analysis, TGF-β1 can be accurately described as a healing molecule that manifests anti-inflammatory and fibrotic effects while inducing wound healing. On closer analysis, it is clear that this is only partially correct and that the effector profile of TGF-β1 can appear confusing and even contradictory [30,31,32,33]. This can be seen in inflammation where TGF-β1 has important anti-inflammatory effects in some settings [34,35] and proinflammatory effects in others [35,36]. This is also seen in oncogenesis where TGF-β1 inhibits tumor cell growth while enhancing tumor migration and invasion [32]. TGF-β1 is essential for wound healing, stimulates matrix molecule deposition and angiogenesis and is an essential mediator of the pathologic scaring in fibrotic disorders [22,23,30,37,38,39]. On the other hand, TGF-β1 can also induce tissue injury [40], induce cellular apoptosis, decrease epithelialization and inhibit wound healing [31,33,41,42,43]. The complexity of TGF-β1 effector functions can be attributed to a number of items. In particular, the effects of TGF-β1 proteins vary with the state of activation and differentiation of the target cells and the presence of other stimuli in the local microenvironment. The diversity in TGF-β1 receptor expression, depending on the type of cells, significantly impacts the cellular and tissue responses of TGF-β1. However, the mechanism causing the diversity in cellular and tissue effects of TGF-β1 is still largely elusive and needs to be addressed in future studies.
To define its effector functions in the lung, we developed Tg mice in which bioactive TGF-β1 was inducibly overexpressed in the lung [15]. Studies using these mice demonstrated that Tg TGF-β1 simultaneously induces tissue injury (apoptosis) and activates healing (fibrosis) and that the apoptosis is an obligatory prerequisite for fibrosis [15]. Recent studies demonstrate that the ultimate TGF-β1-induced tissue response is dependent on murine genetic background and that these outcomes can be explained by the relative balance of injury, proteolysis, and fibrogenesis [44,45]. The strain dependency of TGF-β1-stimulated pulmonary fibrosis strongly support the presence of genetically defined "modifiers" that significantly modulate the TGF-β1-stimulated tissue response. In support of this observation, there is similar strain dependency in the radiation- or asbestos-induced pulmonary fibrosis [46,47]. Identification of these genetic modifiers will provide an exciting opportunity to understand the mechanism of TGF-β-induced fibrosis, that will lead to the discovery of novel and effective therapeutic targets with less undesirable effects for the treatment of pulmonary fibrosis.

TGF-β1 SIGNALING AND CROSSTALK WITH EGFR SIGNALING

It has been well demonstrated that TGF-β1 binds and signals primarily through heterodimers of TGF-β1 receptor type I and type II complex that subsequently activates the cascade of Smads (receptor-regulated Smads [R-Smads; Smads1, 2, 3, 5] and common mediator Smads [Co-Smads; Smad4]). The activated Smads complexes are transported to the nucleus and plays an essential role in the expression of TGF-β1 target genes together with other transcription factors such as CREB1-binding protein and p300. In addition, inhibitory Smads (such as inhibitory Smads6 and 7) and interacting molecules (such as SARA or Ski/SnoN) are associated with fine-tuning of this signaling pathway (Fig. 1) [48,49]. This is called canonical or Smad-dependent signaling pathways of TGF-β1 and regarded as a major pathway of TGF-β1 signaling [50]. However, a number of other signaling pathways are also implicated in the tissue responses stimulated by TGF-β1. The MAPK/Erk, p38, c-Jun N-terminal kinase, nuclear factor-κβ, and phosphatidylinositol 3-kinase signaling pathways are differently activated by TGF-β1 stimulation, depending on the type of cells and microenvironment. These noncanonical (Smad-independent) pathways of TGF-β1 also significantly contribute to the diverse biological function of TGF-β1 (Fig. 1) [50].
