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* From the Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.
Correspondence to: Steven L. Kunkel, PhD, Professor, Department of Pathology, 1301 Catherine Rd, Box 0602, University of Michigan Medical School, Ann Arbor, MI 48109-0602; e-mail: slkunkel{at}umich.edu
Abstract
The pathogenesis
of end-stage, chronic lung disease is thought to be characterized by an
initial inflammatory response followed by fibroproliferation and
deposition of extracellular matrix. Many of these chronic lung
disorders share a variety of common properties, including an unknown
etiology, undefined mechanisms of initiation and maintenance, and
progressive fibrosis. Unfortunately, efficacious therapeutic options
are not readily available for the treatment of many chronic lung
diseases, which may reflect the limited scientific and mechanistic
understanding of these disorders. However, recent studies have shown
that cytokine networks are likely operative in dictating the
progression of these diseases, as these mediators can influence
fibroblast activation, proliferation, and collagen deposition during
the maintenance of chronic fibrotic lung disease. Accumulating data
support the concept that the specific cytokine phenotype may provide a
fundamental mechanism for the regulation or continuation of the
fibrotic process. For example, interferon-
appears to suppresses
fibroblast activities, such as proliferation and collagen production,
while interleukin (IL)-4 and IL-13 can augment fibroblast growth and
collagen production. Interestingly, these mediators are prototypic
cytokines that functionally define either a type-1 or a type-2 immune
response. Thus, experimental models of cell-mediated lung inflammation,
which are characterized by either a type-1 or a type-2 response, will
be useful in delineating the mechanisms that either maintain or resolve
chronic lung inflammation and accompanying fibrosis.
Key Words: chemoattractant protein • chemokines • cytokines • experimental models • fibrosis • interferon- • interleukin-4 • interleukin-12 • interleukin-13 • monocyte chemoattractant protein
The clinical manifestations of chronic, end-stage lung disease are likely associated with an initial strong immune and inflammatory response to a persistent antigen or pathogen, leading to tissue injury and progressive fibrosis. The management of these lung disorders is frequently difficult, requiring the use of potent drugs with cytotoxic and immunosuppressive activities. Unfortunately, these therapeutic approaches are often unsuccessful, as these disorders often progress independent of pharmacologic strategies aimed at intervention. The inability to successfully treat these progressive interstitial pulmonary diseases is multifactorial and includes the inability to identify the etiology, the lack of clear mechanisms that support the disease, and the inability of truly efficacious agents to remit the lung pathology.
The mechanism(s) that drive the pathology of many chronic interstitial lung diseases is not well characterized; however, many factors that regulate immune and fibrotic processes have been implicated in the evolution of these disorders. These processes include the persistence of antigen,1 potential viral infections,2 genetic variations,3 environmental factors,4 and immune cell activation. This last category has generated a significant amount of scientific interest, as the classification of effector cell products has led to the assessment of type-1 and type-2 cytokines as mechanisms for either the regulation or maintenance of chronic lung disease. It is indeed likely that cytokine networks with either type-1 or type-2 phenotypes are responsible for cell-to-cell communication and influence the progression of chronic pulmonary inflammation. However, the cytokine profiles, which are mechanistically involved in the progression of pulmonary fibrosis, have remained an enigma. Recent information for experimental models of lung disease would predict that the cytokine disease phenotype characterized by type-2 cytokines results in a fibroproliferative response with extracellular matrix deposition, while a type-1 disease phenotype fails to induce significant fibrotic changes (Table 1) .
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A variety of cytokines have been found associated with chronic
pulmonary inflammation, including interleukin (IL)-1,5
IL-6,6
IL-8,7
macrophage inflammatory
protein-1
,8
monocyte chemoattractant
protein-1,9
tumor necrosis factor,10
transforming growth factors (TGF),11
granulocyte
macrophage-colony stimulating factor,12
and
platelet-derived growth factor.13
While this list is not
all-inclusive, it does contain representative cytokines that possess
early activation, chemotactic, growth and differentiation, and
remodeling activity. For example, TGF-ß possesses a number of
activities that would suggest a profibrotic role in lung disease.
TGF-ß directly increases the gene expression of extracellular matrix
molecules by stromal cells, inhibits collagenase production, and
influences fibroblast proliferation via the induction of fibroblast
growth factors.11
The identification of different
cytokines from either patients or animal models that mimic human
pulmonary fibrosis has provided clues that specific immune mediators
are involved in the evolution of interstitial disease. However, a
causal role of these cytokines in the initiation and maintenance of
lung lesions has not been clearly established. Thus, the biomedical
community is still far from understanding the mechanisms that dictate
either the restoration of normal lung tissue or the progression to
irreversible fibrotic derangements of the pulmonary interstitium
following chronic lung disorders.
