Published online before print October 25, 2007
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University of Maryland School of Medicine and Baltimore VA Medical Center, Baltimore, Maryland, USA
1 Correspondence: University of Maryland School of Medicine, 10 South Pine Street, MSTF 8-34, Baltimore, MD 21201, USA. E-mail: satamas{at}umaryland.edu
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Key Words: lung • collagen • inflammation
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The lack of effective therapies for pulmonary fibrosis is a reflection of the limited insight into its pathophysiological mechanisms. The mechanisms that drive the numeric expansion of fibroblasts and collagen accumulation in pulmonary fibrosis are not well understood. Numerous studies have focused on potential mechanisms, including various processes related to inflammation, epithelial-mesenchymal interactions, epithelial apoptosis, endothelial disturbances, and coagulation. These studies revealed that the mechanisms of pulmonary fibrosis are likely numerous, redundant, and controlled by various genetic and environmental factors. Overall, tissue fibrosis is often viewed as exaggerated wound healing.
As inflammation, with an influx of various cell types expressing cytokines, chemokines, and cell surface molecules, commonly precedes and accompanies fibrosis, initial research focused on the potential role of inflammatory mechanisms driving fibrosis. However, evidence suggests that not every inflammatory process leads to fibrosis and that fibrosis may occur independently of inflammation [1 3 4 5 ]. Moreover, anti-inflammatory or immunosuppressive therapy for patients with IPF has been uniformly ineffective. Nevertheless, mechanistic studies in animal models and in cell culture have suggested that components of the inflammatory process may facilitate or attenuate the development of fibrosis. Overall, it is possible that fibrosis is a direct consequence of inflammation (Fig. 1A ), that inflammation and fibrosis are causally nonconnected co-findings (Fig. 1B) , or that inflammation and fibrosis develop through relatively independent yet mutually interacting mechanisms (Fig. 1C) . This review argues that T lymphocytes, an important component cell type of inflammation, likely affect fibrosis through a set of diverse mechanisms, although they do not appear to be the main propelling force of severe pulmonary fibrosis such as that seen in patients with IPF or connective tissue disease-associated interstitial pneumonias.
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Figure 1. Possible interactions between inflammation and fibrosis, which may be a direct consequence of inflammation and thus, be driven by the mechanisms related to inflammation and its resolution (A), develop independently of fibrosis (B), or develop independently yet involve mutual interactions and cross-regulation between the inflammatory and fibrotic processes (C).
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Figure 2. Pulmonary T lymphocytes may regulate fibrosis in a variety of ways. (A) Profibrotic, antifibrotic, or bystander effects. Depending on their phenotypes, T lymphocytes may stimulate fibroblast proliferation and/or deposition of ECM or alternatively, inhibit these processes. T cells may also accumulate but have minimal, if any, effect on fibrosis. (B) Soluble or membrane-bound factors. T lymphocytes may regulate fibroblast proliferation, apoptosis, and ECM production by producing soluble factors as well as through cell surface interactions. (C) Direct or indirect regulation. Secreted or cell surface molecules produced by T lymphocytes may bind to corresponding receptors on fibroblasts and drive fibroblast proliferation and/or ECM production (direct regulation). Alternatively, T lymphocytes may regulate other cell types (macrophages, epithelial, or endothelial cell), which in turn, produce profibrotic or antifibrotic factors (indirect regulation). (D) Active or passive involvement. T lymphocytes may regulate fibrosis actively by producing profibrotic or antifibrotic factors and by regulating the effects of other cell types on fibroblasts. They may also be involved permissively by failing to regulate the effects of other cells, such as macrophages, on fibroblast activities.
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IPF
IPF is one of the most common forms of pulmonary fibrosis and is one of several diseases grouped under the broad heading of idiopathic interstitial pneumonia. Despite the name "idiopathic" (of unknown causes), IPF is a distinct and specific clinical entity with characteristic clinical, physiologic, radiographic, and pathologic features. The pathologic pattern of fibrosis in IPF is usual interstitial pneumonia (UIP), a pattern of interstitial collagen deposition characterized by temporal heterogeneity, honeycomb cysts, and fibroblastic foci [5
]. This pathologic pattern of UIP is distinctly different from the pathologic patterns seen in the other forms of idiopathic interstitial pneumonia.