Interestingly, recent studies using TGF-β1 Tg mice demonstrated that TGF-β1 overexpression in the lung significantly induces AR, a EGFR ligand, and AR-stimulated EGFR signaling is also crucial for both canonical and noncanonical TGF-β1 signaling (Fig. 2) [17]. In this study, siRNA silencing of AR or chemical ablation of EGFR signaling significantly decreased TGF-β1-stimulated fibroblast proliferation and myofibroblast transformation, suggesting a crucial roles of AR and EGFR signaling in TGF-β1-stimulated fibrotic tissue response in the lung.
These studies suggested that multiple signaling pathways are meticulously connected to each other, presumably for the fine-tuning of cellular responses stimulated by TGF-β1. The profibrotic role of EGFR signaling was also elegantly demonstrated in a bleomycin-stimulated model of pulmonary fibrosis using gefitinib, a specific kinase inhibitor of EGFR signaling [51]. Since EGF is known to stimulate fibroblast proliferation [52], it is interesting to speculate a potential synergistic interaction between TGF-β1 and EGFR signaling in fibroblast proliferation and myofibroblast transformation. Similar crosstalk among Smads2/3, EGFR and p53 pathways was reported in the expression of TGF-β1-induced fibrotic target genes [53]. However, whether and how these two major cellular signaling pathways are being coordinated in the development and progression of pulmonary fibrosis remains to be determined in future studies. It will be an exciting field of future investigation to identify molecules linking different signaling pathways, such as AR, since these molecules could be effective and novel alternative therapeutic targets that regulate complex tissue phenotypes in which multiple signaling pathways are implicated.

CHITOTRIOSIDASE IN SCLERODERMA: A MODIFIER OF TGF-β1 SIGNALING

The GH18 gene family contains Cs that bind and cleave chitin and chitinase-like proteins (CLP) that bind but do not cleave the chitin polysaccharide. These C/CLP are found across species from lower life forms (archea, prokaryotes, eukaryotes) to man. The nature of their contributions has been enigmatic because chitin is the only documented substrate of Cs, chitin and chitin synthase do not exist in mammals, and higher life forms do not use chitin as a nutrient [54,55]. Only acidic mammalian chitinase and chitotriosidase (chitinase 1; Chit1) are Cs. All of the rest are CLP (also called chitolectins) which lack chitinase activity as a result of mutations in their highly conserved putative enzyme sites [56,57]. Among these C/CLPs, Chit1 is the major Cs in humans and the best characterized Cs from a biologic and clinical perspective. In humans, mature monocyte-derived macrophages, Gaucher's cells and lung macrophages express this chitinase. Proinflammatory cytokines such as granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and lipopolysaccharide stimulate the expression of Chit1 in monocyte-derived macrophages, whereas interferon-γ and interleukin-4 inhibit Chit1 expression [58,59,60]. Interestingly, Chit1 can be found in detectable quantities in the circulation of normal individuals and is further increased in a variety of diseases characterized by inflammation, tissue remodeling and/or fibrosis including bacterial or fungal infections, lysosomal storage diseases (Gaucher's), sarcoidosis, and interstitial lung diseases [61,62,63,64,65,66]. However, the effector functions of Chit1 have not been clearly defined and its roles in the pathogenesis of specific diseases have not been elucidated. To begin to define the in vivo roles of Chit1 in pulmonary injury and repair, we characterized the levels of circulating Chit1 activity in patients with scleroderma (SSc) and investigated the bleomycin-induced pulmonary responses in newly generated Chit1 null mutant mice (Chit1-/-) and lung-targeted Chit1 overexpressing transgenic mice (Chit1 Tg) [18]. These studies demonstrate that the levels of circulating Chit1 activity are increased in patients with SSc where they correlate with the presence and severity of interstitial lung disease (SSc-ILD). In these studies, the significant role and effect of Chit1 in the pathogenesis of pulmonary fibrosis have been further demonstrated in an animal model of pulmonary fibrosis. The bleomycin-induced pulmonary fibrosis is significantly ameliorated in Chit1-/- mice, but enhanced in Chit1 Tg mice compared to wild type (WT) controls, suggesting that Chit1 plays a critical role in the pathogenesis of pulmonary fibrosis [18].
