0
Translating Basic Research Into Clinical Practice |

Molecular Targets in Pulmonary Fibrosis*: The Myofibroblast in Focus FREE TO VIEW

Chris J. Scotton, PhD; Rachel C. Chambers, PhD
Author and Funding Information

*From the Centre for Respiratory Research, University College London, Rayne Institute, London, UK.

Correspondence to: Rachel Chambers, PhD, Centre for Respiratory Research, University College London, Rayne Institute, 5 University St, London WC1E 6JJ, UK; e-mail: r.chambers@ucl.ac.uk



Chest. 2007;132(4):1311-1321. doi:10.1378/chest.06-2568
Text Size: A A A
Published online

Idiopathic pulmonary fibrosis (IPF) is one of a group of interstitial lung diseases that are characterized by excessive matrix deposition and destruction of the normal lung architecture. Long-term survival of IPF patients is poor, with a 5-year survival rate of only 20%. Despite a lack of evidence-based benefit, IPF has historically been treated with corticosteroids and/or cytotoxic agents such as prednisone. Given the poor efficacy of these drugs, novel therapeutic strategies are required for the management of IPF. This demands a better understanding of the molecular mechanisms underlying the pathogenesis and progression of this disease. The primary effector cell in fibrosis is the myofibroblast; these cells are highly synthetic for collagen, have a contractile phenotype, and are characterized by the presence of α-smooth muscle actin stress fibers. They may be derived by activation/proliferation of resident lung fibroblasts, epithelial-mesenchymal differentiation, or recruitment of circulating fibroblastic stem cells (fibrocytes). From a therapeutic viewpoint, interfering with the pathways that lead to myofibroblast expansion should be of considerable benefit in the treatment of IPF. This review will highlight some of the key molecules involved in this process and the clinical trials that have ensued.

Figures in this Article

The interstitial lung diseases (ILDs) comprise a group of acute and chronic lung disorders with varying degrees of inflammation and fibrosis. One of the most prevalent is idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonitis. Current epidemiology studies1 suggests that IPF is more common in male subjects, with onset usually in middle or old age, but it has no distinct geographic distribution and does not distinguish between particular races or ethnic groups. In all cases, however, it is an insidious, progressive disease with a median survival of only 2 to 3 years following diagnosis. Although the precise etiology is unknown, a number of risk factors may contribute to disease development, including smoking, drug exposure, infectious agents, and genetic predisposition.12

Diagnosis of IPF remains problematic, although the recent joint consensus statement from the American Thoracic Society and the European Respiratory Society aims to standardize the criteria for diagnosis and subsequent therapeutic approaches.2Histologically, IPF lungs have alternating regions of normal lung parenchyma, interstitial inflammation, fibrosis, and “honeycombing.” These features are a result of failed alveolar reepithelialization, fibroblast persistence, and excessive deposition of collagen and other extracellular matrix (ECM) components, leading to irreversible loss of lung function. Aberrant vasculogenesis may also contribute to the disease process in a manner similar to that seen during tumorigenesis.3 The specific molecular and cellular mechanisms that lead to disease progression are unknown, although considerable effort is being made to delineate these pathogenic processes. Since the current treatments for IPF are largely ineffective, the identification of pathways that may provide novel therapeutic targets is absolutely crucial. This review will focus on the pathogenesis of IPF, although the paradigms and potential molecular targets described may be relevant to a number of other fibrotic conditions, including sarcoidosis and systemic sclerosis.

Historically, IPF was believed to result mainly from chronic inflammation, leading to persistent epithelial and vascular injury and activation/expansion of the lung mesenchyme. Established treatments based on this assumption involve the use of antiinflammatory or immunosuppressive drugs such as prednisone, azathioprine, or cyclophosphamide.1 Unfortunately, none of these agents have been shown to unequivocally alter the inflammatory process in IPF or reduce severity or progression of the disease; prospective placebo-controlled randomized clinical trials have not been performed, yet clinicians continue to prescribe these drugs primarily because there are no recommended alternatives (see Raghu4for more information). Recent experimental evidence suggests that inflammation is not necessary or sufficient for the progression to fibrosis5; overexpression of the potent profibrotic mediator, transforming growth factor (TGF)-β1, for example, leads to progressive fibrosis in mice, without any significant inflammatory component.6 In the human condition, antiinflammatory treatment during the end stage of fibrosis may well be somewhat ineffective, but this does not preclude a pathogenic role for inflammation in the earlier stages of the disease.3

Myofibroblasts

Irrespective of the uncertainty regarding the precise etiology of IPF, it is generally accepted that aberrant wound healing and epithelial-mesenchymal cross-talk are major components of the pathogenic process. Ongoing damage to the alveolar epithelium and/or capillary endothelium leads to apoptotic events that culminate in the initiation of repair mechanisms; in IPF, these repair mechanisms are apparently dysregulated. In response to a variety of growth factors and cytokines such as TGF-β1 and platelet-derived growth factor (PDGF), the subsequent hyperproliferation of type II alveolar epithelial cells, recruitment of fibroblasts, and formation of fibroblastic foci are the hallmarks of the disease; an increase in the number of these fibrotic foci is associated with disease progression and a worsened prognosis.7Examination of individual tissue sections would suggest that fibrotic foci are isolated lesions, potentially arising from localized injury. However, recent data from Cool et al8 demonstrate that these foci actually form a highly complex, interconnected, and continuous fibrotic reticulum, arising from polyclonal fibroblast proliferation.

The key effector cell in fibrogenesis is the myofibroblast; these spindle- or stellate-shaped cells share features with smooth muscle cells in that they are contractile and contain α-smooth muscle actin (SMA) stress fibers. They localize to fibrotic foci and other sites of active fibrosis, and are the primary cell type responsible for the synthesis and deposition of ECM and the resultant structural remodeling that leads to the loss of alveolar function. When considering potential therapeutic approaches, understanding the pathways that lead to fibroblast proliferation, activation, and differentiation should provide a number of molecular targets that may be worthy of intense investigation for the treatment of IPF.

Current opinion suggests that myofibroblasts have at least three possible origins, although the relative contribution of each of these pathways in IPF is currently unknown (Fig 1 ). The most straightforward suggestion is that resident lung fibroblasts differentiate directly under the influence of the profibrotic microenvironment to form myofibroblasts.9For example, evidence from the bleomycin model of lung fibrosis in rats certainly suggests that the initial α-SMA–positive myofibroblasts arise in the adventia of the distal airways from peribronchiolar/perivascular fibroblasts10; it is highly likely that interstitial fibroblasts can respond in a similar manner.

The second possibility is that epithelial cells undergo transdifferentiation to form fibroblasts and thence myofibroblasts by a process termed epithelial-mesenchymal transition (EMT); epithelial cells lose their characteristic markers such as E-cadherin and zona occludens-1 and acquire mesenchymal markers such as fibroblast-specific protein-1 and α-SMA.11The concept of EMT has been recognized for > 20 years, and evidence is now accumulating to support a role for EMT in IPF. Alveolar epithelial cells in vitro can undergo EMT in response to prolonged TGF-β1 exposure,12 and an experimental animal study13 has conclusively identified epithelial-derived mesenchymal cells in TGF-β1–driven fibrosis. Moreover, both of these research groups identified cells in IPF biopsy samples that coexpress epithelial and mesenchymal markers suggesting that they are in a state of EMT.

