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Chicago, IL
Dr. Kamp is Associate Professor of Medicine, Department of Medicine, Divisions of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine and Veterans Administration Chicago Health Care System, Lakeside Division.
Correspondence to: David W. Kamp, MD, FCCP, Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, Tarry Building 14-707, 303 E. Chicago Ave, Chicago, IL 60611-3010
Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse interstitial lung disease that is associated with the histologic appearance of usual interstitial pneumonitis (UIP).1 IPF, which is the most common idiopathic interstitial lung disease, has the worse prognosis, with a median survival of only 3 to 4 years.1 2 3 This grim prognosis rivals many cancers or disease due to HIV. IPF typically affects people between the age of 50 years and 70 years, and is noted worldwide without any clear ethnic predisposition. The estimated incidence of IPF in the United States is 7 to 11 cases per 100,000 each year.1 The characteristic histologic features of IPF include the following: (1) injury and activation of alveolar epithelial cells in an inhomogeneous subpleural distribution, (2) the distinctive presence of fibroblastic foci, and (3) exuberant extracellular matrix deposition. Although much has been learned recently about the pathogenesis of IPF, the etiology and precise cellular and molecular mechanisms involved are not established. Notably, no specific therapy has been proven unequivocally effective in IPF.4 Accordingly, it is not surprising that there is considerable controversy regarding various aspects of this disease.
Early theories on the pathogenesis of IPF focused on the role of chronic inflammation triggered by unknown stimuli that subsequently leads to lung injury and pulmonary fibrosis.5
Support for this hypothesis was suggested by the presence of interstitial and alveolar inflammatory cells as well as the expression of proinflammatory cytokines, especially interleukin (IL)-1ß, transforming growth factor (TGF)-ß, and tumor necrosis factor (TNF)-
, in the lungs of patients with IPF.6
7
A key role for proinflammatory cytokines is suggested by detecting, blocking, or augmenting cytokine expression in various experimental models of pulmonary fibrosis.8
9
More recently, an imbalance in the expression of T-helper type 1 (Th1) [including interferon (IFN)-
and others] and T-helper type 2 (Th2) [including IL-4, IL-5, and others] cytokines have been implicated in having an important role in the pathogenesis of pulmonary fibrosis.6
10
The Th1 and Th2 cytokines are expressed in a wide variety of cells besides lymphocytes. These data plus a limited number of treatment trials formed the scientific basis on which the American Thoracic Society recommended combined anti-inflammatory therapy (corticosteroids and either azathioprine or cyclophosphamide) in the management of IPF.1
Additional support for the inflammation hypothesis was suggested by the findings of a large prospective study11 examining the histopathologic variability of surgical lung biopsies in 109 patients with idiopathic interstitial pneumonia. In 47% of the patients, UIP was the only finding in all the lobes that were sampled (concordant) [mean age, 63 years; fibrosis score (FS), 2.13]. Notably, UIP was intermixed with nonspecific interstitial pneumonitis (NSIP) in 26% (discordant) [mean age, 57 years; FS, 1.42], while NSIP alone was present in 27% (mean age, 55 years; FS, 0.8). The biopsy findings combined with the progressive age and fibrosis score going from NSIP to UIP/NSIP (discordant) to UIP (concordant) suggested to these investigators and others of an evolving disease process from NSIP to UIP with a pathogenic role for chronic inflammation.11 12 Since NSIP has not been fully characterized and the cellular and fibrotic forms of NSIP may not necessarily be related,11 13 Flaherty and associates11 cautioned that additional prospective studies are required to assess the longitudinal changes in pulmonary physiology and high-resolution CT in these patients.