In earlier studies on SSc-ILD patients, the fibrotic lungs from scleroderma patients showed significant activation (expression) of signature genes associated with TGF-β1 signaling without notable expression of TGF-β1 [67,68]. Interestingly, Tg expression of Chit1 did not increase the expression of TGF-β1 in the lung, however, in a separate in vitro experiment using fibroblast cell line, Chit1 significantly enhanced the TGF-β1-stimulated cellular responses by enhancing TGF-β1 receptor expression as well as canonical and noncanonical signaling pathways of TGF-β1 [18]. These findings led us to speculate that Chit1 contributes to the development of TGF-β1-stimulated pulmonary fibrosis by sensitizing TGF-β1 signaling pathways. If this is the case, Chit1 could be also an effective therapeutic target to block or delay the development or the progression of pulmonary fibrosis in which TGF-β1 plays a significant role.

CONCLUSIVE REMARKS AND FUTURE PROSPECTS

Pulmonary fibrosis is a complex disease with multiple factors are implicated in the development and progression of pathologic tissue responses. As demonstrated in a number of studies, TGF-β1 plays a central role in fibrotic tissue responses including pulmonary fibrosis, and the intervention of TGF-β1 expression or its signaling would be the most promising therapeutic targets for the intervention of fibroproliferative diseases. Accordingly, a number of antibodies, siRNAs and small molecules have been developed to block the expression of TGF-β1 or its receptor or signaling molecules, and some of them are currently under extensive clinical trials [13]. However, because of the vital physiologic function of TGF-β1 in normal immune and cellular homeostasis, direct or complete blocking of TGF-β1 or its signaling would not be tolerable especially in long term therapeutic use. Thus, alternative ways to selectively inhibit the pathologic effect of TGF-β1 while preserving other essential biological function of TGF-β1 would be the best strategy for the treatment of pulmonary fibrosis in which TGF-β1 plays a significant role.
In this regard, recent studies from our laboratory and others identified a number of promising candidate molecules that effectively regulate TGF-β1-stimulated fibrotic tissue responses at different levels, from TGF-β1 activation to extracellular matrix (indicated as A to E in Fig. 1). As discussed above, they are genetically determined modifiers, downstream mediators of TGF-β1, and signaling modifiers. They include integrins (such as integrins av), matrix metalloproteases, semaphorin 7a, phosphatase and tensin homolog agonist, and prostaglandin E2 [69,70,71,72,73]. A number of noncoding microRNAs have been identified to directly or indirectly regulate the expression and signaling of TGF-β1 [11]. The molecules directly associated with collagen processing, such as lysyl oxidase-like 2 [74], could be an effective therapeutic target to reduce the pathologic tissue accumulation of collagen by TGF-β1 stimulation. Since TGF-β1-induced injury responses are crucial for subsequent pulmonary fibrosis, pan-apoptosis inhibitors (such as pan-caspase inhibitors) or mesenchymal stem cells that replace the injured cells could be also therapeutic modifiers of TGF-β1-induced fibrotic tissue responses [75,76]. Although each of these modifiers alone has specific regulatory function on TGF-β1-induced tissue response, targeting multiple modifiers in a patient could provide better therapeutic effect than targeting a single modifier. This needs to be further validated in future studies.
When viewed in combination, a number of "modifiers" of TGF-β1 effector function including AR and Chit1 are already identified, and they are in the main road to be developed as effective and tolerable antifibrotic drugs. Continuous identification and targeting of different types of modifiers of TGF-β1 effector function through systematic and combinatorial approaches will lead us to a better position to control pulmonary fibrosis and other devastating fibrotic diseases in the near future.

