© 2004 American Thoracic Society doi: 10.1164/rccm.2406007
Chemokine Profiling in Pulmonary FibrosisReady for Prime Time?Division of Pulmonary and Critical Care Medicine David Geffen School of Medicine at UCLA Los Angeles, California Pulmonary fibrosis is the end result of a variety of insults and is associated with many different diseases including idiopathic interstitial pneumonias, collagen vascular diseases, and sarcoidosis. The classification of the idiopathic interstitial pneumonias has recently been more clearly defined pathologically, although the differentiation can still be a formidable challenge (1, 2). Furthermore, the pathologic classification has prognostic implications; the histologic pattern of nonspecific interstitial pneumonia appears to carry a more favorable prognosis than usual interstitial pneumonia. The identification of a marker that could differentiate these histologic patterns would be a significant advance. Members of the human CC chemokine family of chemotactic cytokines behave as potent chemotactic factors for eosinophils, basophils, monocytes, mast cells, dendritic cells, NK cells, and T- and B-lymphocytes. Several studies have demonstrated the presence of CC chemokines in human interstitial lung disease (3). However, no single mediator or chemokine has been shown to be specific to any one histologic pattern. In this issue of the Journal (pp. 508–515), Choi and coworkers describe enhanced expression of the chemokines CCL7 and CCL22 in lung tissue of patients with idiopathic pulmonary fibrosis, as compared with nonspecific interstitial pneumonia and nonidiopathic interstitial pneumonia (4). Furthermore, they describe increased expression of CCL5 in nonspecific interstitial pneumonia as compared with usual interstitial pneumonia. Choi and colleagues used several approaches to identify expression of chemokines. First, they looked at an extensive panel of chemokines and chemokine receptors by gene array analysis and found that the majority were present in both biopsies and fibroblast lines from both idiopathic and nonidiopathic interstitial pneumonias. The one exception was CCL7, which was detected in both lung biopsies and fibroblasts only from patients with usual interstitial pneumonia and nonspecific interstitial pneumonia. Therefore, the presence of CCL7 gene expression in both lung biopsies and fibroblasts could differentiate these patterns from nonidiopathic pneumonias. These findings were confirmed by real-time quantitative polymerase chain reaction (PCR) of gene expression and ELISA measurement of protein, where both CCL7 and CCL22 were found to be significantly elevated in usual interstitial pneumonia. CCL5 protein was identified in nonspecific interstitial pneumonia more prominently than any of the other histologic patterns studied, including usual interstitial pneumonia. This finding is all the more interesting as CCL5, through its interactions with CCR5, is a major stimulus for the production of CCL7. The results in this paper raise the possibility that there is a continuum from nonspecific interstitial pneumonia to usual interstitial pneumonia with higher levels of CCL5 in nonspecific interstitial pneumonia leading to subsequent increased CCL7 expression as the disease progresses to usual interstitial pneumonia. There is considerable controversy as to whether nonspecific interstitial pneumonia is an earlier stage of usual interstitial pneumonia. Several studies have demonstrated the presence of usual interstitial pneumonia and nonspecific interstitial pneumonia patterns in the same patients, which would suggest that these are overlapping processes (5–7). The current study demonstrates a transition from a predominance of CCL5 to CCL7 and provides further support for this notion. Choi and coworkers did not find significant differences in global expression of CCL7 or CCL22 between lobes in the same patients, suggesting that a particular chemokine profile is consistent throughout the lung. However, fibroblasts isolated from the lower lobes of patients with usual interstitial pneumonia had a greater increase in CCL7 protein expression on stimulation with CCL5 than did fibroblasts from the upper lobe, suggesting that there is heterogeneity in fibroblast biology between lobes. Heterogeneity of fibroblasts from patients with idiopathic pulmonary fibrosis as compared with normal fibroblasts has been previously reported, but it has not been described within the lung of the same patients (8). CCL7 can act as natural antagonist at the CCR5 receptor, suggesting that CCL7 may play a role in regulating its own production (9). It would be interesting to know if fibroblasts from patients with usual interstitial pneumonia have an inherent defect that prevents CCL7 from shutting off its own production. Choi and colleagues also found that CCL7 was primarily associated with interstitial areas and was produced by isolated pulmonary fibroblasts from patients with usual interstitial pneumonia. This underscores the importance of the pulmonary fibroblast as a source of inflammatory mediators. There has been much debate as to the importance of inflammation in usual interstitial pneumonia (10, 11). CCL7 in common with CCL2 is a potent chemotactic factor for T cells and monocytes via CCR2. Because these are classic inflammatory cells, the hypothesis that usual interstitial pneumonia is a noninflammatory disease would not appear to be justified. There is evidence that pulmonary fibrosis is a Th2-mediated process, and the current report further supports this notion (12). The finding of elevated levels of CCL22 in this study is of significant interest, as CCL22 binds to CCR4, which is expressed on Th2 cells including lymphocytes and macrophages. Taken together, these results suggest that inflammation may indeed have a role to play in usual interstitial pneumonia and that polarization of inflammation is important in the progression of fibrosis. An ideal test to differentiate idiopathic interstitial pneumonia from nonidiopathic interstitial pneumonia as well as nonspecific interstitial pneumonia from usual interstitial pneumonia would be simple and reproducible. A serum marker would be the most attractive. However, if a specific chemokine could be measured from a transbronchial biopsy and combined with clinical and radiologic findings, it would greatly improve our ability to differentiate these diseases and would obviate the need for surgical lung biopsies. It would be important to see if the findings of Choi and coworkers would be applicable to transbronchial biopsies; it is conceivable that they would be. The current study suggests that CCL7 and CCL22 would be expressed to a greater extent in usual interstitial pneumonia as opposed to nonspecific interstitial pneumonia and the nonidiopathic interstitial pneumonias, and that CCL5 could potentially differentiate between nonspecific interstitial pneumonia and usual interstitial pneumonia. Further studies will be necessary to define the functional significance of these findings. A multicenter study of chemokine levels in transbroncial biopsies would be required to define specific thresholds for the various chemokines, similar to the analysis recently performed in patients with usual interstitial pneumonia treated with interferon (13). Such a study could be performed within the framework of the proposed NIH pulmonary fibrosis network and is further support for such a network. FOOTNOTES Conflict of Interest Statement: M.P.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this editorial. REFERENCES
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1b on biomarker expression in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2004;170:133–140.