Several groups2
14
15
16
have challenged the inflammation hypothesis; their rationale centers on four lines of evidence. First, inflammation is a not a major histopathologic feature in IPF; rather, the distinctive feature is the predominance of fibroblastic foci. Second, studies in animals have been able to dissociate the extent of pulmonary inflammation from fibrosis. Although no ideal animal model of IPF exists, bleomycin has been widely used to study the mechanisms underlying the formation of pulmonary fibrosis with the understanding of its limitation. It is now clear that bleomycin-induced inflammation can ensue in the absence of fibrosis in mice deficient in either the epithelial cell integrin vß6 (ß6-/-), which activates latent TGF-ß, or CD44, a transmembrane adhesion receptor that is involved in T-cell recruitment.17
18
Alternatively, pulmonary fibrosis can occur in the absence of inflammation in areas of ongoing alveolar epithelial injury.8
19
Third, inflammatory markers are not associated with IPF outcome. The number of fibroblastic foci directly correlates with mortality as well as greater declines in the FVC and measures of gas transfer (diffusion capacity of the lung for carbon monoxide), whereas the level of interstitial inflammation is less predictive.20
21
Finally, perhaps most troublesome for the inflammation hypothesis, is that anti-inflammatory therapy has never been definitively shown to alter the course of IPF. These observations have led opponents of the inflammation hypothesis to reason that IPF results from abnormal wound healing arising from altered signaling mechanisms derived from areas of activated epithelial and mesenchymal cells in a milieu of abnormal extracellular matrix.2
14
15
16
In this issue of CHEST (see page 1206), Tajima and colleagues add another piece of the puzzle to the IPF inflammation hypothesis. These investigators show that serum soluble ST2 protein, which is preferentially expressed in Th2 cells, increases during an acute exacerbation of IPF. In this retrospective study involving 49 patients, serum ST2 levels in control patients and stable IPF patients were comparable; however, during an acute exacerbation of IPF, which was defined clinically after excluding infection and heart failure, the serum ST2 levels were increased sixfold. Furthermore, serum ST2 levels were directly correlated with other nonspecific serum markers of inflammation, such as C-reactive protein or lactate dehydrogenase levels, and inversely correlated with oxygenation and the percentage of predicted vital capacity. The authors speculate that the increased serum ST2 levels during an acute exacerbation of IPF reflects the severity of inflammation and Th2 activity in the lungs.
To better understand the findings of Tajima and colleagues, one must understand the biology of ST2. The ST2 gene was originally identified as an oncogene and serum-responsive gene expressed in fibroblasts22
and subsequently found to be expressed by Th2, but not Th1, cells.23
It encodes a membrane receptor of the IL-1 receptor family and a truncated soluble receptor that can be detected in the serum of patients with an exacerbation of asthma or heart failure.24
25
Although ST2 is an IL-1 receptor family member, it does not bind IL-1 and no ligand or function has yet been ascribed to either the soluble or membrane form of ST2. A role for ST2 in modulating Th2 function was suggested by studies26
27
using neutralizing antibodies against ST2 as well as in ST2-deficient mice. The messenger RNA encoding ST2 has also been found in a rapidly expanding list of cells including a variety human lung cells such as pulmonary epithelial cells.28
There is accumulating evidence that ST2 has anti-inflammatory properties that function in part by inhibiting Toll-like receptor 4 expression which subsequently prevents inflammatory stimuli-induced IL-1ß and TNF- release.28
29
Collectively, these data suggest that soluble ST2 protein can reduce the severity and pathology of acute inflammatory conditions that may occur in the setting of an acute exacerbation of IPF as well as other diverse conditions. Although the findings of Tajima et al may stimulate a renewed interest in the role of acute inflammation in IPF, caution is warranted. Further studies are necessary to better understand the biology of ST2 in the lungs. It will be important to determine the cellular origin of ST2 in the lungs, since fibroblasts, epithelial cells, endothelial cells, macrophages, as well as Th2 cells may all be involved. Also, the precise cellular and molecular mechanisms regulating ST2 gene expression, the identity of the ST2 receptor, as well as down-stream signaling mechanisms that lead to inhibition of the Toll-like receptor 4 expression must be identified. In the broader context, we need a better understanding of the mechanisms by which the principal proinflammatory and anti-inflammatory mediators in IPF alter epithelial barrier function and wound healing in the lung. These are important scientific goals for not only resolving the IPF inflammation controversy but for developing novel therapeutic targets for this challenging disease.
Acknowledgements
The author is grateful for the helpful comments of Jacob I. Sznajder and Peter Sporn.
Footnotes
This work was supported by a Merit Review grant from the Department of Veterans Affairs.
References
and its mRNA in idiopathic pulmonary fibrosis. Am J Pathol 1993;143,651-655[Abstract]
-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999;341,1264-1269vß6 binds and activates latent TGFß1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999;96,319-328[CrossRef][ISI][Medline]
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