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. 2009 Aug 29;10(1):80.
doi: 10.1186/1465-9921-10-80.

Macrophage derived chemokine (CCL22), thymus and activation-regulated chemokine (CCL17), and CCR4 in idiopathic pulmonary fibrosis

Yurika Yogo  1 , Seitaro Fujishima, Takashi Inoue, Fumitake Saito, Takayuki Shiomi, Kazuhiro Yamaguchi, Akitoshi Ishizaka
Affiliations

Macrophage derived chemokine (CCL22), thymus and activation-regulated chemokine (CCL17), and CCR4 in idiopathic pulmonary fibrosis

Yurika Yogo et al. Respir Res. .

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a chronically progressive interstitial lung disease of unknown etiology. Previously, we have demonstrated the selective upregulation of the macrophage-derived chemokine CCL22 and the thymus activation-regulated chemokine CCL17 among chemokines, in a rat model of radiation pneumonitis/pulmonary fibrosis and preliminarily observed an increase in bronchoalveolar (BAL) fluid CCL22 levels of IPF patients.

Methods: We examined the expression of CCR4, a specific receptor for CCL22 and CCL17, in bronchoalveolar lavage (BAL) fluid cells, as well as the levels of CCL22 and CCL17, to elucidate their pathophysiological roles in pulmonary fibrosis. We also studied their immunohistochemical localization.

Results: BAL fluid CCL22 and CCL17 levels were significantly higher in patients with IPF than those with collagen vascular diseases and healthy volunteers, and there was a significant correlation between the levels of CCL22 and CCL17 in patients with IPF. CCL22 levels in the BAL fluid did not correlate with the total cell numbers, alveolar lymphocytes, or macrophages in BAL fluid. However, the CCL22 levels significantly correlated with the numbers of CCR4-expressing alveolar macrophages. By immunohistochemical and immunofluorescence analysis, localization of CCL22 and CCR4 to CD68-positive alveolar macrophages as well as that of CCL17 to hyperplastic epithelial cells were shown. Clinically, CCL22 BAL fluid levels inversely correlated with DLco/VA values in IPF patients.

Conclusion: We speculated that locally overexpressed CCL22 may induce lung dysfunction through recruitment and activation of CCR4-positive alveolar macrophages.

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Figures

Figure 1
Figure 1
BAL fluid CCL22 and CCL17 in fibrotic lung diseases. BAL fluid levels of CCL22 and CCL17 were determined by sensitive ELISAs. CCL22 and CCL17 levels were significantly higher in patients with idiopathic pulmonary fibrosis (IPF) than in those with CVD-IP and healthy volunteers (A, B). In IPF patients, BAL fluid CCL22 levels correlated significantly with CCL17 levels (C). IPF, idiopathic pulmonary fibrosis; HV, healthy volunteers; CVD-IP, collagen vascular disease with interstitial pneumonia; Sar, sarcoidosis.
Figure 2
Figure 2
Correlations between BAL fluid CCL22 and CCR4-positive alveolar macrophages and lymphocytes in all patients examined. To further elucidate the roles of the chemokines in recruiting cells to the lungs in fibrotic lung diseases, we analyzed CCR4-positive BAL fluid cell subpopulations by flow cytometry in IPF. CCL22 levels significantly correlated with the number of CCR4-positive alveolar macrophages (A). CCL22 levels in IPF patients were significantly correlated with the number of CCR4-positive alveolar macrophages and lymphocytes. These correlations were not observed between these subpopulations and BAL fluid CCL17 levels.
Figure 3
Figure 3
Lung immunohistochemical photomicrograph of CCL17, CCL22, CCR4, and CD68 in patients with idiopathic pulmonary fibrosis (IPF). We examined the localization of CCL17, CCL22, CCR4, and CD68 by immunohistochemistry. The sections were initially incubated with anti-CCL22 antibody (A), anti-CCL17 antibody (B), anti-CCR4 antibody (C), anti-CD68 antibody (D), or their diluent buffer (E), and then stained using an indirect streptavidin-biotinylated complex method. A fraction of the alveolar macrophages was positive for CCL22, whereas CCL17 was exclusively expressed by some hyperplastic epithelial cells (A, B). There were few alveolar macrophages which were weakly positive for CCR4 (C). The tissue distribution of alveolar macrophages was confirmed by their positivity for CD68 (D). In contrast, no lung cells were positively stained in negative control (NC) sections (E).
Figure 4
Figure 4
Lung immunofluorescence photomicrograph of CCL22 and CCR4 in patients with idiopathic pulmonary fibrosis (IPF). We examined the localization of CCL22 and CCR4 in CD68-positive alveolar macrophages by a dual immunofluorescence technique. A. Localization of CCL22 (red) to a certain fraction of CD68 (green) -positive alveolar macrophages was shown. B. Localization of CCR4 (red) to a small fraction of CD68 (green) -positive alveolar macrophages was shown. Nuclei were counterstained with DAPI (blue).
Figure 5
Figure 5
Correlation between BAL fluid CCL22 and lung diffusing capacity in idiopathic pulmonary fibrosis (IPF) patients. We examined the correlation of BAL fluid chemokines with indices of lung function tests in IPF patients. An inverse correlation was observed between BAL fluid CCL22 levels and DLco/VA values. Although BAL fluid CCL17 also tended to correlate inversely with DLco/VA, there was no statistical significance. DLco, single-breath carbon monoxide diffusing capacity; VA, alveolar ventilation per minute.
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