Acknowledgments

This research was supported by Korea Drug Development Fund (KDDF) funded by Ministry of Science, ICT and Future Planning, Ministry of Trade, Industry & Energy, and Ministry of Health and Welfare (KDDF-201312-11). This research was also partly supported by a grant from NIH/NHLBI (HL114501-01A1).

Conflict of interest

No potential conflict of interest relevant to this article was reported.

References

1. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 2007;117:524–529PMID : 17332879.
crossref pmid pmc
2. Raghu G. Interstitial lung diseases: a clinical overview and general approach. In: Fishman AP, Elias JA, Fishman JA, Grippi MA, Senior RM, Pack AI, eds. Fishman's Pulmonary Diseases and Disorders. New York: McGraw Hill, 1998;1037–1053.

3. Krein PM, Winston BW. Roles for insulin-like growth factor I and transforming growth factor-beta in fibrotic lung disease. Chest 2002;122(6 Suppl):289S–293SPMID : 12475802.
crossref pmid
4. Selman M, King TE, Pardo A. American Thoracic Society. European Respiratory Society. American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136–151PMID : 11177318.
crossref pmid
5. Gharaee-Kermani M, Hu B, Phan SH, Gyetko MR. Recent advances in molecular targets and treatment of idiopathic pulmonary fibrosis: focus on TGFbeta signaling and the myofibroblast. Curr Med Chem 2009;16:1400–1417PMID : 19355895.
crossref pmid
6. Hardie WD, Glasser SW, Hagood JS. Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol 2009;175:3–16PMID : 19497999.
crossref pmid pmc
7. Strieter RM, Keeley EC, Burdick MD, Mehrad B. The role of circulating mesenchymal progenitor cells, fibrocytes, in promoting pulmonary fibrosis. Trans Am Clin Climatol Assoc 2009;120:49–59PMID : 19768162.
pmid pmc
8. Yue X, Shan B, Lasky JA. TGF-β: titan of lung fibrogenesis. Curr Enzym Inhib 2010;6(2.
crossref pmid pmc
9. Fernandez IE, Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet 2012;380:680–688PMID : 22901889.
crossref pmid
10. Fernandez IE, Eickelberg O. The impact of TGF-β on lung fibrosis: from targeting to biomarkers. Proc Am Thorac Soc 2012;9:111–116PMID : 22802283.
crossref pmid
11. Bowen T, Jenkins RH, Fraser DJ. MicroRNAs, transforming growth factor beta-1, and tissue fibrosis. J Pathol 2013;229:274–285PMID : 23042530.
crossref pmid
12. Samarakoon R, Overstreet JM, Higgins PJ. TGF-β signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities. Cell Signal 2013;25:264–268PMID : 23063463.
crossref pmid pmc
13. Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov 2012;11:790–811PMID : 23000686.
crossref pmid pmc
14. Zhou L, Dey CR, Wert SE, Whitsett JA. Arrested lung morphogenesis in transgenic mice bearing an SP-C-TGF-beta 1 chimeric gene. Dev Biol 1996;175:227–238PMID : 8626028.
crossref pmid
15. Lee CG, Cho SJ, Kang MJ, et al. Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis. J Exp Med 2004;200:377–389PMID : 15289506.
crossref pmid pmc
16. Pulichino AM, Wang IM, Caron A, et al. Identification of transforming growth factor beta1-driven genetic programs of acute lung fibrosis. Am J Respir Cell Mol Biol 2008;39:324–336PMID : 18403781.
crossref pmid
17. Zhou Y, Lee JY, Lee CM, et al. Amphiregulin, an epidermal growth factor receptor ligand, plays an essential role in the pathogenesis of transforming growth factor-β-induced pulmonary fibrosis. J Biol Chem 2012;287:41991–42000PMID : 23086930.