The third hypothesis addresses the possibility that mesenchymal cells may be derived from circulating fibrocytes or other bone marrow-derived progenitor cells.14Fibrocytes were originally identified by Bucala et al15in 1994 as collagen I+/CD34+/CD45RO+ cells that are likely derived from hematopoietic stem cells. A pathogenic role for fibrocytes in IPF has been postulated from experimental models in which blockade of fibrocyte recruitment is protective following bleomycin challenge.17 However, evidence that fibrocytes are capable of differentiating into fully activated myofibroblasts, especially in patients with IPF, is still lacking.

Given the various pathways leading to myofibroblast expansion, what molecular targets might therefore prove useful therapeutically? This review will focus specifically on a selection of the molecules that we believe are relevant in this regard; an overview of possible targets in other pathways and, where applicable, their associated clinical trials is given in Table 1 . There are also a number of excellent recent reviews.1819

TGF-β

As mentioned previously, there is overwhelming evidence for a pathogenic role for TGF-β in IPF disease progression. This cytokine can drive EMT, fibroblast-to-myofibroblast differentiation, and is the most potent inducer of ECM production characterized to date. As a result, there is considerable optimism that drugs targeting TGF-β will be of benefit in IPF. One caveat to this approach is that TGF-β has an important role in regulating inflammation and acts as a tumor suppressor in certain contexts; in a clinical setting, reduced systemic levels of this cytokine could therefore have undesirable side effects. However, Cambridge Antibody Technology (Cambridge, UK) and Genzyme Corporation (Cambridge, MA) are currently collaborating on a phase I clinical trial in IPF patients with GC1008, a neutralizing antibody that targets all three mammalian TGF-β isoforms: TGF-β1, TGF-β2, and TGF-β3. This study has an expected completion date of November 2006 and will evaluate safety, tolerability, and potential clinical outcomes of this antibody (see http://www.clinicaltrials.gov for more information).

Another promising approach is to develop compounds that interfere with TGF-β activation or signaling. Here we describe two examples, but a number of other anti–TGF-β targets are in development (see Antoniou et al20for review). An important mechanism for the conversion of inactive latent TGF-β to an active signaling molecule in the context of pulmonary fibrosis involves the epithelial integrin, αvβ6. This integrin is up-regulated in pulmonary fibrosis, and mice deficient for β6 are protected in the bleomycin model of lung fibrosis, suggesting a significant role for this molecule in lung fibrogenesis.21 Anti-αvβ6 neutralizing antibodies developed by Biogen (Cambridge, MA) are currently in preclinical trials in IPF. Finally, binding of active TGF-β to its high-affinity serine/threonine kinase receptor TGF-βRI (activin-like kinase receptor-5 [ALK-5]) activates downstream signaling events via the Smad family of intracellular signal transducers. An orally active ALK-5 kinase inhibitor, SD-208, was effective in blocking fibrotic progression in a rat model of established fibrosis,22 suggesting that small-molecule antagonists of this type may be useful in IPF.

Connective Tissue Growth Factor

Connective tissue growth factor (CTGF), a prototypic member of the CCN protein family, is thought to be a downstream mediator of TGF-β, with a particular role in stimulating fibroblast matrix production and myofibroblast differentiation.23CTGF is induced by a number of profibrotic mediators other than TGF-β, including thrombin.24Its expression is increased in IPF (both in the fibrotic lung tissue and within cells obtained by BAL) and localizes to proliferating type II alveolar epithelium and activated fibroblasts.25Experimentally, although overexpression of CTGF alone produces only mild and transient fibrosis,26it is capable of conferring susceptibility to bleomycin-induced fibrosis in the fibrosis-resistant Balb/c mouse strain.27A phase I clinical trial assessing a fully human neutralizing antibody directed against CTGF (FG-3019 from FibroGen; San Francisco, CA) was recently completed; the results demonstrate that this antibody is safe and well tolerated.28 Further studies are required to assess potential therapeutic benefits of this antibody in IPF.

Interleukin-13

Interleukin (IL)-13 is a prototypic T-helper type 2 (Th2) cytokine that is also strongly profibrotic; in IPF, there is an imbalance in T-helper type 1/Th2 cytokine expression, with Th2 cytokines predominating. Mice deficient for IL-13 are protected in a fluorescein isothiocyanate-induced model of lung fibrosis, and IL-13 can stimulate fibroblast collagen production independently of TGF-β.29However, a recent study by Fichtner-Feigl et al30has shown that signaling through IL-13Rα2, originally thought to be a decoy receptor for IL-13, results in the production of TGF-β. Moreover, in vivo gene silencing of IL-13Rα2 using small interfering RNA attenuates bleomycin-induced lung fibrosis, with decreases in TGF-β1 secretion and collagen formation. IL-13 can also stimulate production of FIZZ (found in inflammatory zone)-1 by airway epithelial cells31; the precise biological function of this protein is unknown, but FIZZ-1 can stimulate myofibroblast differentiation in vitro.32 Since epithelial-mesenchymal cross-talk is thought to be important for the formation of fibroblastic foci, FIZZ-1 may play a significant role in this process, downstream of IL-13. These data suggest that therapies targeting either IL-13 or the IL-13Rα2 receptor may be of interest; a study33 in mice has shown that a recombinant fusion protein composed of IL-13 and a derivative of pseudomonas exotoxin has efficacy in the bleomycin model of lung fibrosis.

PDGF

PDGF is a potent mitogen and chemoattractant for mesenchymal cells, including myofibroblasts.34It can also stimulate the production of ECM components such as fibronectin and collagen I. In the lung, its expression is significantly increased in alveolar macrophages,35although myofibroblasts themselves can secrete PDGF, creating an autocrine feedback loop for proliferation and matrix deposition. This cytokine signals via the PDGF-α or -β receptors, causing receptor dimerization and tyrosine-kinase dependent phosphorylation events. Imatinib mesylate (Gleevec; Novartis; East Hanover, NJ) is a tyrosine kinase inhibitor that has activity against the PDGF receptor and may therefore have antifibrotic properties. In addition, there is evidence that imatinib may inhibit signaling pathways directly downstream of TGF-β2 (independently of PDGF receptor activation), thereby blocking TGF-β–induced gene expression, morphologic transformation, and cell proliferation.36 In experimental models, imatinib reduced collagen deposition following bleomycin injury3637 and reduced mesenchymal cell proliferation37; it is feasible that imatinib may represent a therapeutic approach that can block both PDGF- and TGF-β–mediated fibrotic events. A phase II, randomized, double-blind, placebo-controlled study of the clinical effects of orally administered Gleevec in patients with IPF has finished the recruitment phase and will complete its 2-year follow-up in August 2007; the primary end point is disease progression, defined as a > 10% decline in FVC, or death.