There is a growing body of scientific evidence suggesting that the
cytokine profile of the natural immune/inflammatory response likely
determines the disease phenotype responsible for either resolution or
progression to end-stage fibrosis. Much of the supporting evidence is
derived from studies demonstrating that interferons, especially
interferon (IFN)-, have profound suppressive effects on the
production of such extracellular matrix proteins as collagen and
fibronectin.14
Investigations have demonstrated that IFNs
can inhibit both fibroblast and chondrocyte collagen production
in vitro, as well as decrease the expression of steady-state
type-I and type-III procollagen messenger RNA levels in these
cells.15
In addition, the administration of IFN-
in vivo can cause a reduction of extracellular matrix in
animal models of fibrosis.16
This information supports the
concept that IFN-, one of the major type-1 cytokines, possesses
profound regulatory activity for collagen deposition during chronic
inflammation. Interestingly, IL-4 and IL-13 have been identified as
potent stimuli for the production of fibroblast-derived extracellular
matrix.17
18
These studies have demonstrated that either
IL-4 or IL-13 treatment of fibroblasts can increase fibroblast
activation and the deposition of extracellular matrix. These studies
lend support to the theory that the disease phenotype characterized by
either type-1 or type-2 cytokines may be paramount in determining the
course of chronic pulmonary inflammation, leading to fibrosis.
Cellular Sources of Type-2 Cytokines
The criteria that type-1 and type-2 responses are only expressed by particular T-helper (Th) cells have become less rigid, as other cells have been identified as producing type-2 cytokines (Table 2) . Mast cells, macrophages, monocytes, epithelial cells, and activated fibroblasts have all been shown to produce significant levels of IL-4, IL-10, or IL-13 when appropriately stimulated.19 20 Thus, it may be more appropriate to define certain diseases in terms of the predominant cytokine profile rather than the predominant Th cell subset. The strict definition of Th1 and Th2 responses may break down in a scenario where the initial inciting agent triggers an unsuccessful Th1-type response. The subsequent host reaction to the antigen or the chronicity of the disorder may induce a switch to a response dominated by type-2 cytokines. One of the likely manifestations of this scenario is stromal cell/fibroblast proliferation and fibrosis. Thus, the cytokine pattern in a particular disease is often predictable and appropriate, whereas pathologic consequences may result if an inappropriate cytokine phenotype is expressed. This latter situation may play a role in certain chronic, end-stage inflammatory diseases, where unknown etiologies lead to aggressive fibroblast proliferation and matrix deposition.
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Information derived from a variety of experimental animal models suggests that a number of cytokines play a role in the initiation, maintenance, and resolution of chronic pulmonary inflammation. However, the likely mechanism for each cytokine during the evolution of the inflammatory response has only recently been addressed. For example, pulmonary inflammation initiated by antigens from either the parasite Schistosoma mansoni, or the fungus Aspergillus fumigatus, was greatly influenced by IL-4 and IL-13.18 19 20 21 22 The involvement of these cytokines suggests that cell-mediated inflammation involves not only type-1 cytokines but also type-2 cytokines (Table 3) .18 19 20 21 22 These models proved to be important for assessing the role of type-2 cytokines as important mechanisms for fibrotic processes, as the progression of the inflammation in either of these experimental situations resulted in in vivo fibroblast proliferation and matrix deposition.
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Footnotes
This research was supported by National Institutes of Health grants 1PO50HL46487, HL31693, HL35276, and HL50057
Abbreviations: IFN = interferon; IL = interleukin; TGF = transforming growth factor; Th = T-helper
References
2 macroglobulin and interleukin-6 release by human alveolar macrophages from normal and sarcoidosis patients. Am Rev Respir Dis 141,A8712
expression in interstitial lung disease. J Immunol 151,2852-2863
Interferon is the lymphokine and ß interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation. J Exp Med 162,516-527
on bleomycin-induced lung collagen fibrosis in mice. Biochem Med Metab Biol 36,194-197
in Schistosoma mansoni egg-induced hypersensitivity granuloma formation. J Immunol 148,900-910
and IL-4 knockout mice: analysis of local and regional cytokine and chemokine networks. J Immunol 159,3565-3573
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