crossref pmid pmc
18. Lee CG, Herzog EL, Ahangari F, et al. Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-β1 signaling. J Immunol 2012;189:2635–2644PMID : 22826322.
crossref pmid pmc
19. Khalil N, O'Connor RN, Flanders KC, Unruh H. TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study. Am J Respir Cell Mol Biol 1996;14:131–138PMID : 8630262.
crossref pmid pmc
20. Khalil N, Parekh TV, O'Connor R, et al. Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis. Thorax 2001;56:907–915PMID : 11713352.
crossref pmid pmc
21. Xu YD, Hua J, Mui A, O'Connor R, Grotendorst G, Khalil N. Release of biologically active TGF-beta1 by alveolar epithelial cells results in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2003;285:L527–L539PMID : 12598227.
crossref pmid
22. Yehualaeshet T, O'Connor R, Begleiter A, Murphy-Ullrich JE, Silverstein R, Khalil N. A CD36 synthetic peptide inhibits bleomycin-induced pulmonary inflammation and connective tissue synthesis in the rat. Am J Respir Cell Mol Biol 2000;23:204–212PMID : 10919987.
crossref pmid
23. Nakao A, Fujii M, Matsumura R, et al. Transient gene transfer and expression of Smad7 prevents bleomyc-ininduced lung fibrosis in mice. J Clin Invest 1999;104:5–11PMID : 10393693.
crossref pmid pmc
24. Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997;100:768–776PMID : 9259574.
crossref pmid pmc
25. Kelly M, Kolb M, Bonniaud P, Gauldie J. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Des 2003;9:39–49PMID : 12570673.
crossref pmid
26. Kuwano K, Maeyama T, Inoshima I, et al. Increased circulating levels of soluble Fas ligand are correlated with disease activity in patients with fibrosing lung diseases. Respirology 2002;7:15–21PMID : 11896896.
crossref pmid
27. Kuwano K, Miyazaki H, Hagimoto N, et al. The involvement of Fas-Fas ligand pathway in fibrosing lung diseases. Am J Respir Cell Mol Biol 1999;20:53–60PMID : 9870917.
crossref pmid
28. Kuwano K, Kunitake R, Kawasaki M, et al. P21Waf1/Cip1/Sdi1 and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1996;154:477–483PMID : 8756825.
crossref pmid
29. Kuwano K, Hagimoto N, Kawasaki M, et al. Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. J Clin Invest 1999;104:13–19PMID : 10393694.
crossref pmid pmc
30. Ling E, Robinson DS. Transforming growth factor-beta1: its anti-inflammatory and pro-fibrotic effects. Clin Exp Allergy 2002;32:175–178PMID : 11929477.
crossref pmid
31. Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol 2002;160:1057–1068PMID : 11891202.
crossref pmid pmc
32. Akhurst RJ, Derynck R. TGF-beta signaling in cancer: a double-edged sword. Trends Cell Biol 2001;11:S44–S51PMID : 11684442.
pmid
33. Roberts AB, Piek E, Bottinger EP, Ashcroft G, Mitchell JB, Flanders KC. Is Smad3 a major player in signal transduction pathways leading to fibrogenesis? Chest 2001;120(1 Suppl):43S–47SPMID : 11451911.
crossref pmid
34. Fargeas C, Wu CY, Nakajima T, Cox D, Nutman T, Delespesse G. Differential effect of transforming growth factor beta on the synthesis of Th1- and Th2-like lymphokines by human T lymphocytes. Eur J Immunol 1992;22:2173–2176PMID : 1386318.
crossref pmid
35. Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol 1998;16:137–161PMID : 9597127.
crossref pmid
36. Zhang X, Giangreco L, Broome HE, Dargan CM, Swain SL. Control of CD4 effector fate: transforming growth factor beta 1 and interleukin 2 synergize to prevent apoptosis and promote effector expansion. J Exp Med 1995;182:699–709PMID : 7650478.
crossref pmid pmc
37. Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med 2001;194:809–821PMID : 11560996.