Interferon-γ1b

Interferon (IFN)-γ is thought to play a key role in counter-regulating TGF-β expression and activity, thus limiting fibroblast proliferation, differentiation, and collagen synthesis. In mice, daily treatment with IFN-γ following bleomycin injury reduced lung messenger RNA levels of TGF-β, collagen I, and collagen III, and attenuated the increase in lung collagen levels, based on assessment of hydroxyproline.38Patients with IPF are known to have reduced levels of IFN-γ; a preliminary study by Ziesche et al39showed substantial improvements in the condition of a small number of IPF patients following 12 months of IFN-γ1b treatment. This favorable outcome led to a number of follow-up studies assessing the effects of IFN-γ in IPF, including a large, multicenter, randomized, placebo-controlled trial40in IPF patients who had failed to respond to corticosteroids. This study showed no significant difference in the composite primary end point of progression-free survival (defined by either a decrease of at least 10% in the predicted FVC or an increase of at least 5 mm Hg in the alveolar-arterial oxygen pressure gradient at rest, or death) or the secondary outcomes of pulmonary function and quality of life. However, post hoc analysis did reveal increased survival in a subset of patients who had a baseline FVC > 62% of predicted. A similar finding was recently reported by Antoniou et al,41 in which long-term treatment with IFN-γ1b appeared to have a beneficial effect on survival, outcome, and predicted FVC in a well-defined population of patients with mild-to-moderate IPF. In an effort to determine the molecular basis for the effects of IFN-γ in IPF patients, Strieter et al42 undertook a study assessing blood and lung biomarkers following IFN-γ treatment. They generated data consistent with the notion that IFN-γ can down-regulate molecules involved with fibrosis, inflammation, and proliferation, while up-regulating molecules associated with antiangiogenesis and antimicrobial defense. In light of these encouraging data, a follow-up phase III trial (International Study of Survival Outcomes in Idiopathic Pulmonary Fibrosis With Interferon γ-1b Early Intervention [INSPIRE]) is currently being conducted by InterMune (Brisbane, CA); this study recently finished enrolling patients and should conclude in August 2007. Disappointingly, the INSPIRE trial has now been terminated early. According to a recent press release from InterMune, the data monitoring committee for this clinical trial recommended that the study be discontinued based on the results of a planned interim analysis. Among the 826 randomized patients (including 115 deaths), there was no statistically significant difference between treatment groups for overall mortality (14.5% in the Actimmune (InterMune) group as compared to 12.7% in the placebo group). This overall survival result crossed their predefined stopping boundary for lack of benefit of Actimmune relative to placebo.

CXCR4 and CXCL12

Chemotactic cytokines (chemokines) are abundantly expressed in experimental models of fibrosis and in the human disease (see Agostini and Gurrieri43 for review). As their name suggests, chemokines can function as chemoattractants, but they also play roles in angiogenesis (see Strieter3 for review), development, differentiation, hematopoiesis, and inflammation. In terms of directly influencing fibrotic responses, CCL2 (monocyte chemoattractant protein-1), for example, has been reported to induce TGF-β1 and procollagen gene expression by fibroblasts.44Serum levels of CCL2 may help to predict the clinical outcome of IPF,45while a number of other chemokines are increased in patients with ILD, including CCL7,46CXCL8,47CCL18,48and CCL22.49 An imbalance of angiogenic-vs-angiostatic chemokines may contribute to the aberrant vasculogenesis seen in IPF. IFN-γ1b treatment can increase levels of the ELR-negative angiostatic CXC chemokine CXCL11 in IPF patients3; mice treated systemically with this chemokine had significantly attenuated bleomycin-induced lung fibrosis.50

Recent interest has focused on the role of chemokines in recruiting fibrocytes to the injured lung. Mice deficient for CC chemokine receptor 2 (the main CCL2 receptor) are protected from both bleomycin- and fluorescein isothiocyanate-induced fibrosis.16,51This effect has been attributed to the role of CCL12 in fibrocyte recruitment, rather than CCL2; however, murine CCL12 actually has greater homology to human CCL2 than does murine CCL2.52 In human IPF, the CXCL12/CXCR4 axis may be of particular significance.17 Circulating human fibrocytes express CXCR4 and α-SMA, and can traffic toward the unique CXCR4 ligand, CXCL12. Moreover, an anti-CXCL12 neutralizing antibody attenuated bleomycin-induced fibrosis in mice. These data suggest that interfering with chemokine/chemokine networks may help to block myofibroblast recruitment/expansion in IPF, as well as promoting a shift toward an antifibrotic and antiangiogenic microenvironment (discussed by Agostini and Gurrieri43).

The canonical Wnt signaling pathway involves the binding of Wnt proteins (cysteine-rich secreted glycoproteins) to frizzled-cell surface receptors or low-density lipoprotein coreceptors. A detailed description of this pathway is beyond the scope of this review (see Morrisey53and Kikuchi et al54for more information), but, briefly, it results in the inhibition of glycogen synthase kinase-3β and the consequent hypophosphorylation of β-catenin; this cytoskeletal protein can then translocate to the nucleus, where its binding to the lymphoid enhancer-binding factor/T-cell factor family of transcription factors converts them from transcriptional repressors to activators. Wnt proteins can also signal via protein kinase C (the Wnt/Ca2+ pathway) or c-Jun N-terminal kinase (the planar cell polarity pathway). The Wnt pathway plays an essential role during lung organogenesis, regulating both epithelial and mesenchymal development via autocrine and paracrine signals. In IPF, Chilosi et al55 showed that nuclear β-catenin immunoreactivity localized to proliferative bronchiolar lesions and fibroblastic foci; these features were not seen in other ILDs or normal lung. It is unclear from this work whether aberrant Wnt signaling is a responsive rather than causative event in IPF, but it could provide autocrine survival signals to fibroblasts within these foci, as well as stimulating type II cell proliferation. Moreover, β-catenin signaling can play a role in experimental EMT,55suggesting that the aberrant nuclearization of β-catenin in bronchiolar lesions could promote EMT in the diseased lung. Finally, matrix metalloproteinase-7 (matrilysin) is an important target gene of the β-catenin/lymphoid enhancer-binding factor-1 signaling pathway; expression of this gene is significantly increased in IPF and mice deficient for matrix metalloproteinase-7 are protected from bleomycin-induced lung fibrosis.56 These data suggest that drugs that inhibit Wnt signaling may be of use in IPF, by controlling fibroblast and epithelial proliferation and possibly interfering with EMT.

In 2005, Kubo et al57 published the results of a nonblinded, randomized trial of 56 patients with IPF administered prednisolone alone or prednisolone plus anticoagulation (oral warfarin for outpatients or low-molecular-weight heparin for hospitalized patients). These investigators reported a significant increase in survival in the anticoagulant group, with 63% survival at 3 years in the anticoagulant group vs 35% in the nonanticoagulant group. Both groups had a comparable incidence of acute exacerbations, but mortality associated with acute exacerbation was lower in the anticoagulant group (18% vs 71%). Despite some methodologic caveats (eg, possible selection bias toward advanced disease, concerns regarding patient randomization), this remains one of the most significant beneficial outcomes on survival in an IPF clinical study.

