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Department of Clinical and Experimental Medicine, Clinical Immunology and Hematology Branches, Padua University School of Medicine, Padua, Italy
Correspondence and requests for reprints should be addressed to Carlo Agostini, M.D., Dipartimento di Medicina Clinica e Sperimentale, Università di Padova, Immunologia Clinica and Ematologia, Via Giustiniani 2, 35128 Padova, Italy. E-mail: carlo.agostini{at}unipd.it
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing lung disease of unknown etiology and with an unfavorable outcome, leading ultimately to death due to respiratory failure. To date, no treatment strategies have been effective in modifying the natural course of IPF and its fatal outcome. The aberrant parenchymal remodeling is characterized by the expansion of fibroblasts/myofibroblasts, which form characteristic subepithelial foci, and by the abnormal deposition of extracellular matrix in the lung parenchyma. Although the pathophysiology underlying this disease has not yet been fully elucidated, animal models of pulmonary fibrosis have provided contributions in dissecting the molecular basis of this disease, focusing on the role of cytokines and chemokines as important pathogenetic mediators of lung fibrosis. Starting with the data obtained from animal models, this article provides a comment on a number of findings that suggest the possible role of the chemokine/cytokine system in the pathogenesis of IPF.
Key Words: idiopathic pulmonary fibrosis • cytokine • chemokine • bleomycin
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease of unknown etiology, characterized by progressive parenchymal fibrosis and ventilatory restriction. Conventional treatment of IPF by immunosuppressive therapy (corticosteroids, azathioprine, cyclophosphamide) has been disappointing so far and the prognosis for this disease remains poor. The median survival time for patients with IPF is less than 3 yr and lung transplantation represents the only option for those patients who are refractory to medical therapy. For this reason one of the major goals of IPF research is to identify potential target molecules for therapeutic intervention that could allow effective treatment of this fatal disease.
The pathogenesis of IPF is complex and poorly understood. For a long time it has been assumed that IPF represents a disease induced by a persistent antigenic stimulation that favors an unsettled chronic inflammation, which in turn triggers the fibrotic response. However, more recent data suggest that inflammation does not play a major role in inducing the initiation of the disease. On the basis of a number of data it has been proposed that IPF is an epithelial/fibroblastic disorder. According to this hypothesis epithelial injury and activation rather than alveolitis represent the key factor in the pathogenesis of IPF. The importance of alveolar epithelial cell and myofibroblast cross-talk in the pathogenesis of the disease has been confirmed in animal models of lung fibrosis, although it should be anticipated that the majority of data obtained in animals suggest that the aberrant healing response of pulmonary fibrosis is initiated and keenly regulated by molecules produced during the inflammatory response (see Figure 1 and Table 1).
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ANIMAL MODELS OF LUNG FIBROSIS
BLM, which unlike other cytotoxic drugs does not induce major myelosuppression or immunosuppression, does exhibit dose-dependent pulmonary toxicity (1). This well-known side effect has turned out to be useful in generating experimental models of pulmonary fibrosis in animals (2). The BLM model produces biochemical and functional features that closely resemble those found in human pulmonary fibrosis: alveolar epithelial cell damage, recruitment of inflammatory cells releasing mediators of inflammation, and abnormal fibroblast activation and proliferation with consequent extracellular matrix deposition in the interstitium and alveolar spaces, which result in a drastic reduction of lung volume and compliance (2). Although several studies have pointed out the presence of important differences between the late chronic stages of the animal pulmonary fibrosis and features of the human disease (3), the BLM model represents an invaluable tool with which to test in vivo molecular players involved in the pathogenesis of lung fibrosis. Moreover, mouse genetic manipulation through the knockout/transgenic approach has been instrumental in demonstrating the involvement of specific genes in lung diseases characterized by fibrosis.