crossref pmid pmc
38. Martin M, Lefaix J, Delanian S. TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 2000;47:277–290PMID : 10802350.
crossref pmid
39. Kalluri R, Sukhatme VP. Fibrosis and angiogenesis. Curr Opin Nephrol Hypertens 2000;9:413–418PMID : 10926178.
crossref pmid
40. Pittet JF, Griffiths MJ, Geiser T, et al. TGF-beta is a critical mediator of acute lung injury. J Clin Invest 2001;107:1537–1544PMID : 11413161.
crossref pmid pmc
41. Fukuda H, Motohiro T, Nakai K, et al. Negative effect of transforming growth factor-beta-1 on intestinal anastomotic tissue regeneration. Eur Surg Res 2001;33:388–394PMID : 11805401.
crossref pmid
42. Chan T, Ghahary A, Demare J, et al. Development, characterization, and wound healing of the keratin 14 promoted transforming growth factor-beta1 transgenic mouse. Wound Repair Regen 2002;10:177–187PMID : 12100379.
crossref pmid
43. Amendt C, Mann A, Schirmacher P, Blessing M. Resistance of keratinocytes to TGFbeta-mediated growth restriction and apoptosis induction accelerates re-epithelialization in skin wounds. J Cell Sci 2002;115:2189–2198PMID : 11973359.
pmid
44. Cho W, Chen N, Tang C, Elias JA, Lee C. Arginase 2 plays an essential role in TGF-β-induced pulmonary fibrosis. Am J Respir Crit Care Med 2010;181:A2700.
crossref
45. Kolb M, Bonniaud P, Galt T, et al. Differences in the fibrogenic response after transfer of active transforming growth factor-beta1 gene to lungs of "fibrosis-prone" and "fibrosis-resistant" mouse strains. Am J Respir Cell Mol Biol 2002;27:141–150PMID : 12151305.
crossref pmid
46. Ward WF, Sharplin J, Franko AJ, Hinz JM. Radiation-induced pulmonary endothelial dysfunction and hydroxyproline accumulation in four strains of mice. Radiat Res 1989;120:113–120PMID : 2552496.
crossref pmid
47. Brass DM, Hoyle GW, Poovey HG, Liu JY, Brody AR. Reduced tumor necrosis factor-alpha and transforming growth factor-beta1 expression in the lungs of inbred mice that fail to develop fibroproliferative lesions consequent to asbestos exposure. Am J Pathol 1999;154:853–862PMID : 10079263.
crossref pmid pmc
48. Deheuninck J, Luo K. Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell Res 2009;19:47–57PMID : 19114989.
crossref pmid pmc
49. Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-beta signal transduction. J Cell Sci 2001;114:4359–4369PMID : 11792802.
pmid
50. Derynck R, Zhang YE. Smad-independent and Smadindependent pathways in TGF-beta family signalling. Nature 2003;425:577–584PMID : 14534577.
crossref pmid
51. Ishii Y, Fujimoto S, Fukuda T. Gefitinib prevents bleomycin-induced lung fibrosis in mice. Am J Respir Crit Care Med 2006;174:550–556PMID : 16741154.
crossref pmid
52. Laato M, Kahari VM, Niinikoski J, Vuorio E. Epidermal growth factor increases collagen production in granulation tissue by stimulation of fibroblast proliferation and not by activation of procollagen genes. Biochem J 1987;247:385–388PMID : 3501286.
crossref pmid pmc
53. Samarakoon R, Dobberfuhl AD, Cooley C, et al. Induction of renal fibrotic genes by TGF-β1 requires EGFR activation, p53 and reactive oxygen species. Cell Signal 2013;25:2198–2209PMID : 23872073.
crossref pmid
54. Bussink AP, Speijer D, Aerts JM, Boot RG. Evolution of mammalian chitinase(-like) members of family 18 glycosyl hydrolases. Genetics 2007;177:959–970PMID : 17720922.