Increased local procoagulant activity is a characteristic feature of IPF (see Chambers and Laurent58for review), with extravascular generation of tissue factor, factor VIIa, factor Xa, and thrombin. In experimental animals, direct thrombin inhibition abrogates lung collagen accumulation in bleomycin-induced pulmonary fibrosis.59These coagulation factors can all exert cellular effects through the activation of proteinase-activated receptors (PARs), particularly PAR1. Expression of this receptor is increased in IPF60 and in patients with pulmonary fibrosis associated with scleroderma.61 Mice deficient for PAR1 are significantly protected from bleomycin-induced lung fibrosis, and this is associated with a reduction in both CCL2 and CTGF expression and TGF-β immunoreactivity.,60 PAR1 activation on lung fibroblasts up-regulates PDGF, CTGF, and procollagen expression and drives myofibroblast differentiation.,58,62Lung epithelial PAR1 ligation can activate the αvβ6 integrin, leading to TGF-β activation.63 These data suggest that activation of the coagulation system (an early event in lung injury and maintained in fibrosis) can link to many of the profibrotic mechanisms described earlier and may also be relevant in terms of the beneficial effects observed with anticoagulant therapy reported by Kubo et al. Clearly, further investigation is warranted; to this end, phase I clinical trials are underway in Germany to assess the effects of inhaled heparin in patients with IPF.5 Moreover, given the central role of PAR1 in transducing the proinflammatory and profibrotic effects of several coagulation proteinases, the development of PAR1 receptor antagonists will be of considerable interest in this area.

This review has outlined a few of the key molecular targets in pulmonary fibrosis that are intimately involved with fibroblast/myofibroblast recruitment, expansion, and differentiation; further understanding of how these molecules interact will undoubtedly bring novel therapeutic targets into focus. A brief perusal of the literature would reveal that there are many more potential targets that are the subject of current research; well over a thousand papers describe experiments in the bleomycin model of lung fibrosis alone. Our understanding of these molecular mechanisms and pathogenic pathways is constantly increasing, and we can now appreciate just how complex IPF really is: involving epithelial and endothelial injury, a state of hypercoagulation, fibroblast activation and differentiation, EMT, fibrocyte recruitment, ECM deposition, angiogenesis, and aberrant repair mechanisms. Further studies will hopefully help to delineate the complex temporal and spatial relationships between these pathways.

The use of high-throughput gene expression profiling technology may be of particular benefit in understanding the complex interplays seen in pulmonary fibrosis. Microarray analysis can reveal regulatory networks and expression profiles that underlie disease progression (see Kaminski and Rosas64 for review). It is unlikely that individual therapeutic approaches will be sufficiently efficacious; rather, combinatorial approaches will be required. Moreover, given the heterogeneity of the disease process, targeting a particular pathway may have both beneficial effects in one disease setting while having deleterious effects in another, resulting in unwanted side effects. Nonetheless, IPF is a devastating disease that demands far superior treatments than are currently available; the considerable efforts in the pursuit of novel therapies will one day provide a brighter future for these patients.

Abbreviations: ALK-5 = activin-like kinase receptor-5; CTGF = connective tissue growth factor; ECM = extracellular matrix; EMT = epithelial-mesenchymal transition; FIZZ = found in inflammatory zone; IFN = interferon; IL = interleukin; ILD = interstitial lung disease; INSPIRE = International Study of Survival Outcomes in Idiopathic Pulmonary Fibrosis With Interferon γ-1b Early Intervention; IPF = idiopathic pulmonary fibrosis; PAR = proteinase-activated receptor; PDGF = platelet-derived growth factor; SMA = smooth muscle actin; TGF = transforming growth factor; Th2 = T-helper type 2

The authors declare that they have no conflicting financial interests.

Figure Jump LinkFigure 1. Origins of myofibroblasts in IPF. Myofibroblasts, the key effector cell type in IPF, are thought to arise from the following: (1) proliferation and differentiation of resident fibroblasts; (2) epithelial-mesenchymal transition; or (3) recruitment of circulating fibrocytes. Various cytokines, growth factors, and signaling pathways are able to mediate these events (black arrows). A number of potential therapeutic strategies (shown in red) are under development (see text for more details).Grahic Jump Location
Table Graphic Jump Location
Table 1. An Overview of Possible Therapeutic Targets in IPF and Current Clinical Trials*
Table Graphic Jump Location
Table 1A. Continued
* 

For more information on clinical trials in IPF, visit http://www.clinicaltrials.gov and http://www.actr.org.au. CAPACITY = Clinical Studies Assessing Perfenidone in IPF: Research of Efficacy and Safety Outcomes; BUILD = Bosentan Use in Interstitial Lung Disease; IFIGENIA = Idiopathic Pulmonary Fibrosis International Group Exploring N-acetylcysteine Annual.

. American Thoracic Society. (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement; American Thoracic Society (ATS), and the European Respiratory Society (ERS).Am J Respir Crit Care Med161(2 pt 1),646-664
 
American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias; this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.Am J Respir Crit Care Med2002;165,277-304. [PubMed]
 
Strieter, RM Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel.Chest2005;128(5 suppl 1),526S-532S
 
Raghu, G Idiopathic pulmonary fibrosis: treatment options in pursuit of evidence-based approaches.Eur Respir J2006;28,463-465. [PubMed] [CrossRef]
 
Ask, K, Martin, GE, Kolb, M, et al Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls.Proc Am Thorac Soc2006;3,389-393. [PubMed]
 
Sime, PJ, Xing, Z, Graham, FL, et al Adenovector-mediated gene transfer of active transforming growth factor-β1 induces prolonged severe fibrosis in rat lung.J Clin Invest1997;100,768-776. [PubMed]
 
King, TE, Jr, Schwarz, MI, Brown, K, et al Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.Am J Respir Crit Care Med2001;164,1025-1032. [PubMed]
 
Cool, CD, Groshong, SD, Rai, PR, et al Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum.Am J Respir Crit Care Med2006;174,654-658. [PubMed]
 
Phan, SH The myofibroblast in pulmonary fibrosis.Chest2002;122(6 suppl),286S-289S
 
Zhang, K, Rekhter, MD, Gordon, D, et al Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis: a combined immunohistochemical andin situhybridization study.Am J Pathol1994;145,114-125. [PubMed]
 
Grunert, S, Jechlinger, M, Beug, H Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis.Nat Rev Mol Cell Biol2003;4,657-665. [PubMed]
 
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 Pathol2005;166,1321-1332. [PubMed]
 
Kim, KK, Kugler, MC, Wolters, PJ, et al Alveolar epithelial cell mesenchymal transition developsin vivoduring pulmonary fibrosis and is regulated by the extracellular matrix.Proc Natl Acad Sci U S A2006;103,13180-13185. [PubMed]
 
Lama, VN, Phan, SH The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond.Proc Am Thorac Soc2006;3,373-376. [PubMed]
 
Bucala, R, Spiegel, LA, Chesney, J, et al Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.Mol Med1994;1,71-81. [PubMed]
 
Moore, BB, Kolodsick, JE, Thannickal, VJ, et al CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.Am J Pathol2005;166,675-684. [PubMed]
 
Phillips, RJ, Burdick, MD, Hong, K, et al Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.J Clin Invest2004;114,438-446. [PubMed]
 
Bhatt, N, Baran, CP, Allen, J, et al Promising pharmacologic innovations in treating pulmonary fibrosis.Curr Opin Pharmacol2006;6,284-292. [PubMed]
 
Walter, N, Collard, HR, King, TE, Jr Current perspectives on the treatment of idiopathic pulmonary fibrosis.Proc Am Thorac Soc2006;3,330-338. [PubMed]
 
Antoniou KM, Pataka A, Bouros D, et al. Pathogenetic pathways and novel pharmacotherapeutic targets in idiopathic pulmonary fibrosis. Pulm Pharmacol Ther 2007 (in press). Available at: http://sciencedirect.com/science. Accessed June 1, 2007.
 