Although recent works in IPF have de-emphasized the importance of inflammation, the presence of T lymphocytes within lung tissue [6 7 8 9 ] and bronchoalveolar lavage (BAL) [10 11 ] of patients with IPF has been observed consistently. T lymphocytes are present diffusely throughout the alveolar septae and interstitium, within focal perivascular aggregates, and within alveolar spaces. The location of the T cell accumulation is greatest in the areas of lung tissue with interstitial fibrosis and honeycomb change, and there are only a few T cells present in areas of relatively normal tissue [8 ]. These T lymphocytes are activated and antigen-experienced [9 12 ]. Neutrophils, macrophages, and B lymphocytes are also present, although to a lesser degree [6 7 8 ]. Despite the significant number of T lymphocytes consistently seen within lung tissue of IPF, the findings in BAL fluids from patients with IPF have been more variable, suggesting that BAL fluids may not accurately reflect the cellular abnormalities present within the lung tissue of patients with IPF [6 ].
In IPF lung tissue, most studies have shown that CD4+ and CD8+ T cells are present, with the suggestion that CD8+ cells usually represent the majority [6 7 8 9 13 ]. CD8+ T cells are often distributed diffusely throughout the lung interstitium, whereas CD4+ cells tend to be localized in lymphoid follicles [6 9 ]. In BAL fluids, the CD4/CD8 ratios are variable [10 ].
Connective tissue diseases
Pulmonary fibrosis often occurs in association with systemic connective tissue diseases, particularly scleroderma [4
12
], rheumatoid arthritis (RA) [14
], and polymyositis/dermatomyositis [15, 16]. A broad term such as connective tissue disease-associated interstitial pneumonia may be used in these cases. The pathologic pattern of lung fibrosis associated with the connective tissue diseases is most often nonspecific interstitial pneumonia, a pattern of fibrosis distinct from IPF, consisting of varying degrees of inflammation and fibrosis, temporal uniformity, absent honeycomb change, and absent fibroblast foci [5
].
Surgical lung biopsies from patients with connective tissue disease-associated interstitial pneumonia have demonstrated the presence of increased T lymphocytes within the lungs. The T cells are distributed diffusely throughout the lung interstitium and within focal lymphoid aggregates [4 12 ]. BAL fluid from patients with interstitial pneumonia associated with scleroderma [17 18 ], RA [14 ], and polymyositis/dermatomyositis [15, 16] have all shown accumulation of T cells or T cell subtypes. The data about CD4/CD8 ratios in the lungs and BAL fluids of patients with connective tissue disease-associated interstitial pneumonia have been variable, although CD8+ T cells may have a predominant, mechanistic role [17 18 ].
Other inflammatory pulmonary diseases
Other chronic inflammatory lung diseases that involve a significant T lymphocytic infiltration may be associated with pulmonary accumulation of excessive amounts of ECM. Such diseases include chronic hypersensitivity pneumonitis [19
], sarcoidosis [20
] and berylliosis [21
], radiation-induced lung disease [22
], and chronic GVHD [23
]. These diseases are characterized predominantly by chronic, often granulomatous, inflammation, although a mild-to-moderate degree of fibrosis may accompany the inflammation. Occasionally, severe fibrosis may develop in these patients, but this is much less common than in patients with connective tissue disease-associated interstitial pneumonias or IPF, where pulmonary fibrosis is invariably progressive and severe. Moreover, unlike IPF and connective tissue disease-associated interstitial pneumonias, pulmonary fibrosis in patients with inflammatory lung diseases appears to be a consequence of inflammation, likely following the pattern shown in Figure 1A
. Anti-inflammatory therapies in these patients are generally more effective in improving overall lung function.
Thus, there is a well-established consensus about the association of pulmonary fibrosis with T lymphocytic infiltration. An important weakness of these observational studies is that they do not necessarily imply a causal link between the two phenomena. Such an association may be indicative of T cell profibrotic action, inflammation unrelated to fibrosis, or an attempt to counteract developing fibrosis by recruiting antifibrotic T cells into the lung.
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Genetic lack of T cells
Several studies have suggested that T lymphocytes are not necessary for the development of pulmonary fibrosis in animal models. Mice with genetic defects manifesting in a total lack of T lymphocytes, such as athymic (nude) mice [27
] and SCID mice [28
], developed alveolitis and pulmonary fibrosis in response to bleomycin, similar to that in normal (wild-type) mice. Similarly, SCID mice or mice that lack functional T cells in a different genetic model (RAG knockout) were equal to wild-type mice with normal T cell repertoires in their sensitivity to pulmonary fibrosis induced by intratracheal instillation of a chemical termed FITC [29
].