crossref pmid pmc
55. Funkhouser JD, Aronson NN Jr. Chitinase family GH18: evolutionary insights from the genomic history of a diverse protein family. BMC Evol Biol 2007;7:96. PMID : 17594485.
crossref pmid pmc
56. Chang NC, Hung SI, Hwa KY, et al. A macrophage protein, Ym1, transiently expressed during inflammation is a novel mammalian lectin. J Biol Chem 2001;276:17497–17506PMID : 11297523.
crossref pmid
57. Bleau G, Massicotte F, Merlen Y, Boisvert C. Mammalian chitinase-like proteins. EXS 1999;87:211–221PMID : 10906962.
crossref pmid
58. Di Rosa M, Musumeci M, Scuto A, Musumeci S, Malaguarnera L. Effect of interferon-gamma, interleukin-10, lipopolysaccharide and tumor necrosis factor-alpha on chitotriosidase synthesis in human macrophages. Clin Chem Lab Med 2005;43:499–502PMID : 15899671.
crossref pmid
59. Malaguarnera L, Musumeci M, Di Rosa M, Scuto A, Musumeci S. Interferon-gamma, tumor necrosis factor-alpha, and lipopolysaccharide promote chitotriosidase gene expression in human macrophages. J Clin Lab Anal 2005;19:128–132PMID : 15900564.
crossref pmid
60. van Eijk M, van Roomen CP, Renkema GH, et al. Characterization of human phagocyte-derived chitotriosidase, a component of innate immunity. Int Immunol 2005;17:1505–1512PMID : 16214810.
crossref pmid
61. Gordon-Thomson C, Kumari A, Tomkins L, et al. Chitotriosidase and gene therapy for fungal infections. Cell Mol Life Sci 2009;66:1116–1125PMID : 19169854.
crossref pmid
62. Labadaridis I, Dimitriou E, Theodorakis M, Kafalidis G, Velegraki A, Michelakakis H. Chitotriosidase in neonates with fungal and bacterial infections. Arch Dis Child Fetal Neonatal Ed 2005;90:F531–F532PMID : 16244214.
crossref pmid pmc
63. Brunner J, Scholl-Burgi S, Prelog M, Zimmerhackl LB. Chitotriosidase as a marker of disease activity in sarcoidosis. Rheumatol Int 2007;27:1185–1186PMID : 17252260.
crossref pmid
64. Boot RG, Hollak CE, Verhoek M, Alberts C, Jonkers RE, Aerts JM. Plasma chitotriosidase and CCL18 as surrogate markers for granulomatous macrophages in sarcoidosis. Clin Chim Acta 2010;411:31–36PMID : 19808030.
crossref pmid
65. Bargagli E, Margollicci M, Luddi A, et al. Chitotriosidase activity in patients with interstitial lung diseases. Respir Med 2007;101:2176–2181PMID : 17631992.
crossref pmid
66. Bargagli E, Margollicci M, Nikiforakis N, et al. Chitotriosidase activity in the serum of patients with sarcoidosis and pulmonary tuberculosis. Respiration 2007;74:548–552PMID : 17347558.
crossref pmid
67. Ihn H, Yamane K, Kubo M, Tamaki K. Blockade of endogenous transforming growth factor beta signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: association with increased expression of transforming growth factor beta receptors. Arthritis Rheum 2001;44:474–480PMID : 11229480.
crossref pmid
68. Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine transforming growth factor beta signaling in systemic sclerosis fibroblasts. Arthritis Rheum 2005;52:2897–2905PMID : 16142753.
crossref pmid
69. Bozyk PD, Moore BB. Prostaglandin E2 and the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol 2011;45:445–452PMID : 21421906.
crossref pmid pmc
70. Miyoshi K, Yanagi S, Kawahara K, et al. Epithelial Pten controls acute lung injury and fibrosis by regulating alveolar epithelial cell integrity. Am J Respir Crit Care Med 2013;187:262–275PMID : 23239155.