In taking advantage of the BLM model, it has been shown that the chemokine/cytokine network is capable of modulating the different phases of lung fibrosis pathogenesis, namely inflammation and fibrogenesis (4). Among the several cytokines and chemokines that have been implicated in the pathogenesis of lung fibrosis, particular relevance has been given to interleukin-1 (IL-1), tumor necrosis factor-
(TNF-), members of the CXC family such as IL-8 (IL-8/CXCL8), epithelial neutrophil-activating protein-78 (ENA-78/CXCL5), monokine induced by IFN-
(MIG/CXCL9), IFN-–inducible protein (IP-10/CXCL10), IFN-inducible T-cell chemoattractant (I-TAC/CXCL11). However, there are data indicating the relative contribution in lung fibrosis of members of the CC chemokine family, such as monocyte chemotactic protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1 (MIP-1/CCL3), thymus and activation–regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22), whereas other cytokines have been involved in tissue repair and fibrosis, including transforming growth factor-ß (TGF-ß) and platelet-derived growth factor (PDGF). All these molecules are individually discussed in the following sections.
IL-1
IL-1 and IL-1ß are widely expressed cytokines known to exert potent inflammatory properties (5). Early studies reported the expression of these cytokines in alveolar macrophages from the lungs of patients with IPF (6, 7). Both these molecules are able to induce a profibrotic phenotype through induction of the secretion of PDGF, of fibroblast proliferation, and of procollagen type I and type III synthesis (8, 9).
Studies on animal models have confirmed the role of IL-1ß in pulmonary tissue injury and repair. In a rodent in vivo lung injury model, transient overexpression of IL-1ß in lung epithelial cells causes acute inflammation and tissue destruction, followed by production of fibrogenic cytokines, such as TGF-ß, and progressive interstitial fibrosis (10). As shown, IL-1ß also exerts its profibrotic effects by inducing the expression in lung fibroblasts of osteopontin, a multifunctional matrix cellular protein up-regulated in IPF as well as in BLM-induced fibrosis (11). Inhibition of IL-1ß in animal models of fibrosis results in milder disease (12), in theory suggesting the rationale of inhibiting IL-1 in IPF. From a clinical point of view, in clinical trials antagonism of IL-1 (anakinra) has proven effective in slowing progression of autoimmune disorders, including rheumatoid arthritis, in which the drug is able to inhibit synovial fibrosis (13). Despite the in vivo antifibrotic effect of anakinra and the expression of IL-1 in pulmonary fibrotic areas, it is difficult to anticipate the risk:benefit ratio of anti–IL-1 treatment in IPF. It is sufficient to mention that in the rheumatoid arthritis group treated with anti–IL-1 biologic agents interstitial lung disease that was accompanied by pulmonary fibrosis was observed in one patient (13).
TNF-
TNF- has pleiotropic effects, most of which stimulate an inflammatory response by acting on mononuclear cells, neutrophils, and endothelial cells. TNF- is produced by activated macrophages and lymphocytes, epithelial cells, and endothelial cells. This proinflammatory cytokine has a central role in the stimulation of cell–cell adhesion and transendothelial migration as well as in the early events leading to the cytokine and chemokine production cascade (14). It directly or indirectly stimulates the production of several factors, such as TGF-ß, IL-1, IL-6, CXCL8, CCL2, PDGF, and granulocyte-macrophage colony–stimulating factor. TNF- triggers fibroblast proliferation and their ability to degrade the extracellular matrix.
A large body of studies on IPF has demonstrated that this cytokine is present in areas of lung fibrosis. TNF-–transgenic mice, in which transcription of this cytokine is under the control of a alveolar-specific promoter (surfactant protein-C), develop a T-cell–mediated alveolitis and subsequent fibrosis (15). In mouse models of lung injury and fibrosis, such as BLM- and silica-dependent damage, TNF- levels have been shown to be markedly increased; cytokine levels parallel those of TGF-ß and procollagen types I and III (14), and TNF- knockout mice fail to develop fibrosis after treatment with BLM (16). Finally, anti–TNF- antibodies are effective in reducing the production of TGF-ß, IL-5, and lung inflammation, providing the rationale for the experimental use of agents blocking TNF- for the therapy of IPF (see below).