Munger, JS, Huang, X, Kawakatsu, H, et al The integrin alpha v beta 6 binds and activates latent TGF β 1: a mechanism for regulating pulmonary inflammation and fibrosis.Cell1999;96,319-328. [PubMed]
 
Bonniaud, P, Margetts, PJ, Kolb, M, et al Progressive transforming growth factor β1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor.Am J Respir Crit Care Med2005;171,889-898. [PubMed]
 
Leask, A, Abraham, DJ The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology.Biochem Cell Biol2003;81,355-363. [PubMed]
 
Chambers, RC, Leoni, P, Blanc-Brude, OP, et al Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1.J Biol Chem2000;275,35584-35591. [PubMed]
 
Allen, JT, Knight, RA, Bloor, CA, et al Enhanced insulin-like growth factor binding protein-related protein 2 (connective tissue growth factor) expression in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis.Am J Respir Cell Mol Biol1999;21,693-700. [PubMed]
 
Bonniaud, P, Margetts, PJ, Kolb, M, et al Adenoviral gene transfer of connective tissue growth factor in the lung induces transient fibrosis.Am J Respir Crit Care Med2003;168,770-778. [PubMed]
 
Bonniaud, P, Martin, G, Margetts, PJ, et al Connective tissue growth factor is crucial to inducing a profibrotic environment in “fibrosis-resistant” BALB/c mouse lungs.Am J Respir Cell Mol Biol2004;31,510-516. [PubMed]
 
Mageto, Y, Flaherty, K, Brown, K, et al Safety and tolerability of human monoclonal antibody fg-3019, anti-connective tissue growth factor, in patients with idiopathic pulmonary fibrosis [abstract].Chest2004;126,773S-773S
 
Kolodsick, JE, Toews, GB, Jakubzick, C, et al Protection from fluorescein isothiocyanate-induced fibrosis in IL-13–deficient, but not IL-4–deficient, mice results from impaired collagen synthesis by fibroblasts.J Immunol2004;172,4068-4076. [PubMed]
 
Fichtner-Feigl, S, Strober, W, Kawakami, K, et al IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis.Nat Med2006;12,99-106. [PubMed]
 
Liu, T, Jin, H, Ullenbruch, M, et al Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6.J Immunol2004;173,3425-3431. [PubMed]
 
Liu, T, Dhanasekaran, SM, Jin, H, et al FIZZ1 stimulation of myofibroblast differentiation.Am J Pathol2004;164,1315-1326. [PubMed]
 
Jakubzick, C, Choi, ES, Joshi, BH, et al Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4– and IL-13–responsive cells.J Immunol2003;171,2684-2693. [PubMed]
 
Bonner, JC Regulation of PDGF and its receptors in fibrotic diseases.Cytokine Growth Factor Rev2004;15,255-273. [PubMed]
 
Nagaoka, I, Trapnell, BC, Crystal, RG Upregulation of platelet-derived growth factor-A and -B gene expression in alveolar macrophages of individuals with idiopathic pulmonary fibrosis.J Clin Invest1990;85,2023-2027. [PubMed]
 
Daniels, CE, Wilkes, MC, Edens, M, et al Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis.J Clin Invest2004;114,1308-1316. [PubMed]
 
Aono, Y, Nishioka, Y, Inayama, M, et al Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice.Am J Respir Crit Care Med2005;171,1279-1285. [PubMed]
 
Gurujeyalakshmi, G, Giri, SN Molecular mechanisms of antifibrotic effect of interferon γ in bleomycin-mouse model of lung fibrosis: downregulation of TGF-β and procollagen I and III gene expression.Exp Lung Res1995;21,791-808. [PubMed]
 
Ziesche, R, Hofbauer, E, Wittmann, K, et al A preliminary study of long-term treatment with interferon γ-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med1999;341,1264-1269. [PubMed]
 
Raghu, G, Brown, KK, Bradford, WZ, et al A placebo-controlled trial of interferon γ-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med2004;350,125-133. [PubMed]
 
Antoniou, KM, Nicholson, AG, Dimadi, M, et al Long-term clinical effects of interferon γ-1b and colchicine in idiopathic pulmonary fibrosis.Eur Respir J2006;28,496-504. [PubMed]
 
Strieter, RM, Starko, KM, Enelow, RI, et al Effects of interferon-γ1b on biomarker expression in patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med2004;170,133-140. [PubMed]
 
Agostini, C, Gurrieri, C Chemokine/cytokine cocktail in idiopathic pulmonary fibrosis.Proc Am Thorac Soc2006;3,357-363. [PubMed]
 
Gharaee-Kermani, M, Denholm, EM, Phan, SH Costimulation of fibroblast collagen and transforming growth factor β1 gene expression by monocyte chemoattractant protein-1 via specific receptors.J Biol Chem1996;271,17779-17784. [PubMed]
 
Suga, M, Iyonaga, K, Ichiyasu, H, et al Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases.Eur Respir J1999;14,376-382. [PubMed]
 
Choi, ES, Jakubzick, C, Carpenter, KJ, et al Enhanced monocyte chemoattractant protein-3/CC chemokine ligand-7 in usual interstitial pneumonia.Am J Respir Crit Care Med2004;170,508-515. [PubMed]
 
Ziegenhagen, MW, Zabel, P, Zissel, G, et al Serum level of interleukin 8 is elevated in idiopathic pulmonary fibrosis and indicates disease activity.Am J Respir Crit Care Med1998;157,762-768. [PubMed]
 
Kodera, M, Hasegawa, M, Komura, K, et al Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis.Arthritis Rheum2005;52,2889-2896. [PubMed]
 
Inoue, T, Fujishima, S, Ikeda, E, et al CCL22 and CCL17 in rat radiation pneumonitis and in human idiopathic pulmonary fibrosis.Eur Respir J2004;24,49-56. [PubMed]
 
Burdick, MD, Murray, LA, Keane, MP, et al CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling.Am J Respir Crit Care Med2005;171,261-268. [PubMed]
 
Gharaee-Kermani, M, McCullumsmith, RE, Charo, IF, et al CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis.Cytokine2003;24,266-276. [PubMed]
 
Moore, BB, Murray, L, Das, A, et al The role of CCL12 in the recruitment of fibrocytes and lung fibrosis.Am J Respir Cell Mol Biol2006;35,175-181. [PubMed]
 