crossref pmid
71. Kang HR, Cho SJ, Lee CG, Homer RJ, Elias JA. Transforming growth factor (TGF)-beta1 stimulates pulmonary fibrosis and inflammation via a Bax-dependent, bid-activated pathway that involves matrix metalloproteinase-12. J Biol Chem 2007;282:7723–7732PMID : 17209037.
crossref pmid
72. Kang HR, Lee CG, Homer RJ, Elias JA. Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis. J Exp Med 2007;204:1083–1093PMID : 17485510.
crossref pmid pmc
73. Henderson NC, Arnold TD, Katamura Y, et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 2013;19:1617–1624PMID : 24216753.
crossref pmid pmc
74. Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010;16:1009–1017PMID : 20818376.
crossref pmid
75. Wang R, Ibarra-Sunga O, Verlinski L, Pick R, Uhal BD. Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 2000;279:L143–L151PMID : 10893213.
pmid
76. Toonkel RL, Hare JM, Matthay MA, Glassberg MK. Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am J Respir Crit Care Med 2013;188:133–140PMID : 23306542.
crossref pmid
Figure 1
Transforming growth factor (TGF)-β1 activation and signaling pathways leading to tissue fibrosis. On the cell surface, integrins activate the latent form of TGF-β1 (A) then the bioactive TGF-β1 binds to the TGF-β1 receptor complex (B). The Smads proteins are the major signaling molecules mediating canonical TGF-β1 signaling (C). Receptor activated receptor-regulated Smads (R-Smads; Smad2 and 3) binds to common mediator Smad (Co-Smad; Smad4), the complexes are transmitted into nucleus and regulate the expression of target genes together with other transcription factors (TFs) and coactivators. Inhibitory Smads (I-Smads; Smad6 and 7) are known to block Smad signaling by binding and directing TGF-β1 receptors to degradation. There are also Smad-independent pathways that include mitogen-activated protein kinase/Erk, TAK1/c-Jun N-terminal kinase (JNK), or phosphatidylinositol 3-kinase (PI3K)/Akt activation by TGF-β1 and other receptors. Finally, these TGF-β1 signaling pathways ultimately lead to the increases in the synthesis of profibrotic mediators and extracellular matrix (ECM) protein including collagens (E). A variety of "modifiers of TGF-β" can be targeted to modulate the final outcome of TGF-β1-stimulated fibrotic tissue responses at different levels of TGF-β activation and signaling as indicated (A-E).
kjim-29-281-g001
Figure 2
Synergistic crosstalk and interaction between transforming growth factor (TGF)-β1 and epidermal growth factor receptor (EGFR) signaling mediated by amphiregulin (AR). TGF-β1 induces the expression of AR, and AR in turn stimulates fibroblasts proliferation through EGFR activation of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/Erk. The EGFR activation also regulates TGF-β1-stimulated Smad activation, suggesting an intimate crosstalk and synergistic interaction between these two signaling pathways that ultimately lead to enhanced fibrotic tissue responses.
kjim-29-281-g002
TOOLS
PDF Links  PDF Links
PubReader  PubReader
ePub Link  ePub Link
Full text via DOI  Full text via DOI
Full text via PMC  Full text via PMC
Download Citation  Download Citation
CrossRef TDM  CrossRef TDM
  E-Mail
Share:      
METRICS
16
Crossref
21
Scopus
5,173
View
68
Download
Related article
Editorial Office
101-2501, Lotte Castle President, 109 Mapo-daero, Mapo-gu, Seoul 04146, Korea
Tel: +82-2-2271-6792   Fax: +82-2-790-0993    E-mail: kaim@kams.or.kr
Copyright © 2017 The Korean Association of Internal Medicine. All rights reserved.
About |  Browse Articles |  Current Issue |  For Authors and Reviewers
powerd by m2community