In rat models, overexpression of TNF- in the lung induces inflammation, fibrosis, and secretion of TGF-ß. However, studies in mice have been contradictory regarding the direct fibrogenic potential of TNF-, as this cytokine has been shown to exert proinflammatory and profibrotic actions as well as to cause pulmonary emphysema and hypertension, when overexpressed in the lung under the control of the surfactant protein-C promoter (15, 17). Moreover, to add further complexity to the picture, others have demonstrated that TNF- may protect against BLM-induced lung inflammation (18). One study reexamined the phenotype of transgenic mice overexpressing TNF- under the control of the surfactant protein-C promoter and showed that structural alterations in the lungs are characterized by loss of alveolar spaces and emphysema as well as inflammation and fibrosis (19), confirming the dual role of this molecule.
In patients with IPF, TNF- is abundantly expressed in fibrotic lungs (6) and genetic polymorphisms have been linked to its expression (20). However, although the evidence suggesting that this proinflammatory cytokine is involved in the pathogenesis of diseases characterized by lung fibrosis, from the clinical standpoint efforts attempting to inhibit TNF- effects in patients with IPF have so far met with little success (21, 22).
CC CHEMOKINES AND THEIR RECEPTORS
MCP-1/CCL2 and MIP-1/CCL3 are proinflammatory chemokines responsible for monocyte recruitment and are secreted by a variety of cell types such as lymphocytes, macrophages, fibroblasts, and endothelial cells. CCL2 and CCL3 are significantly up-regulated both in bronchoalveolar lavage fluids of patients with IPF and in BLM-induced lung fibrosis (23, 24). Activation of discoidin domain receptor-1, a receptor tyrosine kinase activated by collagen, induces the production of these chemokines, among others, in bronchoalveolar lavage monocytes of patients with IPF (25). Data obtained in knockout/transgenic mice have confirmed the role of these chemokines in driving lung fibrosis. MCP-1 receptor CC chemokine receptor-2 (CCR2)– deficient mice are protected from BLM-induced pulmonary fibrosis (26), exhibiting impaired fibrogenic cytokine expression and fibroblast responsiveness to TGF-ß (27). More recently, other groups reported that CCR2 deficiency is accompanied by decreased macrophage recruitment to the lung and reduced production by these cells of the extracellular matrix–remodeling enzymes, including matrix metalloprotease (MMP)-2 and MMP-9, in a BLM-induced mouse model of lung fibrosis (28). Overexpression of a CCL2 dominant negative inhibitor seems to result in consistent reduction in the degree of BLM-induced fibrosis, which is particularly confined to the later stages of the disease (29). Taken together, these data suggest that these chemokines could play a role in IPF pathogenesis by recruiting mononuclear cells able to influence the epithelial–myofibroblast axis.
The molecular pathway leading to the pathologic overexpression of CCL2 and CCL3 has begun to be unraveled. Specifically, IL-13 dysregulation could be important in regulating chemokine synthesis. Levels of IL-13 are markedly up-regulated in alveolar macrophages of patients with IPF and data on animal models have shown that IL-13 expression in the lung led to potent activation of extracellular signal-regulated kinases (ERKs) 1 and 2. ERK1 and ERK2, also called p44 and p42 mitogen-activated protein kinases (MAPKs), are members of the MAPK family of proteins found in all eukaryotes. It has been demonstrated that ERK1/2 may be activated by IL-13 in the lung in a STAT6 (signal transducer and activator of transcription factor-6)–independent manner (30). The MAPK/ERK pathway contributes to IL-13–induced remodeling and fibrogenesis and is required for optimal IL-13 stimulation of specific chemokines and proteases as well as the inhibition of specific antiproteases. In particular, ERK1/2 signaling in lung epithelia seems to be particularly crucial in alveolar remodeling; MIP-1/CCL-3, MIP-1ß/CCL-4, RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL-5, and MIP-2/CXCL-1 production; and MMP-2, MMP-9, MMP-12, and MMP-14 and cathepsin-B mRNA accumulation. This suggests the need for future investigation designed to identify ERK1/2 regulators that could be useful in the treatment of IL-13–induced disorders, including IPF.