Morrisey, EE Wnt signaling and pulmonary fibrosis.Am J Pathol2003;162,1393-1397. [PubMed]
 
Kikuchi, A, Yamamoto, H, Kishida, S Multiplicity of the interactions of Wnt proteins and their receptors.Cell Signal2007;19,659-671. [PubMed]
 
Chilosi, M, Poletti, V, Zamo, A, et al Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis.Am J Pathol2003;162,1495-1502. [PubMed]
 
Zuo, F, Kaminski, N, Eugui, E, et al Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans.Proc Natl Acad Sci U S A2002;99,6292-6297. [PubMed]
 
Kubo, H, Nakayama, K, Yanai, M, et al Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest2005;128,1475-1482. [PubMed]
 
Chambers, RC, Laurent, GJ Coagulation cascade proteases and tissue fibrosis.Biochem Soc Trans2002;30,194-200. [PubMed]
 
Howell, DC, Goldsack, NR, Marshall, RP, et al Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis.Am J Pathol2001;159,1383-1395. [PubMed]
 
Howell, DC, Johns, RH, Lasky, JA, et al Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis.Am J Pathol2005;166,1353-1365. [PubMed]
 
Bogatkevich, GS, Gustilo, E, Oates, JC, et al Distinct PKC isoforms mediate cell survival and DNA synthesis in thrombin-induced myofibroblasts.Am J Physiol Lung Cell Mol Physiol2005;288,L190-L201. [PubMed]
 
Blanc-Brude, OP, Archer, F, Leoni, P, et al Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR1 activation.Exp Cell Res2005;304,16-27. [PubMed]
 
Jenkins, RG, Su, X, Su, G, et al Ligation of protease-activated receptor 1 enhances alpha (v) β6 integrin-dependent TGF-β activation and promotes acute lung injury.J Clin Invest2006;116,1606-1614. [PubMed]
 
Kaminski, N, Rosas, IO Gene expression profiling as a window into idiopathic pulmonary fibrosis pathogenesis: can we identify the right target genes?Proc Am Thorac Soc2006;3,339-344. [PubMed]
 
Riha, RL, Duhig, EE, Clarke, BE, et al Survival of patients with biopsy-proven usual interstitial pneumonia and nonspecific interstitial pneumonia.Eur Respir J2002;19,1114-1118. [PubMed]
 
Richeldi, L, Davies, HR, Ferrara, G, et al Corticosteroids for idiopathic pulmonary fibrosis.Cochrane Database Syst Rev2003;3,CD002880. [PubMed]
 
Collard, HR, Ryu, JH, Douglas, WW, et al Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis.Chest2004;125,2169-2174. [PubMed]
 
Raghu, G, Depaso, WJ, Cain, K, et al Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial.Am Rev Respir Disease1991;144,291-296
 
Davies, HR, Richeldi, L, Walters, EH Immunomodulatory agents for idiopathic pulmonary fibrosis.Cochrane Database Syst Rev2003;3,CD003134. [PubMed]
 
Raghu, G, Lasky, JA, Costabel, U, et al A randomized placebo controlled trial assessing the efficacy and safety of etanercept in patients with idiopathic pulmonary fibrosis (IPF) [abstract].Chest2005;128,496S-496S
 
Chen, J, Ziboh, V, Giri, SN Up-regulation of platelet-activating factor receptors in lung and alveolar macrophages in the bleomycin-hamster model of pulmonary fibrosis.J Pharmacol Exp Ther1997;280,1219-1227. [PubMed]
 
Kolb, M, Margetts, PJ, Sime, PJ, et al Proteoglycans decorin and biglycan differentially modulate TGF-β–mediated fibrotic responses in the lung.Am J Physiol Lung Cell Mol Physiol2001;280,L1327-L1334. [PubMed]
 
Azuma, A, Nukiwa, T, Tsuboi, E, et al Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med2005;171,1040-1047. [PubMed]
 
Nadrous, HF, Ryu, JH, Douglas, WW, et al Impact of angiotensin-converting enzyme inhibitors and statins on survival in idiopathic pulmonary fibrosis.Chest2004;126,438-446. [PubMed]
 
Failla, M, Genovese, T, Mazzon, E, et al Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury.Respir Res2006;7,137. [PubMed]
 
Hodges, RJ, Jenkins, RG, Wheeler-Jones, CP, et al Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E(2) production.Am J Pathol2004;165,1663-1676. [PubMed]
 
Stratton, R, Shiwen, X, Martini, G, et al Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients.J Clin Invest2001;108,241-250. [PubMed]
 
Simler, NR, Howell, DC, Marshall, RP, et al The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats.Eur Respir J2002;19,1124-1127. [PubMed]
 
Raghu G, Brown K, Bradford W, et al. Phase 3, randomized, double-blind, placebo-controlled trial of interferon gamma-1b (IFN-g1b) in patients with idiopathic pulmonary fibrosis (IPF) [abstract]. American Thoracic Society 99th International Conference 2003; A091.
 
Brewer, GJ, Ullenbruch, MR, Dick, R, et al Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice.J Lab Clin Med2003;141,210-216. [PubMed]
 
Demedts, M, Behr, J, Buhl, R, et al High-dose acetylcysteine in idiopathic pulmonary fibrosis.New Engl J Med2005;353,2229-2242. [PubMed]
 
Gunther, A, Lubke, N, Ermert, M, et al Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits.Am J Respir Crit Care Med2003;168,1358-1365. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Origins of myofibroblasts in IPF. Myofibroblasts, the key effector cell type in IPF, are thought to arise from the following: (1) proliferation and differentiation of resident fibroblasts; (2) epithelial-mesenchymal transition; or (3) recruitment of circulating fibrocytes. Various cytokines, growth factors, and signaling pathways are able to mediate these events (black arrows). A number of potential therapeutic strategies (shown in red) are under development (see text for more details).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. An Overview of Possible Therapeutic Targets in IPF and Current Clinical Trials*
Table Graphic Jump Location
Table 1A. Continued
* 

For more information on clinical trials in IPF, visit http://www.clinicaltrials.gov and http://www.actr.org.au. CAPACITY = Clinical Studies Assessing Perfenidone in IPF: Research of Efficacy and Safety Outcomes; BUILD = Bosentan Use in Interstitial Lung Disease; IFIGENIA = Idiopathic Pulmonary Fibrosis International Group Exploring N-acetylcysteine Annual.