Other studies in genetic models have suggested that the presence of T lymphocytes worsens pulmonary fibrosis. Administration of bleomycin in athymic mice caused decreased fibroblast proliferation and less ECM accumulation compared with wild-type mice [30 ]. In another genetic model, mice whose T cells lack CD28, a central costimulatory cell surface molecule that is necessary for full T cell activation, showed markedly attenuated pulmonary fibrosis following exposure to bleomycin [31 ]. It is important that transferring CD28-positive T cells from wild-type mice into these CD28-deficient animals restored the usual fibrotic response to bleomycin [31 ].
In contrast, one animal study has suggested that T lymphocytes may be protective against fibrosis [32 ]. Exposure of athymic and SCID mice to asbestos resulted in more fibrosis than in their wild-type counterparts. Reconstitution of these SCID mice with functional T lymphocytes reduced the excessive, fibrotic response to asbestos [32 ].
Systemic depletion of T cells
Separate studies have used an alternative approach consisting of acute T cell depletion with antibodies in wild-type animals, as opposed to a genetic lack of T cells. However, these studies also reported conflicting results. Systemic depletion of T lymphocytes in the bleomycin [33
] or FITC [29
] pulmonary fibrosis models failed to affect the extent or severity of lung damage. In contrast, different studies in the bleomycin model reported that depletion of T cells prevents collagen accumulation [34
] or diminishes pulmonary fibrosis and increases survival [35
].
The conflicting observations in genetic models may be explained by the known ability of these animals to adapt to their defects by "rewiring" the immune, inflammatory, and repair mechanisms in an environment-dependent manner. In the T cell depletion studies, the controversial observations may be explained by variability in the degree of T cell depletion achieved. It is also possible that the dose of bleomycin used to induce lung damage may be important, with a low but not high dose of bleomycin leading to T cell-dependent fibrosis [36 ]. Finally, the acute nature of the bleomycin model, although well established, may not accurately reflect the chronic processes, which occur in human pulmonary fibrosis.
Selective attraction of T cells
A limitation of the approaches discussed above is that T cells accumulate as part of complex inflammatory processes that may confound the specific contribution of T cells to fibrosis. Our group used an alternative approach, in which instead of depletion, T lymphocytes were selectively attracted to otherwise healthy [37
] or injured [38
] mouse lungs. This effect was achieved by overexpressing CCL18, a chemokine that is highly selective for T cells, but not other cell types. A prolonged perivascular and peribronchial infiltration of T lymphocytes occurred, and moderate collagen accumulation developed in association with these T cell infiltrates [37
]. A systemic depletion of T cells in this model prevented collagen accumulation, despite the continuous expression of CCL18, suggesting that T cells were indeed the driving force of fibrosis [37
].
To further investigate the role of T cells in this model, CCL18 overexpression was used in combination with bleomycin injury. We observed additive effects of CCL18 overexpression and bleomycin injury on accumulation of T cells; however, the amount of collagen was surprisingly less than in mice treated with bleomycin alone [38 ]. This observation suggests that the effect of T cells in the combined injury model may be partially protective. The effect of T cells may thus be profibrotic [37 ] or partially antifibrotic [38 ], depending on the presence of an inflammatory milieu.
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Several mechanisms can be envisioned for T cell-driven fibrosis. In fibrosis, fibroblasts may expand through excessive proliferation and/or attenuated apoptosis of resident fibroblasts, homing, and fibroblastic differentiation of bone marrow-derived fibrocytes and phenotypic transition of other cell types such as epithelium into fibroblasts. ECM accumulates as a result of accelerated production and slowed turnover of its components by fibroblasts as a result of numerous signals from cytokines, cell surface molecules, clotting factors, and the ECM itself. It is likely that cytokines and chemokines produced by T cells not only activate proliferation and collagen production directly in resident fibroblasts but also may contribute to homing of fibrocytes and fibroblastic transdifferentiation of other cell types. For example, CD4+ and especially CD8+ T cells are capable of producing CCL3 (MIP-1
) [40
], and this chemokine is involved in pulmonary recruitment of fibrocytes in association with development of pulmonary fibrosis in an animal model [41
]. The discussion below focuses on the overall mechanisms by which T cells of various phenotypes may drive pulmonary fibrosis.