Helper T type 2 (Th2) cells have been implicated in the development of lung fibrosis. In particular it is believed that the lung fibroproliferative response is associated with immune deviation toward a Th2 cytokine profile. A number of data indicate a strict relationship between Th2 cytokines, chemokines, and their receptors. It has been shown that two CC chemokines that are regulated by Th2 cytokines (CCL17 and CCL22) are associated with pulmonary fibrosis (31). These chemokines and their receptor, namely CCR4, have been found to be elevated in areas of fibrotic lung tissue as compared with normal pulmonary parenchyma. In particular, CCR4 was found to be expressed mostly by macrophages present in fibrotic areas. However, it has been shown that neutralization of CCL17 and CCL22 leads to a significant reduction of lung damage (31).
CXC CHEMOKINES
CXC chemokines are heparin-binding proteins, structurally characterized by a common CXC motif (32) and by the presence/absence of the ERL motif, which dictates their angiogenic activity (33). Members of the CXC chemokine family that contain the ERL motif and thus behave as angiogenic factors include IL-8/CXCL8 and ENA-78/CXCL5, whereas angiostatic members of this chemokine family, the expression of which is up-regulated by IFN-, are MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11 (33). CXCR2 is the receptor that mediates ERL+ CXC chemokine–dependent angiogenic activity, whereas CXCR3 mediates the activity of the angiostatic chemokines (34, 35).
Levels of IL-8/CXCL8 and ENA-78/CXCL5 have been demonstrated to be significantly elevated in patients with IPF, whereas IP-10/CXCL10 levels are significantly lower compared with control subjects (36, 37). Blockade of IL-8/CXCL8 or ENA-78/CXCL5 significantly inhibits the angiogenic activity in IPF samples. The imbalance of the local expression of these chemokines seems to be crucial in the promotion of aberrant angiogenesis in IPF. Animal model studies support this idea, showing that expression levels of the murine functional homolog of IL-8/CXCL8, macrophage inflammatory protein-2 (MIP-2), and of IP-10/CXCL10 are directly and inversely correlated, respectively, with the degree of lung damage on BLM administration and with the extent of neovascularization and fibrogenesis (38, 39). IP-10/CXCL10 seems to be able to attenuate fibroblast accumulation by limiting fibroblast migration, as demonstrated by the dramatically increased accumulation of fibroblasts in the lung after BLM exposure in IP-10/CXCL10–deficient mice (40).
More recently, the chemokine I-TAC/CXCL11 has been implicated in the IFN-–dependent negative regulation of fibrogenesis and angiogenesis. Exogenous administration of I-TAC/CXCL11 to BLM-treated mice greatly reduced lung damage, but without altering leukocyte populations; instead, it inhibited neoangiogenesis and vascular remodeling in treated lung mice (41). Other studies have shown that the angiostatic chemokine receptor CXCR3 (i.e., the receptor for MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11) plays a fundamental role in the process of BLM-induced lung fibrosis (42). BLM-challenged CXCR3 knockout mice die at a higher frequency compared with wild-type mice. Early IFN- production is reduced, as is the expression of ligand IP-10/CXCL10. Therefore, CXCR3 seems to be able to limit lung fibrosis in response to BLM by promoting endogenous production of IFN-. Along this line, a survey of bronchoalveolar lavage CD4+ T cells has shown an imbalance in CXCR3/CCR4 expression in favor of CCR4 and reduced levels of IP-10/CXCL10 in patients with IPF (43). Finally, another CXC chemokine, stromal cell–derived factor-1 (SDF-1/CXCL12), has been found to be essential for lung recruitment of circulating fibrocytes (fibroblast precursors expressing CD45, collagen I, and CXCR4), with the degree of accumulation of these cells in the lung parenchyma directly correlating with the maximal extent of collagen deposition (44).