References

. American Thoracic Society. (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement; American Thoracic Society (ATS), and the European Respiratory Society (ERS).Am J Respir Crit Care Med161(2 pt 1),646-664
 
American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias; this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.Am J Respir Crit Care Med2002;165,277-304. [PubMed]
 
Strieter, RM Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel.Chest2005;128(5 suppl 1),526S-532S
 
Raghu, G Idiopathic pulmonary fibrosis: treatment options in pursuit of evidence-based approaches.Eur Respir J2006;28,463-465. [PubMed] [CrossRef]
 
Ask, K, Martin, GE, Kolb, M, et al Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls.Proc Am Thorac Soc2006;3,389-393. [PubMed]
 
Sime, PJ, Xing, Z, Graham, FL, et al Adenovector-mediated gene transfer of active transforming growth factor-β1 induces prolonged severe fibrosis in rat lung.J Clin Invest1997;100,768-776. [PubMed]
 
King, TE, Jr, Schwarz, MI, Brown, K, et al Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.Am J Respir Crit Care Med2001;164,1025-1032. [PubMed]
 
Cool, CD, Groshong, SD, Rai, PR, et al Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum.Am J Respir Crit Care Med2006;174,654-658. [PubMed]
 
Phan, SH The myofibroblast in pulmonary fibrosis.Chest2002;122(6 suppl),286S-289S
 
Zhang, K, Rekhter, MD, Gordon, D, et al Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis: a combined immunohistochemical andin situhybridization study.Am J Pathol1994;145,114-125. [PubMed]
 
Grunert, S, Jechlinger, M, Beug, H Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis.Nat Rev Mol Cell Biol2003;4,657-665. [PubMed]
 
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 Pathol2005;166,1321-1332. [PubMed]
 
Kim, KK, Kugler, MC, Wolters, PJ, et al Alveolar epithelial cell mesenchymal transition developsin vivoduring pulmonary fibrosis and is regulated by the extracellular matrix.Proc Natl Acad Sci U S A2006;103,13180-13185. [PubMed]
 
Lama, VN, Phan, SH The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond.Proc Am Thorac Soc2006;3,373-376. [PubMed]
 
Bucala, R, Spiegel, LA, Chesney, J, et al Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.Mol Med1994;1,71-81. [PubMed]
 
Moore, BB, Kolodsick, JE, Thannickal, VJ, et al CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.Am J Pathol2005;166,675-684. [PubMed]
 
Phillips, RJ, Burdick, MD, Hong, K, et al Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.J Clin Invest2004;114,438-446. [PubMed]
 
Bhatt, N, Baran, CP, Allen, J, et al Promising pharmacologic innovations in treating pulmonary fibrosis.Curr Opin Pharmacol2006;6,284-292. [PubMed]
 
Walter, N, Collard, HR, King, TE, Jr Current perspectives on the treatment of idiopathic pulmonary fibrosis.Proc Am Thorac Soc2006;3,330-338. [PubMed]
 
Antoniou KM, Pataka A, Bouros D, et al. Pathogenetic pathways and novel pharmacotherapeutic targets in idiopathic pulmonary fibrosis. Pulm Pharmacol Ther 2007 (in press). Available at: http://sciencedirect.com/science. Accessed June 1, 2007.
 
Munger, JS, Huang, X, Kawakatsu, H, et al The integrin alpha v beta 6 binds and activates latent TGF β 1: a mechanism for regulating pulmonary inflammation and fibrosis.Cell1999;96,319-328. [PubMed]
 
Bonniaud, P, Margetts, PJ, Kolb, M, et al Progressive transforming growth factor β1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor.Am J Respir Crit Care Med2005;171,889-898. [PubMed]
 
Leask, A, Abraham, DJ The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology.Biochem Cell Biol2003;81,355-363. [PubMed]
 
Chambers, RC, Leoni, P, Blanc-Brude, OP, et al Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1.J Biol Chem2000;275,35584-35591. [PubMed]
 
Allen, JT, Knight, RA, Bloor, CA, et al Enhanced insulin-like growth factor binding protein-related protein 2 (connective tissue growth factor) expression in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis.Am J Respir Cell Mol Biol1999;21,693-700. [PubMed]
 
Bonniaud, P, Margetts, PJ, Kolb, M, et al Adenoviral gene transfer of connective tissue growth factor in the lung induces transient fibrosis.Am J Respir Crit Care Med2003;168,770-778. [PubMed]
 
Bonniaud, P, Martin, G, Margetts, PJ, et al Connective tissue growth factor is crucial to inducing a profibrotic environment in “fibrosis-resistant” BALB/c mouse lungs.Am J Respir Cell Mol Biol2004;31,510-516. [PubMed]
 
Mageto, Y, Flaherty, K, Brown, K, et al Safety and tolerability of human monoclonal antibody fg-3019, anti-connective tissue growth factor, in patients with idiopathic pulmonary fibrosis [abstract].Chest2004;126,773S-773S
 
Kolodsick, JE, Toews, GB, Jakubzick, C, et al Protection from fluorescein isothiocyanate-induced fibrosis in IL-13–deficient, but not IL-4–deficient, mice results from impaired collagen synthesis by fibroblasts.J Immunol2004;172,4068-4076. [PubMed]
 
Fichtner-Feigl, S, Strober, W, Kawakami, K, et al IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis.Nat Med2006;12,99-106. [PubMed]
 
Liu, T, Jin, H, Ullenbruch, M, et al Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6.J Immunol2004;173,3425-3431. [PubMed]
 
Liu, T, Dhanasekaran, SM, Jin, H, et al FIZZ1 stimulation of myofibroblast differentiation.Am J Pathol2004;164,1315-1326. [PubMed]
 
Jakubzick, C, Choi, ES, Joshi, BH, et al Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4– and IL-13–responsive cells.J Immunol2003;171,2684-2693. [PubMed]
 
Bonner, JC Regulation of PDGF and its receptors in fibrotic diseases.Cytokine Growth Factor Rev2004;15,255-273. [PubMed]
 
Nagaoka, I, Trapnell, BC, Crystal, RG Upregulation of platelet-derived growth factor-A and -B gene expression in alveolar macrophages of individuals with idiopathic pulmonary fibrosis.J Clin Invest1990;85,2023-2027. [PubMed]
 
Daniels, CE, Wilkes, MC, Edens, M, et al Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis.J Clin Invest2004;114,1308-1316. [PubMed]
 
Aono, Y, Nishioka, Y, Inayama, M, et al Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice.Am J Respir Crit Care Med2005;171,1279-1285. [PubMed]
 
Gurujeyalakshmi, G, Giri, SN Molecular mechanisms of antifibrotic effect of interferon γ in bleomycin-mouse model of lung fibrosis: downregulation of TGF-β and procollagen I and III gene expression.Exp Lung Res1995;21,791-808. [PubMed]
 
Ziesche, R, Hofbauer, E, Wittmann, K, et al A preliminary study of long-term treatment with interferon γ-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med1999;341,1264-1269. [PubMed]
 
Raghu, G, Brown, KK, Bradford, WZ, et al A placebo-controlled trial of interferon γ-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med2004;350,125-133. [PubMed]
 
Antoniou, KM, Nicholson, AG, Dimadi, M, et al Long-term clinical effects of interferon γ-1b and colchicine in idiopathic pulmonary fibrosis.Eur Respir J2006;28,496-504. [PubMed]
 
Strieter, RM, Starko, KM, Enelow, RI, et al Effects of interferon-γ1b on biomarker expression in patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med2004;170,133-140. [PubMed]
 
Agostini, C, Gurrieri, C Chemokine/cytokine cocktail in idiopathic pulmonary fibrosis.Proc Am Thorac Soc2006;3,357-363. [PubMed]
 