CD4 and CD8 T cells: regulation by soluble and membrane-bound factors
Th cells (CD4+) specialize in production of soluble factors (cytokines) that may act profibrotically (IL-4, IL-13, TGF-β, oncostatin M) or antifibrotically (IFN-
, TNF-) [42
]. Cytotoxic (CD8+) T cells eliminate virus-infected and tumor cells through cytotoxic mechanisms, including membrane-bound and soluble molecules, which may also contribute to regulation of fibroblast activities. However, such functional specialization is not strict; CD8+ T cells may also serve as a significant source of cytokines, and CD4+ T cells may induce cell death. Two major pathways of T cell-mediated cytotoxicity are the perforin/granzyme pathway, which is predominant in CD8+ T cells, and the Fas-mediated pathway, which is active in all cytotoxic cells but particularly important for IFN--producing CD4+ T cells.
The binding of Fas ligand (FasL) to Fas commonly induces programmed cell death (apoptosis). However, evidence suggests that activation of the Fas/FasL pathway may have a profibrotic effect. In a genetically manipulated animal model, selective inactivation of Fas in T cells leads to a complex syndrome manifested by up-regulation of FasL on activated T cells, leukocyte infiltration in the lungs, and pulmonary fibrosis [43 ]. Mediators of another apoptotic pathway, perforin and granzyme B, were up-regulated in infiltrating lymphocytes in lung tissue from IPF patients, compared with normal controls, and that the degree of inflammation and fibrosis was decreased following bleomycin instillation in perforin knockout mice [44 ].
Another cell membrane-associated mechanism involves the CD40-CD40 ligand (CD40L) activation pathway. Activated T lymphocytes express CD40L on their cell surface that binds to CD40, expressed on other cell types including fibroblasts. Activated T cells that express CD40L may stimulate proliferation of pulmonary fibroblasts and thus, contribute to fibrosis [45 46 ].
These observations suggest that in addition to regulation of fibrosis through soluble factors (cytokines), T lymphocytes may use membrane-dependent mechanisms as well. Although the details of these mechanisms are yet to be investigated fully, these data suggest that the relative proportion of CD4+ and CD8+, as well as quiescent and activated T cells accumulating in the lungs, may define what specific, profibrotic mechanisms become predominantly involved in pulmonary fibrosis.
In several studies, increased numbers of CD8+ T cells were associated with impairments in measures of pulmonary function [7 17 18 ]. Pulmonary function testing (PFT) is often used in clinical medicine to measure lung volumes and to assess the gas exchange capability of the lungs. Indices, which measure lung volumes and the mechanical properties of the lungs, include the forced expiratory volume in 1 s (FEV1), the forced vital capacity (FVC), and the total lung capacity. The parameter used to assess the gas exchange properties of the lungs during pulmonary function testing is termed the diffusing capacity of the lung for carbon monoxide (DLCO), in which the ability of the lung to transfer a small amount of CO from the alveolar space into the blood is assessed. This DLCO parameter generally correlates well with the ability of the patient to maintain adequate oxygenation in the presence of lung disease. Improvements or deteriorations in lung volumes or the DLCO usually correlate well with the overall respiratory status of the patient.
Several studies in IPF have compared PFT parameters and clinical outcomes with specific phenotypes of pulmonary T lymphocytes, suggesting more severe disease with higher numbers of CD8 cells. In IPF patients with surgical lung biopsies, increased numbers of CD8+ T cells in lung tissue were associated with worse PFT parameters, increased shortness of breath, and worse gas exchange [7 ]. In agreement with these data, IPF patients with higher CD4/CD8 ratios in BAL fluid had a better response clinically to anti-inflammatory therapy than those with lower CD4/CD8 ratios [10 ]. In the latter study, having the ratio CD4+/CD8+ >1 was associated with higher BAL lymphocytosis, dramatically lower numbers of neutrophils, tendency to higher FEV1 and FVC values, and significantly higher DLCO values [10 ]. The CD4+/CD8+ ratio was also decreased in the interstitium and BAL of patients with scleroderma lung disease [17 18 ] and dermatomyositis/polymyositis [15, 16].
In sarcoidosis [20 ], beryliosis [21 ], RA [14 ], and hypersensitivity pneumonitis [19 ], CD4+ T cells are predominant in the lungs of patients with pulmonary inflammation and fibrosis. These findings are consistent with the generally accepted notion of a better prognosis in terms of pulmonary fibrosis for these two diseases. In general, it appears that although CD8+ and CD4+ T cells are associated with pulmonary fibrosis, the CD8+ T cell may be associated with a worse prognosis [7 10 15 16 17 18 ].