In conclusion, aberrant vascular remodeling is a central hallmark of the development and progression of idiopathic pulmonary fibrosis, and a number of data indicate the importance of the balance between pro- and antiangiogenic CXC chemokines in the pathophysiologic alteration seen in IPF. As confirmation, data from a phase II trial of IFN--1b confirm the importance of interfering with vascular remodeling in IPF. Strieter and coworkers (45) have demonstrated variation in CXCL11 and CXCL5, but not in TGF-ß and connective tissue growth factor (CTGF), levels after IFN--1b treatment, suggesting that IFN-- 1b affects IPF progression by interfering with the angiogenesis pathway. If we consider that systemic treatment with CXCL11 reduces BLM-induced pulmonary fibrosis (41), the strategy of attenuating vascular remodeling via IFN-inducible CXC chemokines could in theory represent a novel therapeutic option for the treatment of IPF.
TGF-ß
TGF-ß is a multifaceted cytokine produced by several cell types and is involved in the modulation of a wide array of biological processes including cell growth and differentiation, ECM production, embryonic development, and wound healing (46). Of the three isoforms of TGF-ß (TGF-ß1, TGF-ß2, and TGF-ß3), TGF-ß1 plays a pivotal role in the regulation of lung fibrosis (47). TGF-ß1 gene expression and protein secretion are increased in BLM-induced fibrosis in mouse models (48) as well as in human IPF (49). Adenovirus- or IL-13–mediated overexpression of the active form of TGF-ß1 results in prolonged and severe lung fibrosis in animal models (50, 51) which is in turn inhibited by the blockade of this cytokine with neutralizing antibodies or soluble receptors, or by gene transfer of the TGF-ß inhibitor Smad7 (52, 53).
TGF-ß modulates lung fibrosis through recruitment and activation of monocytes and fibroblasts, induction of ECM, and stimulation of angiogenesis. As shown, IPF fibroblasts exhibit a profibrotic secretory phenotype, with a lower growth rate and increased spontaneous apoptosis (55, 56). Lung fibroblast proliferation would be an indirect effect of TGF-ß1 via induction of fibroblast growth factor-2 and consequent activation of the MAP kinase pathway (p38 MAPK and c-Jun N-terminal kinase) (57). Moreover, fibroblasts are induced by TGF-ß to differentiate into myofibroblasts, which represents the main source of ECM during pulmonary fibrogenesis. TGF-ß signaling modulates ECM production by promoting ECM gene transcription, including collagens I, III, IV, and V, fibronectin, and proteoglycans, and by suppressing the activity of matrix metalloproteinases, plasminogen activators, and elastases, which results in the inhibition of collagen degradation (58–60). The intracellular factor Smad3 has been demonstrated to be downstream of TGF-ß1 in studies on the targeted repression of this pathway in mice, which fail to develop pulmonary fibrosis when challenged with TGF-ß1 (61). Taken together these data suggest the need for clinical trials investigating the efficacy and safety of drugs able to neutralize TGF-ß in IPF. As an example, an important Smad-independent mediator of TGF-ß–driven fibroblast proliferation and ECM gene expression has been identified in the c-Abelson (c-Abl) tyrosine kinase. Inhibition of c-Abl kinase activity may be obtained with imatinib mesylate (Gleevec), and there are data from animal models indicating that Gleevec attenuates BLM-induced pulmonary fibrosis (62). These considerations have suggested the need for a phase II clinical trial on the safety and clinical effect of Gleevec in IPF.
PDGF
The PDGF family comprises disulfide-bonded homodimers or heterodimers of four possible subunits (PDGF-A, PDGF-B, PDGF-C, and PDGF-D) that exert their effects through binding to PDGF receptor (PDGFR- and PDGFR-ß) tyrosine kinases (63). PDGF is produced by a wide array of lung cell types, including macrophages, fibroblasts, and epithelial and endothelial cells, and its increased expression in human and murine bleomycin-induced pulmonary fibrosis has been demonstrated (64, 65). The role of PDGF in the pathogenesis of IPF is supported by several reports that place this molecule downstream of molecular pathways activated by profibrotic cytokines, including TGF-ß, TNF-, and IL-1ß (9, 10, 66, 67). Inhibition of PDGF receptor tyrosine kinase significantly attenuated the development of pulmonary fibrosis in a radiation-induced fibrosis mouse model (68).