Gharaee-Kermani, M, Denholm, EM, Phan, SH Costimulation of fibroblast collagen and transforming growth factor β1 gene expression by monocyte chemoattractant protein-1 via specific receptors.J Biol Chem1996;271,17779-17784. [PubMed]
 
Suga, M, Iyonaga, K, Ichiyasu, H, et al Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases.Eur Respir J1999;14,376-382. [PubMed]
 
Choi, ES, Jakubzick, C, Carpenter, KJ, et al Enhanced monocyte chemoattractant protein-3/CC chemokine ligand-7 in usual interstitial pneumonia.Am J Respir Crit Care Med2004;170,508-515. [PubMed]
 
Ziegenhagen, MW, Zabel, P, Zissel, G, et al Serum level of interleukin 8 is elevated in idiopathic pulmonary fibrosis and indicates disease activity.Am J Respir Crit Care Med1998;157,762-768. [PubMed]
 
Kodera, M, Hasegawa, M, Komura, K, et al Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis.Arthritis Rheum2005;52,2889-2896. [PubMed]
 
Inoue, T, Fujishima, S, Ikeda, E, et al CCL22 and CCL17 in rat radiation pneumonitis and in human idiopathic pulmonary fibrosis.Eur Respir J2004;24,49-56. [PubMed]
 
Burdick, MD, Murray, LA, Keane, MP, et al CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling.Am J Respir Crit Care Med2005;171,261-268. [PubMed]
 
Gharaee-Kermani, M, McCullumsmith, RE, Charo, IF, et al CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis.Cytokine2003;24,266-276. [PubMed]
 
Moore, BB, Murray, L, Das, A, et al The role of CCL12 in the recruitment of fibrocytes and lung fibrosis.Am J Respir Cell Mol Biol2006;35,175-181. [PubMed]
 
Morrisey, EE Wnt signaling and pulmonary fibrosis.Am J Pathol2003;162,1393-1397. [PubMed]
 
Kikuchi, A, Yamamoto, H, Kishida, S Multiplicity of the interactions of Wnt proteins and their receptors.Cell Signal2007;19,659-671. [PubMed]
 
Chilosi, M, Poletti, V, Zamo, A, et al Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis.Am J Pathol2003;162,1495-1502. [PubMed]
 
Zuo, F, Kaminski, N, Eugui, E, et al Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans.Proc Natl Acad Sci U S A2002;99,6292-6297. [PubMed]
 
Kubo, H, Nakayama, K, Yanai, M, et al Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest2005;128,1475-1482. [PubMed]
 
Chambers, RC, Laurent, GJ Coagulation cascade proteases and tissue fibrosis.Biochem Soc Trans2002;30,194-200. [PubMed]
 
Howell, DC, Goldsack, NR, Marshall, RP, et al Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis.Am J Pathol2001;159,1383-1395. [PubMed]
 
Howell, DC, Johns, RH, Lasky, JA, et al Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis.Am J Pathol2005;166,1353-1365. [PubMed]
 
Bogatkevich, GS, Gustilo, E, Oates, JC, et al Distinct PKC isoforms mediate cell survival and DNA synthesis in thrombin-induced myofibroblasts.Am J Physiol Lung Cell Mol Physiol2005;288,L190-L201. [PubMed]
 
Blanc-Brude, OP, Archer, F, Leoni, P, et al Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR1 activation.Exp Cell Res2005;304,16-27. [PubMed]
 
Jenkins, RG, Su, X, Su, G, et al Ligation of protease-activated receptor 1 enhances alpha (v) β6 integrin-dependent TGF-β activation and promotes acute lung injury.J Clin Invest2006;116,1606-1614. [PubMed]
 
Kaminski, N, Rosas, IO Gene expression profiling as a window into idiopathic pulmonary fibrosis pathogenesis: can we identify the right target genes?Proc Am Thorac Soc2006;3,339-344. [PubMed]
 
Riha, RL, Duhig, EE, Clarke, BE, et al Survival of patients with biopsy-proven usual interstitial pneumonia and nonspecific interstitial pneumonia.Eur Respir J2002;19,1114-1118. [PubMed]
 
Richeldi, L, Davies, HR, Ferrara, G, et al Corticosteroids for idiopathic pulmonary fibrosis.Cochrane Database Syst Rev2003;3,CD002880. [PubMed]
 
Collard, HR, Ryu, JH, Douglas, WW, et al Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis.Chest2004;125,2169-2174. [PubMed]
 
Raghu, G, Depaso, WJ, Cain, K, et al Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial.Am Rev Respir Disease1991;144,291-296
 
Davies, HR, Richeldi, L, Walters, EH Immunomodulatory agents for idiopathic pulmonary fibrosis.Cochrane Database Syst Rev2003;3,CD003134. [PubMed]
 
Raghu, G, Lasky, JA, Costabel, U, et al A randomized placebo controlled trial assessing the efficacy and safety of etanercept in patients with idiopathic pulmonary fibrosis (IPF) [abstract].Chest2005;128,496S-496S
 
Chen, J, Ziboh, V, Giri, SN Up-regulation of platelet-activating factor receptors in lung and alveolar macrophages in the bleomycin-hamster model of pulmonary fibrosis.J Pharmacol Exp Ther1997;280,1219-1227. [PubMed]
 
Kolb, M, Margetts, PJ, Sime, PJ, et al Proteoglycans decorin and biglycan differentially modulate TGF-β–mediated fibrotic responses in the lung.Am J Physiol Lung Cell Mol Physiol2001;280,L1327-L1334. [PubMed]
 
Azuma, A, Nukiwa, T, Tsuboi, E, et al Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med2005;171,1040-1047. [PubMed]
 
Nadrous, HF, Ryu, JH, Douglas, WW, et al Impact of angiotensin-converting enzyme inhibitors and statins on survival in idiopathic pulmonary fibrosis.Chest2004;126,438-446. [PubMed]
 
Failla, M, Genovese, T, Mazzon, E, et al Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury.Respir Res2006;7,137. [PubMed]
 
Hodges, RJ, Jenkins, RG, Wheeler-Jones, CP, et al Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E(2) production.Am J Pathol2004;165,1663-1676. [PubMed]
 
Stratton, R, Shiwen, X, Martini, G, et al Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients.J Clin Invest2001;108,241-250. [PubMed]
 
Simler, NR, Howell, DC, Marshall, RP, et al The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats.Eur Respir J2002;19,1124-1127. [PubMed]
 
Raghu G, Brown K, Bradford W, et al. Phase 3, randomized, double-blind, placebo-controlled trial of interferon gamma-1b (IFN-g1b) in patients with idiopathic pulmonary fibrosis (IPF) [abstract]. American Thoracic Society 99th International Conference 2003; A091.
 
Brewer, GJ, Ullenbruch, MR, Dick, R, et al Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice.J Lab Clin Med2003;141,210-216. [PubMed]
 
Demedts, M, Behr, J, Buhl, R, et al High-dose acetylcysteine in idiopathic pulmonary fibrosis.New Engl J Med2005;353,2229-2242. [PubMed]
 
Gunther, A, Lubke, N, Ermert, M, et al Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits.Am J Respir Crit Care Med2003;168,1358-1365. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543