Type 1 versus type 2 dichotomy
Depending on the pattern of cytokine production, T cells are often denoted as type 1 (a pattern predominated by production of IFN-) or type 2 (a pattern predominated by production of IL-4 and IL-13). Th cells, which express CD4, are denoted Th1 or Th2. Cytotoxic T cells (Tc), which express CD8, are denoted Tc1 and Tc2. IFN- is a potent proinflammatory cytokine, but it is one of the most potent antifibrotic factors that inhibits fibroblast proliferation and collagen production directly in fibroblast cultures [42
]. In contrast, IL-4 and IL-13 promote healing and in an exaggerated form, fibrosis [42
]. Accordingly, type 1 T cells are expected to be antifibrotic, whereas type 2 T cells are likely to be profibrotic.
The development of Th1 cells is critically dependent on the transcription factor T-bet, whereas the transcription factor GATA-3 is the key regulator of Th2 differentiation. It is therefore not surprising that recent studies discovered that mice deficient of T-bet were more susceptible to bleomycin-induced pulmonary fibrosis than their wild-type counterparts [47
]. In our combined model of CCL18-driven pulmonary T lymphocytic infiltration and bleomycin injury [38
], the accumulation of T lymphocytes was associated with increased levels of IFN- and with partial protection against collagen accumulation. Consistent with the profibrotic effect of Th2 cells, overexpression of GATA-3 in mice resulted in a phenotype that was more susceptible to the induction of pulmonary fibrosis with bleomycin [48
].
The phenotype of pulmonary T cells in pulmonary fibrosis is consistent with a type 2 predominance, Tc2 in scleroderma lung disease [17 18 ] and Th2 predominance in IPF [11 13 ]. Moreover, data suggest that a type 2 phenotype of pulmonary T cells is associated with a lower DLCO and a more profound decline in FVC in patients with scleroderma [17 18 ] and a lower DLCO in patients with IPF [11 ], whereas a type 1 phenotype of pulmonary T cells appears to be protective [11 17 18 ]. Of important notice, type 1 and type 2 polarized T cells may also exert their effects on fibroblasts indirectly by involving additional cellular intermediaries (Fig. 2) . For example, activation of alveolar macrophages with type 2 cytokines skews their phenotype toward so-called alternative activation, and alternatively activated macrophages are themselves profibrotic [49 ] through production of various cytokines including profibrotic chemokines CCL2 [42 ] and CCL18 [50 51 ].
A pathway that is alternative to Th1 and Th2 differentiation has been discovered recently. These T cells are characterized by production of IL-17 and are denoted as Th17. IL-17 enhances production of cytokines in cultured, pulmonary fibroblasts but appears to have no direct effect on fibroblast proliferation or collagen production [52 ]. IL-17 also contributes to alveolitis but not fibrosis in silica-treated mice [53 ]. Thus, the role of this subpopulation of T cells in fibrosis is likely to be indirect, through regulation of inflammatory pathways.
Inflammatory versus regulatory T cells (Tregs)
Activated T lymphocytes may produce proinflammatory mediators such as IFN- and TNF- as part of the overall inflammatory pattern. These two factors are potent inhibitors of collagen production in cell culture [42
]. In vivo, these cytokines have been shown to have profibrotic and antifibrotic effects [42
], and the profibrotic effects are secondary to inflammation. Recent results [38
] about the elevation of IFN- and TNF- levels in an animal model are more consistent with their antifibrotic action in association with T lymphocytic infiltration. Overexpression of CCL18, a selective chemoattractor of T cells, combined with bleomycin injury led to an elevation of pulmonary IFN- and TNF- and a decline in collagen levels [38
]. Systemic sclerosis T cells may inhibit collagen production by fibroblasts via membrane-associated IFN- [54] or TNF- [55].
Therapeutic use of IFN- in patients with IPF showed minimal beneficial effect [56
]. This failure is not necessarily reflective of a lack of an antifibrotic effect of IFN- but may reflect the short half-life of injected recombinant IFN- and its limited bioavailability in the lungs. Our observations in an animal model [38
] suggest that a local, continuous source of IFN-, such as inflammatory T cells, may have a beneficial antifibrotic effect.