NONIMMUNOCOMPETENT CELLS MAY REPRESENT A CELL SOURCE OF CYTOKINES AND CHEMOKINES REGULATING FIBROGENESIS
Because a large number of chemokines/cytokines can be demonstrated in the IPF lung, one could argue against the hypothesis that inflammatory cells do not play a role in the pathogenesis of IPF. Nonetheless, it should be noted that evidence indicates that the presence of inflammatory cells is not needed to explain the presence of chemokine/cytokines in a tissue. For instance, epithelial cells may per se represent a primary source of profibrotic cytokines and chemokines, because it is known that alveolar/bronchiolar epithelial cells may express a series of molecules that are involved in the pathogenesis of pulmonary fibrosis, including profibrogenic cytokine/chemokines (PDGF, TGF-ß, TNF-, CXCL8, and CCL26), antifibrogenic chemokines (CXCL10 and CXCL11), and chemokine receptors (CXCR1 and CXCR2).
Interestingly, we have shown that CXCR3B, the alternatively spliced variant of CXCR3A, is expressed by epithelium (69). This chemokine receptor is capable of recognizing CXCL9, CXCL10, and CXCL11 but does not induce calcium mobilization and chemotaxis on epithelial cells, while retaining the ability to undergo postligand internalization. Our data allow us to hypothesize that CXCR3B expression is involved in the maintenance of tissue homeostasis. Epithelial cells, including pulmonary epithelial cells, are continuously exposed to a wide variety of pathogens. They are able to maintain the tissue in a state of equilibrium with the normal microbial flora modulating inflammation. However, these cells are important players in the homeostatic trafficking of different cell subsets through the secretion of tissue-specific chemokines. Of note, it has been demonstrated that chemokine proteins can be directed to intracellular storage depots, suggesting that store secretion may provide the rapid initiation of chemokine-driven responses without the delay required to initiate transcription. On the other hand, leukocyte recruitment may be tightly regulated by the absorption of chemokines to avoid excessive inflammatory cell infiltration with subsequent damage of the adjacent, nondistressed cells.
Given that epithelial cells simultaneously express a chemokine receptor as well as its ligand (including CXCR3A and CXCR3B and ligands), it can be hypothesized that chemokines may activate an autocrine or juxtacellular loop in the epithelium of patients with IPF. For instance, we have shown that epithelial cells expressing CXCR3B do not mediate cell migration or calcium flux, while retaining the ability to induce cellular protein tyrosine phosphorylation. This supports the hypothesis that CXCR3B on epithelial cells is able to signal and, starting from this consideration, we are evaluating whether CXCR3A and CXCR3B intracellular signals have a positive or negative role in the dysregulation of epithelium/myofibroblast cross-talk in IPF.
CONCLUSIONS
IPF is a typically fatal form of interstitial lung disease. Immunosuppressive treatments are commonly offered for patients with IPF, but no regimen has been proven effective. More recent data indicate that biologic agents, including IFN-, able to modulate cytokine/chemokine interactions could have some beneficial effect on patients with IPF. On the basis of animal model data, important advances have been made in identifying molecules that are able to block or induce lung fibrosis, including chemokines, cytokines, and their receptors. Considering that a number of agonists/antagonists of chemokine receptors are in development by several pharmaceutical companies, future studies are imperative both in human and animal models to determine whether disrupting chemokine interactions with their receptors may be an effective approach for the therapy of pulmonary fibrosis.
FOOTNOTES
Supported by a PRIN grant (MIUR).
Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form January 19, 2006; accepted in final form March 13, 2006)
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