In contrast to IFN- and TNF- producing inflammatory T cells, the immunosuppressive Tregs, a subject of excitement and numerous studies in modern immunology, are expected to act profibrotically. Tregs exert their action through, among other mechanisms, TGF-β, a powerful, immunosuppressive cytokine and the most potent profibrotic cytokine. These cells produce TGF-β (so-called Th3 cells) or bind active TGF-β on their cell surface [57
]. In our model of selective infiltration of T cells driven by CCL18 [37
], active but not total TGF-β and collagen accumulated in association with these T lymphocytic infiltrates. Our data suggest that these infiltrating T cells are unlikely to be classical Tregs (CD4+CD25+forkhead box P3+) [38
]. Instead, they probably activate TGF-β through a mechanism yet unknown [37
38
].
An interesting mechanism by which TNF--producing T cells or more precisely, a lack thereof, may regulate fibrosis has been suggested in a cutaneous GVHD model of scleroderma [58
]. In sclerodermatous GVHD, the cutaneous CD4+ T cells, may promote fibrosis, not by an active process through production of TGF-β but passively as a result of a lack of production of TNF-, a powerful antagonist of TGF-β-mediated fibrosis. Such an inability of CD4+ T cells to produce TNF- may be the result of insufficient support for T cells from APCs [58
]. It is possible that a similar permissive rather than active mechanism is not limited to dermal fibrosis and may also occur in the lungs (Fig. 2)
.
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It appears that a variety of roles in pulmonary fibrosis, including opposing roles, can be envisioned for T cells. However, it is unlikely that pulmonary T lymphocytes drive fibrosis in the majority of pulmonary fibrotic human diseases or in animal models; their contribution appears to be one of modulating the degree of fibrosis (Fig. 1C)
. The heterogeneity of observations about the possible roles in pulmonary fibrosis is likely a reflection of the phenotypic heterogeneity of the involved T cells and of the complexity of interactions with the local pulmonary environment. Expression of type 2 cytokines and TGF-β, engagement of cell surface molecules CD40L and FasL, and release of granzymes and perforin are likely to make T lymphocytes profibrotic. However, expression of type 1 cytokines and the proinflammatory cytokine TNF-, particularly by CD4+ T cells, is likely to protect against fibrosis, as suggested by observations in vitro, in animal models, and in patients with pulmonary fibrosis. Future antifibrotic therapies may be based on facilitating the continuous production of type 1 and proinflammatory cytokines by infiltrating pulmonary T cells to achieve an overall antifibrotic effect.
Based on the heterogeneity of mechanisms by which T lymphocytes are involved in pulmonary inflammation and fibrosis, it is unlikely that a universal T lymphocyte depletion approach would be therapeutically beneficial in patients with pulmonary fibrosis. Such depletion may be even harmful, considering evidence partially for a protective role of pulmonary T lymphocytes against fibrosis. Indeed, data also suggest that T lymphocytes may act antifibrotically in patients with IPF [10 ] or scleroderma [54 55 ], as well as in the bleomycin-induced [47 ] or asbestos-induced [32 ] models of pulmonary fibrosis. Instead, phenotypic modulation of the infiltrating T cells toward proinflammatory, antifibrotic phenotypes may be beneficial. How exactly such modulation can be achieved is unclear, although it is possible that the overall inflammatory nature of the pulmonary milieu may facilitate the antifibrotic action of T lymphocytes. Better understanding of molecular mechanisms of T cell involvement in pulmonary inflammation and fibrosis is necessary to facilitate the development of novel strategies for therapeutic modulation of pulmonary T cells aimed at the enhancement of their antifibrotic potential.
Received July 29, 2007; revised September 21, 2007; accepted October 5, 2007.
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and macrophage inflammatory protein-1β levels in bronchoalveolar lavage fluid of patients affected by different stages of pulmonary sarcoidosis Am. J. Respir. Crit. Care Med. 165,236-241, MIP-1β and IL-8 by peripheral blood CD4+ and CD8+ T cells in mild allergic asthma Allergy 58,239-245[CrossRef][Medline] mediates CCL18-stimulated collagen production in pulmonary fibroblasts Am. J. Respir. Cell Mol. Biol. 35,298-305 Arthritis Rheum. 48,2593-2604[CrossRef][Medline]-1b in patients with idiopathic pulmonary fibrosis N. Engl. J. Med. 350,125-133-producing CD4(+) T cells and TNF may allow for fibrosis rather than epithelial cytotoxicity in murine sclerodermatous graft-versus-host disease, a model for human scleroderma J. Invest. Dermatol. 127,281-292[CrossRef][Medline]This article has been cited by other articles:
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